The pharmacokinetics, pharmacodynamics and tolerability of SHR6508 in Chinese healthy subjects

The pharmacokinetics, pharmacodynamics and tolerability of SHR6508 in Chinese healthy subjects | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The pharmacokinetics, pharmacodynamics and tolerability of SHR6508 in Chinese healthy subjects Shengting ZHANG, Hong-yi TAN, Shuang YANG, Xiao-yan YANG, Chang CUI, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4096983/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Secondary hyperparathyroidism (SHPT) mainly occurs in patients with chronic renal failure. SHR6508 is a new type of calcimimetic molecule, intended for patients with SHPT who are undergoing maintenance hemodialysis for chronic kidney disease. This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of a new calcimimetic agent, SHR6508 injection, in healthy Chinese subjects. Methods In this phase I study, healthy subjects were administered SHR6508 injection via intravenous infusion according to a randomization table on the morning of the first day after admission. Blood samples were collected at 15 time points to measure the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of SHR6508. Adverse events that occurred during administration were also evaluated. Results 23 subjects were successfully screened and enrolled in the study. Except for 1 subject who withdrew from the study before medication, the remaining 22 subjects completed the study. No serious adverse events or adverse events leading to death occurred. The blood drug concentration of SHR6508 injection in healthy subjects reached its peak rapidly after a single intravenous dose. With the exception of the low-dose group, there was no significant difference in the distribution and elimination-related parameters Vz, t1/2z, and CLz between the other dose groups. The plasma drug exposure level (Cmax and AUC) of SHR6508 increased proportionally with the dose, and it showed linear pharmacokinetic characteristics within the dose range of 0.5-5 mg. The results of variance analysis showed no significant difference in PK characteristics between different genders. Conclusion After a single intravenous injection of 0.5-5 mg of SHR6508 injection in healthy subjects, the iPTH and blood calcium levels in the body decreased, and this effect showed dose-dependent characteristics, which is consistent with the expected effect of this product. The overall safety and tolerability of SHR6508 injection in healthy subjects after a single intravenous dose of 0.5-5 mg was good. Trial Registration: The trial is registered at chinadrugtrials.org.cn (ChiCTR2100048905)(19/07/2021). Chronic kidney disease CKD-SHPT Secondary hyperparathyroidism pharmacokinetics pharmacodynamics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Secondary hyperparathyroidism (SHPT), is a systematic disorder induced by the excessive secreting of Parathyroid hormone, leading to disturbances in calcium, phosphorus, bone metabolism and a range of clinical manifestations [ 1 , 2 ] . SHPT occurs mainly in patients with chronic kidney failure (CKD), and as well as patients suffers deficiency in vitamine D, small intestinal malabsorption, osteochondrosis, etc [ 3 – 5 ] . The incidence of SHPT is 30–50 percent in CKD patients, and the main pathophysiological changes include high level of PTH causes a significant increase in bone conversion, osteocalcinolysis release into the blood resulting in bone damage and extra-bone multi-organ tissue metastatic calcification (e.g., vascular calcification, ocular calcification, visceral calcification, periarticular calcification, and cutaneous calcification), and the clinical manifestations are the corresponding symptoms of bone disease and extra-bone organ damage, such as bone pain, bone fracture, acute periarticular arthritis, alterations in cardiovascular structure and function, sudden cardiac death, and skin itching [ 6 , 7 ] . Phosphorus retention, vitamin D deficiency and abnormal PTH regulatory mechanisms are the prime incentives resulting high level of PTH among CKD-SHPT patients, and Phosphorus binding agents, vitamin D receptor agonists and calcimimetic drugs are the corresponding treatments respectively [ 8 – 10 ] . Nevertheless, aluminum-containing and calcium-containing phosphorus binders commonly used in clinical practice are at risk for aluminum toxicity and hypercalcemia respectively [ 11 ] . Non-aluminum and non-calcium phosphorus binding agents are less likely to trigger elevated blood calcium or aluminum levels, thus it may be advantageous in slowing the progression of vascular calcification [ 3 ] . Vitamin D receptor agonists can inhibit the synthesis and secretion of PTH, promote the absorption of calcium in the small intestine, and reduce the secretion of PTH indirectly. Though it is effective, it may lead to hypercalcinemia in clininc. The mechanism of calcimimetic drugs is to activate the calcium-sensitive receptor (CaSR) on the main cells of the parathyroid gland [ 12 ] . The activated CaSR will suppress the release and synthesis of PTH, thus reducing the level of PTH in the blood. The physiological effects of PTH include the promotion of calcium reabsorption and phosphorus excretion in the kidney, increasing calcium absorption in the intestine and promoting osteolysis by increasing the level of active vitamin D, leading to the release of bone calcium and bone phosphorus [ 13 ] . Therefore, the activation of CaSR by calmimetic reduces PTH level, blood calcium and phosphorus level. The SHR6508 injection, developed by Shanghai Hengrui Pharmaceutical Co., LTD., acts on CaSR. It is intended to be used for the treatment of secondary hyperparathyroidism in patients on maintenance hemodialysis for chronic kidney disease. This product is a new drug not listed neither domesticly nor abroad, so it is a new drug of Class 1 of the New Registration Classification of Chemical Drugs. Therefore, the purpose of this study was to explore the safety, pharmacokinetics, and pharmacodynamics of SHR6508 in healthy Chinese subjects and provide a basis for later clinical medication plans. Materials and Methods Ethics statement : This study was conducted in the Third Xiangya Hospital of Central South University, and has been approved by the Ethics Committee of the Third Xiangya Hospital of Central South University, Approval No. 21109. This clinical trial adheres to the Declaration of Helsinki (2013 edition), Good Clinical Practice (GCP) and related regulations. Before the start of the clinical trial, the subjects are informed of the details of the clinical trial, and all subjects have signed a written informed consent form. Patients The participants of this trial were all healthy subjects. A total of 30 subjects were scheduled to be enrolled, there are 8 subjects in group A, and 8 in B, C and D respectively. Eligible participants were female or male healthy volunteers around 18–45 years old (including the boundary value) with a BMI between 19–26 kg/m 2 (including the boundary value). At the same time, male participants are supposed to weigh at least 50.0 kg, female participants at least 45.0 kg. And the participants have to commit that make no plans to get pregnant, donate sperms or ovums and be willing to take physical contraceptive measures (including their partners) during the trial and after the final dose. All the participants have been informed in detail about the nature of the trial, the potential benefits the trial brings them, and the probable inconveniences and underlying risk as well. Participants volunteer to join the trial and should be able to communicate with the investigators well, defer to the requirements of the trial and sign the written informed consent. Study design :This is a single-center, double-blind, placebo-controlled, single-dose, ascending dose designed clinical study in healthy Chinese subjects with four groups as A, B, C and D. A total of 30 healthy subjects are divided into the four groups, and subjects in each group were equal between men and women. The subjects were randomized to be treated with SHR6508 injections or placebo with a ratio of 2:1 in group A and 3:1 in the remaining groups. The dose of administration is 0.5mg, 2.5mg, 5mg and 10mg in the four groups respectively. The trail flow chart is shown in Table 1 . This trial adheres to the principle of dose escalation, starting from a low dose and proceeding to the next dose group only after completing the safety assessment of the previous group. Each subject receives only one dose group. The trial should be stopped early if the criteria for termination are met during dose escalation, even if the maximum dose is not reached. The maximum climbing dose is initially set at 10 mg, but it can be adjusted based on the safety, tolerability, PK and PD outcomes of the previous groups. Table 1 Study Design Groups Dose group Number of subjects A 0.5 mg SHR6508: 4 + Placebo༚2 B 2.5 mg SHR6508: 6 + Placebo༚2 C 5 mg SHR6508: 6 + Placebo༚2 D 10 mg SHR6508: 6 + Placebo༚2 Efficacy : The primary endpoint of the study including Cmax, Tmax, AUC0-t, AUC0-∞, T1/2z, MRT0-t, and MRT0-∞, the percentage reduction of iPTH (intact parathyroid hormone) and serum corrected calcium from baseline. The following parameters were determined as secondary efficacy endpoints: the changes of FGF23 (fibroblast growth factor 23) and phosphorus ions after the administration of different dose groups. Assessment of safety : The following aspects will be clinically assessed for safety during the trial: 1) any spontaneously reported and all directly observed adverse events, serious adverse events; 2) any abnormal changes in vital signs, physical