Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Patients With Anemia Associated With Chronic Kidney Disease Receiving Hemodialysis

Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Patients With Anemia Associated With Chronic Kidney Disease Receiving Hemodialysis | 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 Research Article Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Patients With Anemia Associated With Chronic Kidney Disease Receiving Hemodialysis Pamela Navarro-Gonzales, Ajit Chavan, Don Wang, Steven Burke, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5396906/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Aug, 2025 Read the published version in BMC Nephrology → Version 1 posted 4 You are reading this latest preprint version Abstract Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia in dialysis-dependent chronic kidney disease (CKD) with a starting dose of 300 mg once daily (dose adjustments up to 600 mg). A recent phase 1b study evaluated the pharmacokinetics, pharmacodynamics, and safety of higher vadadustat doses (500–900 mg) in healthy volunteers. Here we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher doses of vadadustat in patients with CKD receiving dialysis. Methods This phase 1b, randomized, open-label study evaluated the pharmacokinetics and pharmacodynamics of vadadustat (600, 750, or 900 mg) in patients with CKD-related anemia receiving hemodialysis over a 10-day treatment period. Eligible patients were randomized 2:2:2:1 to vadadustat 600, 750, 900 mg daily or an intravenous erythropoiesis-stimulating agent, respectively. For vadadustat groups, blood samples for PK and PD analyses were collected on Day 1 and Day 8. PK analyses included area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration and to infinity, and to maximum plasma concentration (C max ). PD analyses measured serum erythropoietin (EPO), hemoglobin, and red blood cells (RBCs). Safety assessments included adverse events in the safety population (patients who received ≥1 dose of study drug). Results In the vadadustat groups, a dose-dependent increase in plasma exposure of vadadustat (C max and AUC), with modest accumulation, was observed on Day 1 and Day 8. Vadadustat increased plasma EPO concentrations, with a variable EPO response observed in each group. Relative to baseline, mean hemoglobin and RBC levels remained unchanged, with no significant changes observed in any treatment group. Vadadustat was well-tolerated. Conclusions The current study characterized the PK and PD response (EPO and reticulocytes) and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. Overall, vadadustat was well tolerated. These findings will contribute to the development of higher-dose regimens for further investigation in phase 3 studies. Trial Registration ClinicalTrials.gov ID NCT03992066; https://clinicaltrials.gov/study/NCT03992066 ; Updated September 9, 2020. Accessed November 22, 2024. vadadustat HIF-PHI phase 1 pharmacokinetics pharmacodynamics safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Anemia is a frequent complication in patients with chronic kidney disease (CKD). Anemia may develop early in the course of CKD but its severity increases with the decline of renal function [ 1 ]. Although the pathogenesis of anemia in CKD is multifactorial, deficiency of erythropoietin (EPO) production is a predominant cause, as the kidneys are unable to secrete sufficient EPO to support erythropoiesis and maintain hemoglobin within normal ranges [ 2 , 3 ]. The current standard of care for the treatment of anemia in CKD is use of erythropoiesis-stimulating agents (ESAs) alone or in combination with iron supplementation [ 4 ]. However, ESAs are associated with increased risk of cardiovascular and thromboembolic events [ 5 , 6 ]. Furthermore, ESAs require parenteral administration and refrigeration. Thus, oral treatment modalities for anemia associated with CKD may be beneficial [ 7 , 8 ]. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are an oral treatment alternative for patients with CKD-related anemia [ 9 ]. HIF-PHIs have been shown to stabilize HIF, a transcription factor that regulates hypoxia-sensitive genes, stimulating EPO production, with a resultant increase in red blood cell (RBC) production as well as improved iron uptake and utilization [ 10 ]. Vadadustat, an orally bioavailable HIF-PHI, is approved in 37 countries globally for the treatment of CKD-related anemia in dialysis-dependent (DD) patients. It has a starting dose of 300 mg once daily and dose titration in increments or decrements of 150 mg within the range of 150 to 600 mg to achieve or maintain hemoglobin levels within the clinical target range [ 11 , 12 ]. In Japan, vadadustat is approved in both non–DD (NDD)-CKD and DD-CKD populations [ 13 , 14 ]. In previous clinical studies, vadadustat has been shown to maintain and increase mean hemoglobin levels within prespecified physiological target ranges [ 11 , 12 , 15 , 16 ]. In addition, vadadustat has been shown to increase endogenous EPO production, improve iron availability, and increase circulating reticulocytes in patients with CKD and anemia [ 17 ]. Early clinical studies have shown that vadadustat is primarily metabolized through glucuronidation, resulting in vadadustat-O-glucuronide. In healthy individuals, vadadustat and its main metabolite are eliminated from the body through both renal and fecal routes. Vadadustat has also exhibited dose-proportional kinetics and rapid absorption, with a median time to maximum concentration (T max ) of 3 to 4 hours for doses ranging from 80 to 1200 mg. Vadadustat plasma half-life (t 1/2 ) is around 4 to 5 hours [ 18 ]. However, in patients with CKD stages 3 and 4 who are not yet on dialysis, there was a modest increase in t 1/2 from 4.2 hours to 7.9 hours, and a decrease in oral clearance (CL/F) from 1.5 L/h to 1.0 L/h [ 19 ]. Here, we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher daily doses of vadadustat (600, 750, and 900 mg) in patients with CKD who are receiving dialysis. Treatment with vadadustat was compared with an active control group in which patients continued their current ESA treatments of either intravenous (IV) darbepoetin alfa or epoetin alfa. Methods Trial design This was a phase 1b, randomized, open-label study to evaluate the pharmacokinetics and pharmacodynamics of vadadustat 600, 750, or 900 mg daily in patients with CKD-related anemia receiving hemodialysis conducted in the United States between June 2019 and May 2020. The study included a 28-day Screening and Randomization period, a 10-day Treatment Period, and a 30-day Safety Follow-up Period after the last dose of study drug. Eligible patients were randomized 2:2:2:1 to vadadustat 600, 750, 900 mg daily, or IV ESA, respectively. For patients randomized to vadadustat, study duration also included a minimum 5- or 9-day ESA washout period prior to dosing on Day 1 ( Fig. 1 ). Vadadustat was provided as 150 mg white or off-white round bi-convex film-coated tablets for oral administration. Study population Patients eligible for this study were aged ≥18 years at the time of informed consent confirmation and had stable baseline hemoglobin values between 8.5 and 10.5 g/dL based on 2 average values obtained within 28 days prior to randomization. Study participants were required to be on a stable 3 times weekly hemodialysis regimen, with adequate dialysis clearance defined as a single-pool Kt/Vurea of ≥1.2 for at least 12 weeks prior to screening. “K” is dialyzer urea clearance, “t” is total dialysis session time, and “V” is volume of distribution of urea, which is approximately equal to total body water. Study participants were also required to be maintained on IV ESA therapy with a mean dose of <1.5 μg/kg/week for darbepoetin alfa, or mean dose of <300 U/kg/week for epoetin alfa) for 8 weeks prior to randomization. Patients were ineligible for the study if they had an RBC transfusion within 8 weeks prior to randomization. Patients with low values of ferritin (<100 ng/mL) or transferrin saturation (<20%) were also ineligible. Additional exclusion criteria included a planned change in dialysis modality or renal transplant within the study period; significant cardiovascular, hematologic, hepatic, or chronic inflammatory disease; active or recent gastrointestinal (GI) bleeding, history of new or recurrent malignancy within 2 years prior to screening, or currently receiving treatment or suppressive therapy for cancer. Vadadustat pharmacokinetic assessments For each vadadustat treatment group, blood samples for vadadustat PK analysis were collected pre-dose and at 1, 2, 3, 4, 5, 8, 11, and 24 hours post-dose on Day 1 and at pre-dose and at 1, 2, 3, 4, 5, 8, and 11 hours post-dose on Day 8. Primary endpoints were area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration (AUC 0-last ) and to infinity (AUC 0-inf ), as well as maximum plasma concentration (C max ). Additional PK parameters included T max , clearance (CL), volume of distribution (Vd), and elimination half-life (t ½ ). PK parameters were calculated using an SAS® program (SAS Institute Inc.), which followed the same algorithm as that implemented in WinNonlin® Professional (Version 7.0, Pharsight Corporation, a Certara Company) using the PK population (all patients completing the study without any protocol deviation[s] that would impact the PK profile characterization). Additionally, the SAS results were validated using the parameters generated from WinNonlin 7.0. C max and T max were determined directly from the concentration time profiles. For AUC