examination; 3) laboratory tests, electrocardiogram tests abnormalities during the trial period. The trial will be monitored by clinical physicians, who will observe and ask the subjects about their various reactions, record the nature, frequency, management and outcome of adverse events in a timely manner, and conduct causality analysis. They will also analyze the laboratory test results before and after the trial. Statistics analysis The results were processed using American Phoenix WinNonlin 8.0 or above version, which fitted a non-compartmental model to the blood drug concentrations of SHR6508 and calculated the pharmacokinetic parameters. The individual and mean concentration-time (c-t) curves were plotted separately. The blood concentration (c)- time (t) data were analyzed by listing the mean, standard deviation, median, maximum, minimum, and coefficient of variation of the drug concentration at each time point. Results Patients Among the 23 participants who were enrolled, 22 were of Han ethnicity and 1 was of another ethnicity. The median age of the participants was 23.0 years (range, 20 to 28 years), with 12 male and 11 female participants. The mean (± SD) weight was 57.55 ± 7.686 kg, the mean height was 161.57 ± 8.242 cm, and the mean body-mass index (BMI) was 22.00 ± 1.948 kg/m2. There were no reports of previous or concurrent medication use among the participants. Of the 23 participants who were enrolled in this study, 22 completed all the planned doses according to the protocol, except for 1 participant who withdrew from the study before receiving the study drug 1. The demographic characteristics of the subjects are shown in Table 2 . Table 2 Demographic Characteristics of Subjects Placebo (N = 6) SHR6508 0.5 mg (N = 5) SHR6508 2.5 mg (N = 6) SHR6508 5 mg (N = 6) Total (N = 23) Age(year) n 6 5 6 6 23 Mean (SD) 28.3 (9.35) 26.0 (5.48) 22.2 (3.54) 25.3 (9.46) 25.4 (7.34) Median 25.0 26.0 22.5 21.5 23.0 Q1, Q3 21.0, 39.0 22.0, 28.0 19.0, 23.0 20.0, 26.0 20.0, 28.0 Min, Max 19, 41 20, 34 18, 28 19, 44 18, 44 Sex, n(%) Male 3 ( 50.0) 3 ( 60.0) 3 ( 50.0) 3 ( 50.0) 12 ( 52.2) Female 3 ( 50.0) 2 ( 40.0) 3 ( 50.0) 3 ( 50.0) 11 ( 47.8) Ethnic, n(%) Han 5 ( 83.3) 5 (100.0) 6 (100.0) 6 (100.0) 22 ( 95.7) Other 1 ( 16.7) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 4.3) Height(cm) n 6 5 6 6 23 Mean (SD) 157.17 (8.262) 163.60 (9.529) 162.75 (9.032) 163.08 (6.681) 161.57 (8.242) Median 155.00 167.50 161.25 163.00 159.00 Q1, Q3 150.50, 161.50 157.00, 169.50 156.50, 170.50 156.50, 169.00 156.00, 169.50 Min, Max 149.5, 171.5 150.5, 173.5 151.5, 175.5 156.0, 171.0 149.5, 175.5 Weight(kg) n 6 5 6 6 23 Mean (SD) 55.80 (8.326) 59.26 (6.048) 57.02 (9.505) 58.42 (7.947) 57.55 (7.686) Median 54.65 60.40 54.65 57.40 57.60 Q1, Q3 47.90, 62.70 57.90, 60.90 48.90, 66.00 56.60, 59.20 50.20, 62.70 Min, Max 47.0, 67.9 50.2, 66.9 47.8, 70.1 47.6, 72.3 47.0, 72.3 BMI(kg/m 2 ) n 6 5 6 6 23 Mean (SD) 22.48 (1.712) 22.20 (2.075) 21.40 (1.874) 21.95 (2.462) 22.00 (1.948) Median 22.00 22.20 20.65 22.05 21.80 Q1, Q3 21.40, 23.10 20.20, 23.80 20.30, 22.80 19.40, 23.50 20.30, 23.50 Min, Max 20.8, 25.6 20.1, 24.7 19.5, 24.5 19.4, 25.3 19.4, 25.6 Efficacy ： PK results : A total of 15 subjects were included in this study for PK analysis, the main pharmacokinetic parameters of SHR6508 after single intravenous injection of SHR6508 in healthy subjects are shown in Table 3 , and the mean blood concentration-time semi-logarithmic curves are shown in Fig. 1 – 2 . Table 3 Plasma PK parameter tableof SHR6508 in subjects after administration (PK parameter analysis set) PK parameter (Units) SHR6508 0.5 mg (N = 4) SHR6508 2.5 mg (N = 6) SHR6508 5 mg (N = 5) T max (h)* 0.058 (0.03 ~ 0.08) 0.033 (0.03 ~ 0.08) 0.033 (0.03 ~ 0.25) C max (ng/mL) 88.45 ± 49.87 (56.4) 418.67 ± 122.16 (29.2) 617.40 ± 312.58 (50.6) AUC 0 − t (h*ng/mL) 67.42 ± 16.94 (25.1) 488.61 ± 65.78 (13.5) 928.40 ± 158.99 (17.1) AUC 0−∞ (h*ng/mL) 82.84 ± 18.67 (22.5) 538.33 ± 79.25 (14.7) 1041.99 ± 202.76 (19.5) t 1/2z (h) 8.81 ± 1.97 (22.3) 26.40 ± 4.24 (16.1) 28.31 ± 3.88 (13.7) CL z (L/h) 6.27 ± 1.41 (22.5) 4.73 ± 0.69 (14.6) 4.94 ± 0.88 (17.9) λ z (h − 1 ) 0.082 ± 0.019 (23) 0.027 ± 0.0042 (15.7) 0.025 ± 0.0032 (13.1) V z (L) 76.85 ± 6.10 (7.9) 177.78 ± 22.75 (12.8) 198.56 ± 24.16 (12.2) AUC _%Extrap (%) 18.94 ± 2.26 (12) 9.08 ± 1.72 (18.9) 10.60 ± 2.44 (23.1) *Note: Tmax is calculated using the median (minimum, maximum), while all other PK parameters are calculated using Mean ± SD (CV%). The blood concentration reached its peak rapidly after single intravenous injection of SHR6508 in healthy subjects (the median Tmax was about 0.033–0.058 h), and no significant difference in median Tmax was observed between different dose groups. Except for the low-dose group, the pharmacokinetic parameters Vz, t1/2z, and CLz related to drug distribution and elimination were basically the same among other dose groups: the average half-life (t1/2z) of the 0.5 mg dose group was about 8.8 h; that of the 2.5 mg / 5 mg dose group was about 26.4 h and 28.3 h, respectively. The blood drug exposure levels (Cmax and AUC) of SHR6508 increased proportionally with the dose within the range of 0.5-5 mg, and showed linear pharmacokinetic characteristics. The results of variance analysis showed no significant differences in PK characteristics between different genders. PD results : Upon completion of the 5 mg dose group (Group C) study, a blinded analysis revealed a pharmacological signal of reduction in iPTH and blood calcium in healthy subjects following a single intravenous injection of the product, and this reduction was dose-dependent. This trial was terminated early in that the pharmacodynamic profile met expectations. A total of 22 subjects were enrolled in the PDS. iPTH concentrations declined rapidly within 1 h of administration: the mean percent change from baseline in iPTH was minimized in the SHR 6508 0.5 mg group at 10 min after administration to approximately − 35.5%; in the 2.5 mg group, the mean percent change from baseline in iPTH was minimized to -65.9% approximately at 1 h after administration; and in the 5 mg, the mean percentage change from baseline in iPTH was minimized at 30 min after administration to around − 66.9%. The iPTH concentrations in the test drug group essentially returned to placebo levels at 24–48 h. The results of the relative change from baseline in iPTH concentrations are shown in Fig. 3 . Serum corrected calcium concentrations showed a decreasing trend after dosing: the mean percent change from baseline in serum corrected calcium decreased to a minimum of -1.5%, -7.1%, and − 7.5% respectively at approximately 16 h after dosing in the SHR6508 0.5/ 2.5/ 5 mg groups, and then recovered progressively after 24 h. The trend was similar in the 0.5 mg and the placebo group. The results of the change in serum corrected calcium concentration relative to baseline are shown in Fig. 4 . FGF23 concentrations showed a decreasing trend after administration: in the 0.5 mg group, the mean of the percentage change from baseline in FGF23 concentrations decreased to a minimum of -22.4% approximately at 10 min after administration; in the 2.5 mg group, the mean of the percentage change from baseline in FGF23 concentrations decreased to a minimum of -28.0% around at 16 h after administration;. The mean percent change from baseline of FGF23 concentration at 24 h after administration of the 5 mg group decreased to a minimum of -17.0% approximately. No significant dose-dependence of FGF23 concentration was observed between the test drug groups and all recovered gradually after 24 h. The results of the change in FGF23 concentration relative to baseline are shown in Fig. 5 . Phosphorus ion concentration rose to a maximum of 28.9% approximately at 10 h post-dose from baseline percent change mean in the 5 mg group. The trend of blood phosphorus level changes in the remaining dose groups was similar to that of the placebo group, with phosphorus ion concentration rising to a maximum at 16 h post-dose from baseline percent change mean in the 0.5 /2.5 mg and placebo groups of 10.0%, 14.8%, and 25.7%, respectively. And all recovered gradually after 24 h. The results of the change in phosphorus ion concentration relative to baseline are shown in Fig. 6 . Assessment of safety : Among the 23 participants who were enrolled, 16 received SHR6508 and 6 received a placebo. All 22 participants, except for 1 who withdrew from the study before receiving the study drug, were included in the safety dataset. A total of 21 treatment-emergent adverse events (TEAEs) occurred among the 22 participants who received the study drug, and no TEAEs related to the drug were reported. Among the 22 participants who received the study drug, 12 (54.5%) reported 21 TEAEs. The severity of all TEAEs was grade 1. In the placebo group, 3 participants (50.0%) experienced adverse events, while in the experimental drug group, 9 participants (56.3%) experienced adverse events: 3 participants (75.0%) in the SHR6508 0.5 mg dose group, 5 participants (83.3%) in the SHR6508 2.5 mg dose group, and 1 participant (16.7%) in the SHR6508 5 mg dose group experienced adverse events. All TEAEs were judged by the investigators to be possibly unrelated to the drug, and no drug-related adverse events occurred during the study. No serious adverse events occurred during the study period, and no participants withdrew from the study due to adverse events. The outcome of all TEAEs was recovery/resolution or improvement. The treatment-related adverse events sorted by SOC and PT are shown in Table 4 . Table 4 Treatment-Related Adverse Events Sorted by SOC and PT Placebo (N = 6) SHR6508 0.5 mg (N = 4) SHR6508 2.5 mg (N = 6) SHR6508 5 mg (N = 6) Total (N = 16) SOC/PT Events n(%) Events n(%) Events n(%) Events n(%) Events n(%) Number of subjects with at least 1 adverse event 7 3 ( 50.0) 3 3 ( 75.0) 10 5 ( 83.3) 1 1 ( 16.7) 14 9 ( 56.3) All kinds of inspections 7 3 ( 50.0) 3 3 ( 75.0) 9 4 ( 66.7) 1 1 ( 16.7) 13 8 ( 50.0) Positive urine leukocytes 1 1 ( 16.7) 0 0 ( 0.0) 1 1 ( 16.7) 1 1 ( 16.7) 2 2 ( 12.5) Positive urine occult blood 0 0 ( 0.0) 1 1 ( 25.0) 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 6.3) Urine leukocyte esterase positive 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 16.7) 0 0 ( 0.0) 1 1 ( 6.3) Positive urine red blood cells 1 1 ( 16.7) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) Protein in the urine is detected 1 1 ( 16.7) 0 0 ( 0.0) 2 2 ( 33.3) 0 0 ( 0.0) 2 2 ( 12.5) Increased heart rate 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 16.7) 0 0 ( 0.0) 1 1 ( 6.3) Positive bacterial test 1 1 ( 16.7) 1 1 ( 25.0) 2 2 ( 33.3) 0 0 ( 0.0) 3 3 ( 18.8) Elevated vitamin C 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 16.7) 0 0 ( 0.0) 1 1 ( 6.3) Elevated serum uric acid 1 1 ( 16.7) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) 0 0 ( 0.0) Elevated blood triglycerides 2 2 ( 33.3) 1 1 ( 25.0) 1 1 ( 16.7) 0 0 ( 0.0) 2 2 ( 12.5) Diseases of the heart organs 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 16.7) 0 0 ( 0.0) 1 1 ( 6.3) First-degree atrioventricular block 0 0 ( 0.0) 0 0 ( 0.0) 1 1 ( 16.7) 0 0 ( 0.0) 1 1 ( 6.3) Discussion Sinacase is the first marketed calcimimetic molecule, which is developed by Amgen [ 14 , 15 ] . It is administered orally at a therapeutic dose of 30–180 mg, and it needs to adjust dose in 30mg increments based on the patient's iPTH and blood calcium levels [ 16 ] . Sinacase is a strong inhibitor of CYP2D6 with low oral bioavailability and clinical adverse effects such as upper gastrointestinal bleeding, nausea, vomiting, diarrhea, and poor patient compliance. Subsequently, Amgen company developed intravenous molecule Etelcalcetide (Parsabiv), a synthetic eight peptide hydrochloride [ 17 , 18 ] . It is supposed to administrate three times a week by intravenous injection after hemodialysis, and the maintenance treatment dose is 2.5–15 mg/time, according to the patient's iPTH and blood calcium level. At the same time, the dosage needs to be adjusted at 2.5 or 5 mg increment, because the administration timing with the patient dialysis time resulting in better patient compliance, and is also beneficial to the doctor to master the patient dosage and make adjustment appropriately. Etelcalcetide is being mainly cleared by kidney instead of liver in healthy people, and around 60% of drugs in SHPT patients are metabolized by dialysis [ 19 ] . In a phase 3 study, SHPT patients with baseline iPTH levels around 1000 pg/mL receiving 2.5–15 mg or 30–180 mg sinaccase for 26 weeks, iPTH decreased by > 30% in 68.2% subjects of Etelcalcetide group, and 57.7% in Sinacase group, and both of the treatment groups share the equivalent incidence of gastrointestinal adverse effects [ 20 – 22 ] . This trial is a study of safety, pharmacokinetics and pharmacodynamics conducted in healthy adult subjects. Safety, pharmacokinetics, and pharmacodynamics were studied by intravenous administration of SHR6508 injection (0.5mg, 2.5mg, 5mg, placebo) in healthy adults, providing basis for the further development of SHR6508. In this study, healthy subjects were given a single intravenous injection of 0.5-5mg SHR6508 injection. After the administration, the SHR6508 plasma drug concentration rapidly reached its peak, followed by rapid distribution and slow elimination. Among them, the clearance rate of the 0.5 mg group was faster, and the half-life was shorter, which may be due to the lower dose, and the blood drug concentration was below the quantitative lower limit after 24 hours, which had a certain impact on the estimation of the terminal elimination item. The clearance rate and half-life of the 2.5 mg group and the 5 mg group were closer, and the average half-life of the two dose groups was about 26.4 h and 28.3 h, respectively. Linear relationship analysis was performed on the drug exposure of different dose groups, and the results showed that the pharmacokinetics of SHR6508 injection in the dose range of 0.5-5 mg in the human body conforms to linear pharmacokinetic characteristics. After a single intravenous injection of 0.5-5mg SHR6508 injection, the iPTH and blood calcium levels in the body decreased, and the decrease effect had a dose-dependent relationship, which is consistent with the expected effect of this product. The phenomenon of increased phosphate ion levels in the SHR6508 5mg group may be due to physiological regulation caused by the decrease in iPTH level. This indicates that SHR6058 injection may be a useful new treatment option for SHPT-CKD patients. The potential issues regarding efficacy and safety of SHR6508, such as allergies and infusion reactions, also need to be addressed. To address these issues, antibody testing was performed. The serum ADA test results of all completed subjects were negative, and no anti-SHR6508 antibodies were detected. In addition, all adverse events that occurred during the treatment were grade 1, and the outcomes were recovery/resolution or relief. No serious adverse events or adverse events resulting in death were reported during the trial, and no adverse events leading to withdrawal from the trial occurred. The incidence of adverse reactions was not dose-dependent. No known or potential safety risks of similar varieties and this product, such as hypocalcemia, upper gastrointestinal bleeding, and non-dynamic bone disease, occurred, and no hemolysis-related adverse events occurred. In summary, our results indicate that the overall safety and tolerability of a single intravenous injection of 0.5-5 mg SHR6508 injection in healthy subjects are good, providing a new choice for the treatment of SHPT. There are several limitations to this study. First, although small sample sizes are generally acceptable for phase I trials, rare AEs may be difficult to detect. Therefore, further large-scale clinical trials are still needed to accurately prove the safety of SHR6508. Secondly, since healthy subjects cannot represent the patient population, the PK values may be different when SHR6508 is applied in clinical practice, and further data from long-term studies and clinical experience are needed in this regard. Declarations Acknowledgements: This study was sponsored by Shanghai Hengrui Biotech, Inc. Authors’ contributions : Each author was involved in revising the manuscript critically for important intellectual content, and all authors read and approved the final manuscript. Data Availability Statement ： For detailed data, the corresponding author can be contacted directly. Conflict of Interest ：The study was conducted without any business or financial relationship that could be interpreted as a potential conflict of interest. None of the authors declared other competing interests. References 尹素凤 冯 代. 慢性肾脏病继发性甲旁亢的治疗 [J]. 医药卫生科技. 张建荣 张. 《慢性肾脏病继发性甲旁亢》 [M]. 2010. GOKOZAN H N, SCOGNAMIGLIO T. Advances and Updates in Parathyroid Pathology [J]. Adv Anat Pathol, 2023, 30(1): 24-33. SADOWSKI S M, PUSZTASZERI M, BRULHART-MEYNET M C, et al. Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism [J]. J Clin Endocrinol Metab, 2018, 103(6): 2189-98. DRüEKE T B. Hyperparathyroidism in Chronic Kidney Disease [M]//FEINGOLD K R, ANAWALT B, BLACKMAN M R, et al. Endotext. South Dartmouth (MA); MDText.com, Inc. MALBERTI F, FARINA M, IMBASCIATI E. The PTH-calcium curve and the set point of calcium in primary and secondary hyperparathyroidism [J]. Nephrol Dial Transplant, 1999, 14(10): 2398-406. CALIGARA F, GIANGRANDE A, ALLARIA P, et al. The PTH-calcium relationship curve in secondary hyperparathyroidism, an index of sensitivity and suppressibility of parathyroid glands [J]. Nephrol Dial Transplant, 1996, 11 Suppl 3: 136-41. 国家药品监督管理局药品审评中心. 《化学药物临床药代动力学研究技术指导原则》 [J]. 2005年. NMPA. 《药物临床试验质量管理规范》 [J]. 2020年. NMPA. 《药品注册管理办法》 [J]. 2020年. PALMER S C, MAVRIDIS D, JOHNSON D W, et al. Comparative Effectiveness of Calcimimetic Agents for Secondary Hyperparathyroidism in Adults: A Systematic Review and Network Meta-analysis [J]. Am J Kidney Dis, 2020, 76(3): 321-30. ZHANG L X, ZHANG B, LIU X Y, et al. Advances in the treatment of secondary and tertiary hyperparathyroidism [J]. Front Endocrinol (Lausanne), 2022, 13: 1059828. CUNNINGHAM J, LOCATELLI F, RODRIGUEZ M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options [J]. Clin J Am Soc Nephrol, 2011, 6(4): 913-21. HAI M T T, GUETTIER J M, ROSEBRAUGH C J. Dosing of Etelcalcetide and Cinacalcet for Secondary Hyperparathyroidism [J]. Jama, 2017, 317(20): 2132. BOVER J, UREñA P, RUIZ-GARCíA C, et al. Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism [J]. Clin J Am Soc Nephrol, 2016, 11(1): 161-74. CHANDRAN M, BILEZIKIAN J P, LAU J, et al. The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies [J]. Rev Endocr Metab Disord, 2022, 23(3): 485-501. FRIEDL C, ZITT E. Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: a review on current data and place in therapy [J]. Drug Des Devel Ther, 2018, 12: 1589-98. CUNNINGHAM J, BLOCK G A, CHERTOW G M, et al. Etelcalcetide Is Effective at All Levels of Severity of Secondary Hyperparathyroidism in Hemodialysis Patients [J]. Kidney Int Rep, 2019, 4(7): 987-94. WOLF M, BLOCK G A, CHERTOW G M, et al. Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis [J]. Clin Kidney J, 2020, 13(1): 75-84. BLOCK G A, BUSHINSKY D A, CHENG S, et al. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial [J]. Jama, 2017, 317(2): 156-64. FUKAGAWA M, YOKOYAMA K, SHIGEMATSU T, et al. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients [J]. Nephrol Dial Transplant, 2017, 32(10): 1723-30. MARTIN K J, BELL G, PICKTHORN K, et al. Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects [J]. Nephrol Dial Transplant, 2014, 29(2): 385-92. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4096983","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":289007478,"identity":"cd5e4e35-fcb3-4088-984d-9057a972333a","order_by":0,"name":"Shengting ZHANG","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Shengting","middleName":"","lastName":"ZHANG","suffix":""},{"id":289007479,"identity":"a86bbdfa-3be9-4254-a9c2-b36f4eb6c7af","order_by":1,"name":"Hong-yi TAN","email":"","orcid":"","institution":"The Third Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Hong-yi","middleName":"","lastName":"TAN","suffix":""},{"id":289007480,"identity":"768f0b04-a2fe-4f9e-9684-f58199a86e9b","order_by":2,"name":"Shuang YANG","email":"","orcid":"","institution":"The Third Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Shuang","middleName":"","lastName":"YANG","suffix":""},{"id":289007481,"identity":"00262cc3-23a1-459a-bd7e-e74ffbe68c9f","order_by":3,"name":"Xiao-yan YANG","email":"","orcid":"","institution":"The Third Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Xiao-yan","middleName":"","lastName":"YANG","suffix":""},{"id":289007482,"identity":"e3438239-54b9-4e74-a0c0-9fb454efb164","order_by":4,"name":"Chang CUI","email":"","orcid":"","institution":"The Third Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Chang","middleName":"","lastName":"CUI","suffix":""},{"id":289007483,"identity":"a6e55642-f0f1-4d18-8773-b8cf508f22ba","order_by":5,"name":"Jie HUANG","email":"","orcid":"","institution":"The Third Xiangya Hospital of Central South University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"HUANG","suffix":""},{"id":289007484,"identity":"48d7f604-f90c-4638-acf0-76bc2ffca2f0","order_by":6,"name":"Guo-ping YANG","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYHACxgcfKiTk2NibDxCthdlwxhkbYz6eYwlEa2GT5m1LS5wnkaNAnHqD82uPSc44czi9jSGHgeFHxTYitNx4l2zxoeJwbhvD2QOMPWduE6PljOFNoC25bYx9CcyMbcRpMQD65XA6GzOPAZFazvcYgbyfwMZGrBbJG3zJoEA2bONhSzhIlF/4zp89CIpKefn5jw8++FFBhBaFGzkIzgHC6oFAvv8MUepGwSgYBaNgJAMApSVDisg6itsAAAAASUVORK5CYII=","orcid":"","institution":"The Third Xiangya Hospital of Central South University","correspondingAuthor":true,"prefix":"","firstName":"Guo-ping","middleName":"","lastName":"YANG","suffix":""}],"badges":[],"createdAt":"2024-03-14 03:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4096983/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4096983/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54596417,"identity":"cc3d15d4-3496-4f86-9a10-a1d3801a23f1","added_by":"auto","created_at":"2024-04-12 19:04:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3822329,"visible":true,"origin":"","legend":"\u003cp\u003eThe average (Mean+SD) blood drug concentration-time curve (PK concentration analysis set, linear coordinates) of SHR6508 in healthy subjects.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/4f9230c9507ad50c0789da66.png"},{"id":54597069,"identity":"ce3c0192-baaf-455c-9678-c32a977d1513","added_by":"auto","created_at":"2024-04-12 19:12:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3775230,"visible":true,"origin":"","legend":"\u003cp\u003eThe average (Mean+SD) blood drug concentration-time curve (PK concentration analysis set, semi-logarithmic coordinates) of SHR6508 in healthy subjects.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/0f5f73a5f5eed06c5a1fa358.png"},{"id":54597068,"identity":"2684b74a-3e33-43a8-ab4f-91a5f5f03d5b","added_by":"auto","created_at":"2024-04-12 19:12:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4119985,"visible":true,"origin":"","legend":"\u003cp\u003eGraph of the percentage change in iPTH concentration relative to baseline over time in healthy subjects.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/1023d945a6b5981e4787067c.png"},{"id":54596422,"identity":"43b35006-ddae-45f0-857e-f23819e62e2f","added_by":"auto","created_at":"2024-04-12 19:04:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4125833,"visible":true,"origin":"","legend":"\u003cp\u003eThe percentage change in serum-corrected calcium concentration relative to baseline over time in healthy subjects.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/3d1c855f6ace595019197e36.png"},{"id":54596421,"identity":"ed9ca34c-91ff-4b98-8120-10d9c05c6b17","added_by":"auto","created_at":"2024-04-12 19:04:32","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4133712,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage change in FGF23 concentration relative to baseline over time in healthy subjects\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/930e20d78c352933b3c2f9c0.png"},{"id":54596423,"identity":"32620370-05d9-426e-b052-85ca7afc5f1e","added_by":"auto","created_at":"2024-04-12 19:04:32","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":4136290,"visible":true,"origin":"","legend":"\u003cp\u003eThe percentage change in phosphorus ion concentration relative to baseline over time in healthy subjects.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/e8fcabf7d18d276d5882866e.png"},{"id":56505798,"identity":"1f87d8da-73b9-478e-bb27-9a468f9d29ec","added_by":"auto","created_at":"2024-05-15 05:22:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":24839185,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4096983/v1/63e417e6-ff02-49d8-8802-1f4dfae18f88.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The pharmacokinetics, pharmacodynamics and tolerability of SHR6508 in Chinese healthy subjects","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSecondary hyperparathyroidism (SHPT), is a systematic disorder induced by the excessive secreting of Parathyroid hormone, leading to disturbances in calcium, phosphorus, bone metabolism and a range of clinical manifestations\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. SHPT occurs mainly in patients with chronic kidney failure (CKD), and as well as patients suffers deficiency in vitamine D, small intestinal malabsorption, osteochondrosis, etc\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe incidence of SHPT is 30\u0026ndash;50 percent in CKD patients, and the main pathophysiological changes include high level of PTH causes a significant increase in bone conversion, osteocalcinolysis release into the blood resulting in bone damage and extra-bone multi-organ tissue metastatic calcification (e.g., vascular calcification, ocular calcification, visceral calcification, periarticular calcification, and cutaneous calcification), and the clinical manifestations are the corresponding symptoms of bone disease and extra-bone organ damage, such as bone pain, bone fracture, acute periarticular arthritis, alterations in cardiovascular structure and function, sudden cardiac death, and skin itching\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePhosphorus retention, vitamin D deficiency and abnormal PTH regulatory mechanisms are the prime incentives resulting high level of PTH among CKD-SHPT patients, and Phosphorus binding agents, vitamin D receptor agonists and calcimimetic drugs are the corresponding treatments respectively\u003csup\u003e[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, aluminum-containing and calcium-containing phosphorus binders commonly used in clinical practice are at risk for aluminum toxicity and hypercalcemia respectively\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Non-aluminum and non-calcium phosphorus binding agents are less likely to trigger elevated blood calcium or aluminum levels, thus it may be advantageous in slowing the progression of vascular calcification\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVitamin D receptor agonists can inhibit the synthesis and secretion of PTH, promote the absorption of calcium in the small intestine, and reduce the secretion of PTH indirectly. Though it is effective, it may lead to hypercalcinemia in clininc. The mechanism of calcimimetic drugs is to activate the calcium-sensitive receptor (CaSR) on the main cells of the parathyroid gland\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. The activated CaSR will suppress the release and synthesis of PTH, thus reducing the level of PTH in the blood. The physiological effects of PTH include the promotion of calcium reabsorption and phosphorus excretion in the kidney, increasing calcium absorption in the intestine and promoting osteolysis by increasing the level of active vitamin D, leading to the release of bone calcium and bone phosphorus\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Therefore, the activation of CaSR by calmimetic reduces PTH level, blood calcium and phosphorus level.\u003c/p\u003e \u003cp\u003eThe SHR6508 injection, developed by Shanghai Hengrui Pharmaceutical Co., LTD., acts on CaSR. It is intended to be used for the treatment of secondary hyperparathyroidism in patients on maintenance hemodialysis for chronic kidney disease. This product is a new drug not listed neither domesticly nor abroad, so it is a new drug of Class 1 of the New Registration Classification of Chemical Drugs. Therefore, the purpose of this study was to explore the safety, pharmacokinetics, and pharmacodynamics of SHR6508 in healthy Chinese subjects and provide a basis for later clinical medication plans.