calculations, the entire 24-hour sampling period was included for calculating PK parameters on Day 1 using the linear up log down calculation method. AUC 0-last is equivalent to AUC from time 0 to 24 hours (AUC 0-24 ) on Day 1. The pre-dose sample obtained on Day 8 was used as the 24-hour time point on the same day for calculating the AUC 0-24 (which is equivalent to AUC inf ) under the assumption that vadadustat had reached steady state by that day. Pharmacodynamic assessments For each vadadustat treatment group, blood samples for EPO analysis were collected at pre-dose and at 1, 2, 3, 4, 5, 8, 11, and 24 hours post-dose on Day 1 and at pre-dose and at 1, 2, 3, 4, 5, 8, and 11 hours post-dose on Day 8. Blood samples for other PD biomarkers, hemoglobin, and RBC were collected at pre-dose on Days 1, 6, 8, 10, and 12 (follow-up visit). Reticulocyte samples were collected on Days 1, 6, 8, and 10. PD biomarker concentrations were summarized by dose level and by dosing day using descriptive statistics and graphical displays citing the PK population. For the ESA treatment group, blood samples for analysis of EPO were collected at Day 1 at pre-dose, and 0.25, 1, 2, 3, 4, 5, 8, 11, and 24 hours post-dose. Bioanalysis of samples The concentration measurements of vadadustat were performed by a validated liquid chromatography-mass spectrometry/mass spectrometry method at Syneos Health Clinic (Quebec, Canada). The EPO measurements were performed by the enzyme-linked immunosorbent assay method at Q2 Solutions (Marietta, GA). Other PD endpoints (reticulocytes, RBC, and hemoglobin) were tested at the central lab facility (ACM Medical Laboratory, Rochester, NY) using existing validated methods. All study samples were analyzed within analytical runs that complied with the acceptance ranges for the quality control samples and were completed within the known period of analyte stability. Safety assessment Safety assessments included adverse events (AEs), vital signs, clinical laboratory values, and physical examinations in the safety population (all patients who received at least 1 dose of study drug). An AE that started during the treatment period or up to 30 days after the last dose of study drug was considered a treatment-emergent AE (TEAE) if it was not present prior to the first dose of study drug, or it was present prior to the first dose of study drug but increased in severity during the treatment period or up to 30 days after the last dose of study drug. AEs of special interest were also assessed, including, but not limited to, malignancy, elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver enzymes greater than 3 times the upper limit of normal, and pulmonary hypertension. All AEs were coded using Medical Dictionary for Regulatory Activities Version 23.0. Results Trial population A summary of patient demographic characteristics is provided for the randomized population in Table 1 . The treatment groups were well balanced regarding mean age, ethnicity, race, sex, height, and weight, among all vadadustat groups and IV ESA treatment groups. This was similar for the safety and PK populations (data not shown). In the 750-mg dose group, 1 patient had inadvertent ESA administration and another patient had the entire concentration profile below quantitation limit for every vadadustat PK sample and therefore, these 2 patients were excluded from the PK population. Pharmacokineti c results Plasma concentration-time profiles of vadadustat after oral administration are shown in Fig. 2. After the first day of dosing, a rise in vadadustat exposure was observed, measured by AUC, that corresponded with an increase in dose. This dose-dependent increase was consistently seen on both Day 1 and Day 8, as evidenced by the elevated C max and AUC values. Mean values of C max and AUC 0-24 were higher on Day 8 compared with Day 1, indicating minimal accumulation of vadadustat; ratios for Day 8/Day 1 of mean C max values ranged from 1.27 to 1.45, and ratios of mean AUC 0-24 values ranged from 1.39 to 1.84, with the 900-mg dose having the highest ratios. Mean apparent total body clearance (CL/F) values for each dose on Day 8 were similar, indicating dose-proportional pharmacokinetics following multiple doses. The median T max of vadadustat was between 2.0 and 3.0 hours, and appeared to be similar across the 600-, 750-, and 900-mg vadadustat treatment groups when measured on Day 1 and Day 8 during dialysis ( Table 2 ). Mean concentrations of vadadustat-OG (the major vadadustat metabolite which is an inactive and nontoxic) increased with time on Day 1 for all vadadustat groups, but no substantial difference across dose groups was observed ( Fig. 3 ). However, an initial decline in vadadustat-OG concentration was observed at the early time points on Day 8 ( Fig. 3 ). Based on