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cb\u003eEthics statement\u003c/b\u003e: This study was conducted in the Third Xiangya Hospital of Central South University, and has been approved by the Ethics Committee of the Third Xiangya Hospital of Central South University, Approval No. 21109. This clinical trial adheres to the Declaration of Helsinki (2013 edition), Good Clinical Practice (GCP) and related regulations. Before the start of the clinical trial, the subjects are informed of the details of the clinical trial, and all subjects have signed a written informed consent form.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePatients\u003c/strong\u003e \u003cp\u003eThe participants of this trial were all healthy subjects. A total of 30 subjects were scheduled to be enrolled, there are 8 subjects in group A, and 8 in B, C and D respectively. Eligible participants were female or male healthy volunteers around 18\u0026ndash;45 years old (including the boundary value) with a BMI between 19\u0026ndash;26 kg/m\u003csup\u003e2\u003c/sup\u003e (including the boundary value). At the same time, male participants are supposed to weigh at least 50.0 kg, female participants at least 45.0 kg. And the participants have to commit that make no plans to get pregnant, donate sperms or ovums and be willing to take physical contraceptive measures (including their partners) during the trial and after the final dose. All the participants have been informed in detail about the nature of the trial, the potential benefits the trial brings them, and the probable inconveniences and underlying risk as well. Participants volunteer to join the trial and should be able to communicate with the investigators well, defer to the requirements of the trial and sign the written informed consent.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eStudy design\u003c/b\u003e :This is a single-center, double-blind, placebo-controlled, single-dose, ascending dose designed clinical study in healthy Chinese subjects with four groups as A, B, C and D. A total of 30 healthy subjects are divided into the four groups, and subjects in each group were equal between men and women. The subjects were randomized to be treated with SHR6508 injections or placebo with a ratio of 2:1 in group A and 3:1 in the remaining groups. The dose of administration is 0.5mg, 2.5mg, 5mg and 10mg in the four groups respectively. The trail flow chart is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This trial adheres to the principle of dose escalation, starting from a low dose and proceeding to the next dose group only after completing the safety assessment of the previous group. Each subject receives only one dose group. The trial should be stopped early if the criteria for termination are met during dose escalation, even if the maximum dose is not reached. The maximum climbing dose is initially set at 10 mg, but it can be adjusted based on the safety, tolerability, PK and PD outcomes of the previous groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy Design\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDose group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber of subjects\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSHR6508: 4 + Placebo༚2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSHR6508: 6 + Placebo༚2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSHR6508: 6 + Placebo༚2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSHR6508: 6 + Placebo༚2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eEfficacy\u003c/b\u003e: The primary endpoint of the study including Cmax, Tmax, AUC0-t, AUC0-\u0026infin;, T1/2z, MRT0-t, and MRT0-\u0026infin;, the percentage reduction of iPTH (intact parathyroid hormone) and serum corrected calcium from baseline. The following parameters were determined as secondary efficacy endpoints: the changes of FGF23 (fibroblast growth factor 23) and phosphorus ions after the administration of different dose groups.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAssessment of safety\u003c/b\u003e: The following aspects will be clinically assessed for safety during the trial: 1) any spontaneously reported and all directly observed adverse events, serious adverse events; 2) any abnormal changes in vital signs, physical examination; 3) laboratory tests, electrocardiogram tests abnormalities during the trial period. The trial will be monitored by clinical physicians, who will observe and ask the subjects about their various reactions, record the nature, frequency, management and outcome of adverse events in a timely manner, and conduct causality analysis. They will also analyze the laboratory test results before and after the trial.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStatistics analysis\u003c/strong\u003e \u003cp\u003eThe results were processed using American Phoenix WinNonlin 8.0 or above version, which fitted a non-compartmental model to the blood drug concentrations of SHR6508 and calculated the pharmacokinetic parameters. The individual and mean concentration-time (c-t) curves were plotted separately. The blood concentration (c)- time (t) data were analyzed by listing the mean, standard deviation, median, maximum, minimum, and coefficient of variation of the drug concentration at each time point.\u003c/p\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 23 participants who were enrolled, 22 were of Han ethnicity and 1 was of another ethnicity. The median age of the participants was 23.0 years (range, 20 to 28 years), with 12 male and 11 female participants. The mean (± SD) weight was 57.55 ± 7.686 kg, the mean height was 161.57 ± 8.242 cm, and the mean body-mass index (BMI) was 22.00 ± 1.948 kg/m2. There were no reports of previous or concurrent medication use among the participants. Of the 23 participants who were enrolled in this study, 22 completed all the planned doses according to the protocol, except for 1 participant who withdrew from the study before receiving the study drug 1. The demographic characteristics of the subjects are shown in Table\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eDemographic Characteristics of Subjects\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSHR6508\u003c/p\u003e\n \u003cp\u003e0.5 mg\u003c/p\u003e\n \u003cp\u003e(N = 5)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSHR6508\u003c/p\u003e\n \u003cp\u003e2.5 mg\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSHR6508\u003c/p\u003e\n \u003cp\u003e5 mg\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(N = 23)\u003c/p\u003e\n \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(year)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e28.3 (9.35)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e26.0 (5.48)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.2 (3.54)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e25.3 (9.46)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e25.4 (7.34)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e26.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e21.5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e23.0\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1, Q3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e21.0, 39.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.0, 28.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19.0, 23.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.0, 26.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.0, 28.0\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19, 41\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20, 34\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e18, 28\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19, 44\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e18, 44\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eSex, n(%)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 60.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e12 ( 52.2)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e2 ( 40.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e11 ( 47.8)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eEthnic, n(%)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e5 ( 83.3)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (100.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (100.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (100.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22 ( 95.7)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e1 ( 4.