a comparison of mean Day 1, 24-hour post-dose, to pre-dose on Day 8, vadadustat-OG concentrations appeared to have increased 2.5- to 3.5-fold with multiple dosing in patients with DD-CKD ( Fig. 3 ). Vadadustat-OG PK parameters are shown in Table 3 . Pharmacodynamics results: Vadadustat increased plasma EPO concentrations in all participants, but a variable EPO response was observed in each dosing group ( Fig. 4 ). Following Day 1 dosing, the highest EPO increase was observed in the 750-mg vadadustat treatment group. There was a >4-fold increase in peak EPO relative to the baseline in the 600- and 750-mg dosing groups on the first day. This contrasts with the 900-mg dosing group, where the EPO increase was just over 2-fold. EPO levels reached their peak 11 hours post-dose in all dosage groups. Following additional doses of vadadustat on Day 8, there was a >5-fold increase in the 750-mg group, contrasting with the 4-fold increase observed in the 600- and 900-mg groups. As depicted in Fig. 5 , there was a 100-fold increase in EPO levels in the ESA group. In relation to other PD parameters ( Fig. 6 ), all vadadustat dose groups showed an approximately 2-fold increase in mean reticulocyte count on Day 5, which continued to rise through the final on-treatment assessment 9 days after the initial dose, yet there was no significant difference observed among the various doses. In contrast, the reticulocyte count exhibited minimal change in the group receiving the ESA treatment ( Fig. 6 ). Mean hemoglobin and RBC levels remained unchanged relative to baseline, and no significant changes were observed in both the vadadustat and ESA treatment groups. Safety and tolerability In the vadadustat treatment groups, 20 TEAEs were reported by 11 patients, while no TEAEs were reported in the ESA treatment group ( Table 4 ). At least 1 TEAE was experienced by 3 (25.0%), 3 (25.0%), and 5 (38.5%) patients in the vadadustat 600-, 750-, and 900-mg treatment groups, respectively. One patient in each of the groups experienced a drug-related TEAE, and a treatment-emergent serious AE was reported by 1 patient in both the vadadustat 600- and 750-mg treatment groups. In the 600-mg vadadustat treatment group, a TEAE of nausea was considered drug related but nonserious. In the 750-mg vadadustat treatment group, 1 patient experienced decreased appetite and later showed elevations in ALT/AST enzymes, which was considered to be drug related. However, there were no associated symptoms with the elevated liver function tests and no abnormal values of bilirubin or alkaline phosphatase were observed during this period. In the 900-mg group, a TEAE of diarrhea was considered drug related but nonserious. All TEAEs reported in the vadadustat treatment groups were either mild or moderate in intensity, and there were no TEAEs leading to treatment discontinuation or death. Diarrhea was experienced by 3 patients in the vadadustat treatment groups (2 in the 750-mg group and 1 in the 900-mg group). No other TEAE was experienced by >1 patient in the vadadustat treatment group. Discussion Vadadustat is an orally administered HIF-PHI that has been developed to treat anemia associated with CKD [ 15 , 20 ]. Pivotal phase 3 trials included a vadadustat starting dose of 300 mg with a maximum dose of 600 mg [ 16 ]. Here, we report a phase 1b study with a goal to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of vadadustat 600, 750, or 900 mg daily in DD-CKD. An active control group continued prior treatment with IV darbepoetin alfa or epoetin. Vadadustat exhibited a dose-dependent increase in AUC, but consistently similar CL/F values across doses, a result that aligns with prior findings [ 19 ]. The C max and AUC ratios for vadadustat on Day 8 vs Day 1 were < 2, indicating modest accumulation of the parent drug. An initial decrease in vadadustat-OG concentration was observed on Day 8 in the first 4 hours after dosing. These findings are consistent with the delay of formation of the metabolite and its accumulation in plasma in DD-CKD patients. Previous studies have indicated that vadadustat was detected in the urine as vadadustat-OG in healthy volunteers; however, it appears that there are multiple simultaneous elimination pathways in patients with CKD, aligning with nonclinical absorption, distribution, metabolism, and excretion data that propose a combination of renal and hepatic routes for the elimination of vadadustat. Vadadustat triggered a variable EPO response. After the first day of dosing, the most significant increase in EPO was observed in the group treated with 750 mg of vadadustat, primarily due to a single-patient surge in EPO levels. The data suggest that there was no clear dose-response relationship in EPO levels following vadadustat treatment. As expected, there was a much larger