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight(cm)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e157.17 (8.262)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e163.60 (9.529)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e162.75 (9.032)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e163.08 (6.681)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e161.57 (8.242)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e155.00\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e167.50\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e161.25\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e163.00\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e159.00\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1, Q3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e150.50, 161.50\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e157.00, 169.50\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e156.50, 170.50\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e156.50, 169.00\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e156.00, 169.50\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e149.5, 171.5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e150.5, 173.5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e151.5, 175.5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e156.0, 171.0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e149.5, 175.5\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight(kg)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e55.80 (8.326)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e59.26 (6.048)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e57.02 (9.505)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e58.42 (7.947)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e57.55 (7.686)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e54.65\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e60.40\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e54.65\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e57.40\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e57.60\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1, Q3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e47.90, 62.70\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e57.90, 60.90\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e48.90, 66.00\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e56.60, 59.20\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e50.20, 62.70\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e47.0, 67.9\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e50.2, 66.9\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e47.8, 70.1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e47.6, 72.3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e47.0, 72.3\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.48 (1.712)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.20 (2.075)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e21.40 (1.874)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e21.95 (2.462)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.00 (1.948)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.00\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.20\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.65\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e22.05\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e21.80\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eQ1, Q3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e21.40, 23.10\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.20, 23.80\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.30, 22.80\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19.40, 23.50\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.30, 23.50\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.8, 25.6\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e20.1, 24.7\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19.5, 24.5\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19.4, 25.3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e19.4, 25.6\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e：\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePK results\u003c/strong\u003e : A total of 15 subjects were included in this study for PK analysis, the main pharmacokinetic parameters of SHR6508 after single intravenous injection of SHR6508 in healthy subjects are shown in Table\u0026nbsp;\u003cspan\u003e3\u003c/span\u003e, and the mean blood concentration-time semi-logarithmic curves are shown in Fig.\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e–\u003cspan\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003ePlasma PK parameter tableof SHR6508 in subjects after administration (PK parameter analysis set)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003ePK parameter\u003c/p\u003e\n \u003cp\u003e(Units)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSHR6508 0.5 mg\u003c/p\u003e\n \u003cp\u003e(N = 4)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSHR6508 2.5 mg\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSHR6508 5 mg\u003c/p\u003e\n \u003cp\u003e(N = 5)\u003c/p\u003e\n \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e (h)*\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0.058 (0.03 ~ 0.08)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033 (0.03 ~ 0.08)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033 (0.03 ~ 0.25)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e88.45 ± 49.87 (56.4)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e418.67 ± 122.16 (29.2)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e617.40 ± 312.58 (50.6)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0 − t\u003c/sub\u003e (h*ng/mL)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e67.42 ± 16.94 (25.1)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e488.61 ± 65.78 (13.5)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e928.40 ± 158.99 (17.1)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0−∞\u003c/sub\u003e (h*ng/mL)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e82.84 ± 18.67 (22.5)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e538.33 ± 79.25 (14.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1041.99 ± 202.76 (19.5)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003et\u003csub\u003e1/2z\u003c/sub\u003e (h)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e8.81 ± 1.97 (22.3)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e26.40 ± 4.24 (16.1)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e28.31 ± 3.88 (13.7)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eCL\u003csub\u003ez\u003c/sub\u003e (L/h)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e6.27 ± 1.41 (22.5)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e4.73 ± 0.69 (14.6)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e4.94 ± 0.88 (17.9)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eλ\u003csub\u003ez\u003c/sub\u003e(h\u003csup\u003e− 1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0.082 ± 0.019 (23)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0.027 ± 0.0042 (15.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025 ± 0.0032 (13.1)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e (L)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e76.85 ± 6.10 (7.9)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e177.78 ± 22.75 (12.8)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e198.56 ± 24.16 (12.2)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eAUC\u003csub\u003e_%Extrap\u003c/sub\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e18.94 ± 2.26 (12)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e9.08 ± 1.72 (18.9)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e10.60 ± 2.44 (23.1)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e*Note: Tmax is calculated using the median (minimum, maximum), while all other PK parameters are calculated using Mean ± SD (CV%).\u003c/p\u003e\n\u003cp\u003eThe blood concentration reached its peak rapidly after single intravenous injection of SHR6508 in healthy subjects (the median Tmax was about 0.033–0.058 h), and no significant difference in median Tmax was observed between different dose groups. Except for the low-dose group, the pharmacokinetic parameters Vz, t1/2z, and CLz related to drug distribution and elimination were basically the same among other dose groups: the average half-life (t1/2z) of the 0.5 mg dose group was about 8.8 h; that of the 2.5 mg / 5 mg dose group was about 26.4 h and 28.3 h, respectively. The blood drug exposure levels (Cmax and AUC) of SHR6508 increased proportionally with the dose within the range of 0.5-5 mg, and showed linear pharmacokinetic characteristics. The results of variance analysis showed no significant differences in PK characteristics between different genders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD results\u003c/strong\u003e: Upon completion of the 5 mg dose group (Group C) study, a blinded analysis revealed a pharmacological signal of reduction in iPTH and blood calcium in healthy subjects following a single intravenous injection of the product, and this reduction was dose-dependent. This trial was terminated early in that the pharmacodynamic profile met expectations. A total of 22 subjects were enrolled in the PDS. iPTH concentrations declined rapidly within 1 h of administration: the mean percent change from baseline in iPTH was minimized in the SHR 6508 0.5 mg group at 10 min after administration to approximately − 35.5%; in the 2.5 mg group, the mean percent change from baseline in iPTH was minimized to -65.9% approximately at 1 h after administration; and in the 5 mg, the mean percentage change from baseline in iPTH was minimized at 30 min after administration to around − 66.9%. The iPTH concentrations in the test drug group essentially returned to placebo levels at 24–48 h. The results of the relative change from baseline in iPTH concentrations are shown in Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eSerum corrected calcium concentrations showed a decreasing trend after dosing: the mean percent change from baseline in serum corrected calcium decreased to a minimum of -1.5%, -7.1%, and − 7.5% respectively at approximately 16 h after dosing in the SHR6508 0.5/ 2.5/ 5 mg groups, and then recovered progressively after 24 h. The trend was similar in the 0.5 mg and the placebo group. The results of the change in serum corrected calcium concentration relative to baseline are shown in Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eFGF23 concentrations showed a decreasing trend after administration: in the 0.5 mg group, the mean of the percentage change from baseline in FGF23 concentrations decreased to a minimum of -22.4% approximately at 10 min after administration; in the 2.5 mg group, the mean of the percentage change from baseline in FGF23 concentrations decreased to a minimum of -28.0% around at 16 h after administration;. The mean percent change from baseline of FGF23 concentration at 24 h after administration of the 5 mg group decreased to a minimum of -17.0% approximately. No significant dose-dependence of FGF23 concentration was observed between the test drug groups and all recovered gradually after 24 h. The results of the change in FGF23 concentration relative to baseline are shown in Fig.\u0026nbsp;\u003cspan\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003ePhosphorus ion concentration rose to a maximum of 28.9% approximately at 10 h post-dose from baseline percent change mean in the 5 mg group. The trend of blood phosphorus level changes in the remaining dose groups was similar to that of the placebo group, with phosphorus ion concentration rising to a maximum at 16 h post-dose from baseline percent change mean in the 0.5 /2.5 mg and placebo groups of 10.0%, 14.8%, and 25.7%, respectively. And all recovered gradually after 24 h. The results of the change in phosphorus ion concentration relative to baseline are shown in Fig.\u0026nbsp;\u003cspan\u003e6\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of safety\u003c/strong\u003e: Among the 23 participants who were enrolled, 16 received SHR6508 and 6 received a placebo. All 22 participants, except for 1 who withdrew from the study before receiving the study drug, were included in the safety dataset. A total of 21 treatment-emergent adverse events (TEAEs) occurred among the 22 participants who received the study drug, and no TEAEs related to the drug were reported. Among the 22 participants who received the study drug, 12 (54.5%) reported 21 TEAEs. The severity of all TEAEs was grade 1. In the placebo group, 3 participants (50.0%) experienced adverse events, while in the experimental drug group, 9 participants (56.3%) experienced adverse events: 3 participants (75.0%) in the SHR6508 0.5 mg dose group, 5 participants (83.3%) in the SHR6508 2.5 mg dose group, and 1 participant (16.7%) in the SHR6508 5 mg dose group experienced adverse events. All TEAEs were judged by the investigators to be possibly unrelated to the drug, and no drug-related adverse events occurred during the study. No serious adverse events occurred during the study period, and no participants withdrew from the study due to adverse events. The outcome of all TEAEs was recovery/resolution or improvement. The treatment-related adverse events sorted by SOC and PT are shown in Table\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eTreatment-Related Adverse Events Sorted by SOC and PT\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSHR6508\u003c/p\u003e\n \u003cp\u003e0.5 mg\u003c/p\u003e\n \u003cp\u003e(N = 4)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSHR6508\u003c/p\u003e\n \u003cp\u003e2.5 mg\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSHR6508\u003c/p\u003e\n \u003cp\u003e5 mg\u003c/p\u003e\n \u003cp\u003e(N = 6)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(N = 16)\u003c/p\u003e\n \u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eSOC/PT\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eEvents\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eEvents\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eEvents\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eEvents\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003eEvents\u003c/p\u003e\n \u003c/th\u003e\u003cth align=\"left\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of subjects with at least 1 adverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3 ( 75.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e5 ( 83.3)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e9 ( 56.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll kinds of inspections\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3 ( 75.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e4 ( 66.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e8 ( 50.0)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive urine leukocytes\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2 ( 12.5)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive urine occult blood\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 25.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 6.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eUrine leukocyte esterase positive\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 6.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive urine red blood cells\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eProtein in the urine is detected\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2 ( 33.3)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2 ( 12.5)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eIncreased heart rate\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 6.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive bacterial test\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 25.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2 ( 33.3)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e3 ( 18.8)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eElevated vitamin C\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 6.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eElevated serum uric acid\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eElevated blood triglycerides\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2 ( 33.3)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 25.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e2 ( 12.5)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the heart organs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 6.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst-degree atrioventricular block\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 16.7)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e0 ( 0.0)\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\u003ctd align=\"char\"\u003e\n \u003cp\u003e1 ( 6.3)\u003c/p\u003e\n \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\n\u003c/div\u003e\n\n\n\n\n\n\n"},{"header":"Discussion","content":"\u003cp\u003eSinacase is the first marketed calcimimetic molecule, which is developed by Amgen\u003csup\u003e[\u003cspan\u003e14\u003c/span\u003e, \u003cspan\u003e15\u003c/span\u003e]\u003c/sup\u003e. It is administered orally at a therapeutic dose of 30–180 mg, and it needs to adjust dose in 30mg increments based on the patient's iPTH and blood calcium levels\u003csup\u003e[\u003cspan\u003e16\u003c/span\u003e]\u003c/sup\u003e. Sinacase is a strong inhibitor of CYP2D6 with low oral bioavailability and clinical adverse effects such as upper gastrointestinal bleeding, nausea, vomiting, diarrhea, and poor patient compliance. Subsequently, Amgen company developed intravenous molecule Etelcalcetide (Parsabiv), a synthetic eight peptide hydrochloride\u003csup\u003e[\u003cspan\u003e17\u003c/span\u003e, \u003cspan\u003e18\u003c/span\u003e]\u003c/sup\u003e. It is supposed to administrate three times a week by intravenous injection after hemodialysis, and the maintenance treatment dose is 2.5–15 mg/time, according to the patient's iPTH and blood calcium level. At the same time, the dosage needs to be adjusted at 2.5 or 5 mg increment, because the administration timing with the patient dialysis time resulting in better patient compliance, and is also beneficial to the doctor to master the patient dosage and make adjustment appropriately. Etelcalcetide is being mainly cleared by kidney instead of liver in healthy people, and around 60% of drugs in SHPT patients are metabolized by dialysis\u003csup\u003e[\u003cspan\u003e19\u003c/span\u003e]\u003c/sup\u003e. In a phase 3 study, SHPT patients with baseline iPTH levels around 1000 pg/mL receiving 2.5–15 mg or 30–180 mg sinaccase for 26 weeks, iPTH decreased by \u0026gt; 30% in 68.2% subjects of Etelcalcetide group, and 57.7% in Sinacase group, and both of the treatment groups share the equivalent incidence of gastrointestinal adverse effects\u003csup\u003e[\u003cspan\u003e20\u003c/span\u003e–\u003cspan\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis trial is a study of safety, pharmacokinetics and pharmacodynamics conducted in healthy adult subjects. Safety, pharmacokinetics, and pharmacodynamics were studied by intravenous administration of SHR6508 injection (0.5mg, 2.5mg, 5mg, placebo) in healthy adults, providing basis for the further development of SHR6508. In this study, healthy subjects were given a single intravenous injection of 0.5-5mg SHR6508 injection. After the administration, the SHR6508 plasma drug concentration rapidly reached its peak, followed by rapid distribution and slow elimination. Among them, the clearance rate of the 0.5 mg group was faster, and the half-life was shorter, which may be due to the lower dose, and the blood drug concentration was below the quantitative lower limit after 24 hours, which had a certain impact on the estimation of the terminal elimination item. The clearance rate and half-life of the 2.5 mg group and the 5 mg group were closer, and the average half-life of the two dose groups was about 26.4 h and 28.3 h, respectively. Linear relationship analysis was performed on the drug exposure of different dose groups, and the results showed that the pharmacokinetics of SHR6508 injection in the dose range of 0.5-5 mg in the human body conforms to linear pharmacokinetic characteristics.\u003c/p\u003e\u003cp\u003eAfter a single intravenous injection of 0.5-5mg SHR6508 injection, the iPTH and blood calcium levels in the body decreased, and the decrease effect had a dose-dependent relationship, which is consistent with the expected effect of this product. The phenomenon of increased phosphate ion levels in the SHR6508 5mg group may be due to physiological regulation caused by the decrease in iPTH level. This indicates that SHR6058 injection may be a useful new treatment option for SHPT-CKD patients.\u003c/p\u003e\u003cp\u003eThe potential issues regarding efficacy and safety of SHR6508, such as allergies and infusion reactions, also need to be addressed. To address these issues, antibody testing was performed. The serum ADA test results of all completed subjects were negative, and no anti-SHR6508 antibodies were detected. In addition, all adverse events that occurred during the treatment were grade 1, and the outcomes were recovery/resolution or relief. No serious adverse events or adverse events resulting in death were reported during the trial, and no adverse events leading to withdrawal from the trial occurred. The incidence of adverse reactions was not dose-dependent. No known or potential safety risks of similar varieties and this product, such as hypocalcemia, upper gastrointestinal bleeding, and non-dynamic bone disease, occurred, and no hemolysis-related adverse events occurred.\u003c/p\u003e\u003cp\u003eIn summary, our results indicate that the overall safety and tolerability of a single intravenous injection of 0.5-5 mg SHR6508 injection in healthy subjects are good, providing a new choice for the treatment of SHPT.\u003c/p\u003e\u003cp\u003eThere are several limitations to this study. First, although small sample sizes are generally acceptable for phase I trials, rare AEs may be difficult to detect. Therefore, further large-scale clinical trials are still needed to accurately prove the safety of SHR6508. Secondly, since healthy subjects cannot represent the patient population, the PK values may be different when SHR6508 is applied in clinical practice, and further data from long-term studies and clinical experience are needed in this regard.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003cstrong\u003e \u003c/strong\u003eThis study was sponsored by\u0026ensp;Shanghai Hengrui Biotech, Inc.\u0026ensp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003cstrong\u003e \u003c/strong\u003eEach author was involved in revising the manuscript critically for important intellectual content, and all authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eFor detailed data, the corresponding author can be contacted directly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e：The study was conducted without any business or financial relationship that could be interpreted as a potential conflict of interest. None of the authors declared other competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e尹素凤 冯 代. 慢性肾脏病继发性甲旁亢的治疗 [J]. 医药卫生科技.\u003c/li\u003e\n\u003cli\u003e张建荣 张. 《慢性肾脏病继发性甲旁亢》 [M]. 2010.\u003c/li\u003e\n\u003cli\u003eGOKOZAN H N, SCOGNAMIGLIO T. Advances and Updates in Parathyroid Pathology [J]. Adv Anat Pathol, 2023, 30(1): 24-33.\u003c/li\u003e\n\u003cli\u003eSADOWSKI S M, PUSZTASZERI M, BRULHART-MEYNET M C, et al. Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism [J]. J Clin Endocrinol Metab, 2018, 103(6): 2189-98.\u003c/li\u003e\n\u003cli\u003eDR\u0026uuml;EKE T B. Hyperparathyroidism in Chronic Kidney Disease [M]//FEINGOLD K R, ANAWALT B, BLACKMAN M R, et al. Endotext. South Dartmouth (MA); MDText.com, Inc.\u003c/li\u003e\n\u003cli\u003eMALBERTI F, FARINA M, IMBASCIATI E. The PTH-calcium curve and the set point of calcium in primary and secondary hyperparathyroidism [J]. Nephrol Dial Transplant, 1999, 14(10): 2398-406.\u003c/li\u003e\n\u003cli\u003eCALIGARA F, GIANGRANDE A, ALLARIA P, et al. The PTH-calcium relationship curve in secondary hyperparathyroidism, an index of sensitivity and suppressibility of parathyroid glands [J]. Nephrol Dial Transplant, 1996, 11 Suppl 3: 136-41.\u003c/li\u003e\n\u003cli\u003e国家药品监督管理局药品审评中心. 《化学药物临床药代动力学研究技术指导原则》 [J]. 2005年.\u003c/li\u003e\n\u003cli\u003eNMPA. 《药物临床试验质量管理规范》 [J]. 2020年.\u003c/li\u003e\n\u003cli\u003eNMPA. 《药品注册管理办法》 [J]. 2020年.\u003c/li\u003e\n\u003cli\u003ePALMER S C, MAVRIDIS D, JOHNSON D W, et al. Comparative Effectiveness of Calcimimetic Agents for Secondary Hyperparathyroidism in Adults: A Systematic Review and Network Meta-analysis [J]. Am J Kidney Dis, 2020, 76(3): 321-30.\u003c/li\u003e\n\u003cli\u003eZHANG L X, ZHANG B, LIU X Y, et al. Advances in the treatment of secondary and tertiary hyperparathyroidism [J]. Front Endocrinol (Lausanne), 2022, 13: 1059828.\u003c/li\u003e\n\u003cli\u003eCUNNINGHAM J, LOCATELLI F, RODRIGUEZ M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options [J]. Clin J Am Soc Nephrol, 2011, 6(4): 913-21.\u003c/li\u003e\n\u003cli\u003eHAI M T T, GUETTIER J M, ROSEBRAUGH C J. Dosing of Etelcalcetide and Cinacalcet for Secondary Hyperparathyroidism [J]. Jama, 2017, 317(20): 2132.\u003c/li\u003e\n\u003cli\u003eBOVER J, URE\u0026ntilde;A P, RUIZ-GARC\u0026iacute;A C, et al. Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism [J]. Clin J Am Soc Nephrol, 2016, 11(1): 161-74.\u003c/li\u003e\n\u003cli\u003eCHANDRAN M, BILEZIKIAN J P, LAU J, et al. The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies [J]. Rev Endocr Metab Disord, 2022, 23(3): 485-501.\u003c/li\u003e\n\u003cli\u003eFRIEDL C, ZITT E. Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: a review on current data and place in therapy [J]. Drug Des Devel Ther, 2018, 12: 1589-98.\u003c/li\u003e\n\u003cli\u003eCUNNINGHAM J, BLOCK G A, CHERTOW G M, et al. Etelcalcetide Is Effective at All Levels of Severity of Secondary Hyperparathyroidism in Hemodialysis Patients [J]. Kidney Int Rep, 2019, 4(7): 987-94.\u003c/li\u003e\n\u003cli\u003eWOLF M, BLOCK G A, CHERTOW G M, et al. Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis [J]. Clin Kidney J, 2020, 13(1): 75-84.\u003c/li\u003e\n\u003cli\u003eBLOCK G A, BUSHINSKY D A, CHENG S, et al. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial [J]. Jama, 2017, 317(2): 156-64.\u003c/li\u003e\n\u003cli\u003eFUKAGAWA M, YOKOYAMA K, SHIGEMATSU T, et al. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients [J]. Nephrol Dial Transplant, 2017, 32(10): 1723-30.\u003c/li\u003e\n\u003cli\u003eMARTIN K J, BELL G, PICKTHORN K, et al. Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects [J]. Nephrol Dial Transplant, 2014, 29(2): 385-92.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic kidney disease, CKD-SHPT, Secondary hyperparathyroidism, pharmacokinetics, pharmacodynamics","lastPublishedDoi":"10.21203/rs.3.rs-4096983/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4096983/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSecondary hyperparathyroidism (SHPT) mainly occurs in patients with chronic renal failure. SHR6508 is a new type of calcimimetic molecule, intended for patients with SHPT who are undergoing maintenance hemodialysis for chronic kidney disease. This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of a new calcimimetic agent, SHR6508 injection, in healthy Chinese subjects.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this phase I study, healthy subjects were administered SHR6508 injection via intravenous infusion according to a randomization table on the morning of the first day after admission. Blood samples were collected at 15 time points to measure the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of SHR6508. Adverse events that occurred during administration were also evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e23 subjects were successfully screened and enrolled in the study. Except for 1 subject who withdrew from the study before medication, the remaining 22 subjects completed the study. No serious adverse events or adverse events leading to death occurred. The blood drug concentration of SHR6508 injection in healthy subjects reached its peak rapidly after a single intravenous dose. With the exception of the low-dose group, there was no significant difference in the distribution and elimination-related parameters Vz, t1/2z, and CLz between the other dose groups. The plasma drug exposure level (Cmax and AUC) of SHR6508 increased proportionally with the dose, and it showed linear pharmacokinetic characteristics within the dose range of 0.5-5 mg. The results of variance analysis showed no significant difference in PK characteristics between different genders.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAfter a single intravenous injection of 0.5-5 mg of SHR6508 injection in healthy subjects, the iPTH and blood calcium levels in the body decreased, and this effect showed dose-dependent characteristics, which is consistent with the expected effect of this product. The overall safety and tolerability of SHR6508 injection in healthy subjects after a single intravenous dose of 0.5-5 mg was good.\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e \u003cp\u003eThe trial is registered at chinadrugtrials.org.cn (ChiCTR2100048905)(19/07/2021).\u003c/p\u003e","manuscriptTitle":"The pharmacokinetics, pharmacodynamics and tolerability of SHR6508 in Chinese healthy subjects","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-12 19:04:25","doi":"10.21203/rs.3.rs-4096983/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cfbffa26-164f-468c-98ff-1e5244e4ea5a","owner":[],"postedDate":"April 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-15T05:14:43+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-12 19:04:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4096983","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4096983","identity":"rs-4096983","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}