increase in EPO after IV ESA administration. All vadadustat dose groups showed a continuous increase in the mean reticulocyte count until the end of treatment; this result is consistent with previous findings [ 17 ]. Despite this trend, there were no significant differences observed among doses due to the variability of the data. Conversely, in the ESA-treated group, there were no significant changes in the reticulocyte count. This can be attributed to the absence of a washout period in this group, which suggests there was no restimulation of reticulocyte production, unlike in the vadadustat treatment groups. Mean hemoglobin and RBC concentrations did not show clinically meaningful changes in any of the vadadustat or ESA groups during the 10-day treatment due to the short treatment duration. The primary TEAEs in the vadadustat groups, primarily GI related, could be attributed to the use of an oral dosage form (vadadustat) compared with an injectable ESA. There were no deaths or discontinuations from study treatment due to AEs. Conclusions This study characterizes the exposure, biomarker response, and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. This marks the first instance of the higher doses, specifically 750 and 900 mg, being explored within a patient population. These findings will contribute to the development of higher-dose regimens for further investigation in clinical studies. Abbreviations AEs, adverse events ALT, alanine aminotransferase AUC, area under the plasma concentration time curve AUC 0-last , AUC from dosing to last quantifiable concentration AUC 0-inf , AUC from dosing to infinity AUC 0-24 , time 0 to 24 hours AUC tau , AUC to the end of the dosing period AST, aspartate aminotransferase CKD, chronic kidney disease CL/F, oral clearance C max , maximum plasma concentration DD, dialysis-dependent EPO, erythropoietin ESA, erythropoiesis-stimulating agent GI, gastrointestinal HIF-PHI, hypoxia-inducible factor prolyl hydroxylase inhibitor IV, intravenous Kt/Vurea, 'K' is dialyzer urea clearance, 't' is total dialysis session time, and 'V' is volume of distribution of urea NDD, non-dialysis-dependent PD, pharmacodynamic PK, pharmacokinetic RBC, red blood cell t 1/2 , half-life TEAE, treatment-emergent adverse event T max , time to maximum concentration Vd, volume of distribution Declarations Ethics approval The study was conducted in accordance with the protocol, ethical principles of the Declaration of Helsinki, Good Clinical Practice, and International Conference on Harmonisation guidelines, as well as all other applicable regulations. Prior to study implementation, investigators obtained approval from a central institutional review board (IRB; Advarra IRB, Columbia, MD) except for one site that required a local IRB (Committee on the Protection of Human Subjects, Providence, RI). Consent to participate The purpose and nature of the study, as well as the possibility of adverse effects, were explained to study participants in understandable, plain language terms, and written informed consent was obtained from each participant. Availability of data and materials statement Proposal requests for access to original data should be sent to [email protected] . Deidentified patient-level data will be available 12 months after US and EU approval to qualified researchers with an appropriate research proposal. The research proposal is subject to review by an IRB with final approval by Akebia Therapeutics, Inc. Competing interests P.N.G., D.W., S.B., and K.D. are employees of Akebia Therapeutics, Inc., and A.C. is a former employee of Akebia Therapeutics, Inc. Funding The present study was funded by Akebia Therapeutics, Inc. Author contributions All authors contributed to data interpretation and manuscript review. A.C. and S.B. were responsible for the study design. D.W. conducted the statistical analysis of the data. K.D. and P.N.G. wrote the manuscript. Acknowledgments Medical writing assistance was provided by Syneos Health Medical Communications, LLC, and supported by Akebia Therapeutics, Inc. References Stauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS One. 2014;9(1):e84943. Hörl WH. Anaemia management and mortality risk in chronic kidney disease. Nat Rev Nephrol. 2013;9(5):291. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23:1631-34. https://doi.org/10.1681/ASN.2011111078 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2(4). McCullough PA, Barnhart HX, Inrig JK, et al. Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. Am J Nephrol. 2013;37(6):549-58. Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol. 2007;2(6):1274-82. Bonomini M, Del Vecchio L, Sirolli V, Locatelli F. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67(1):133-42. Nova Scotia Health Authority. Patient and Family Guide 2020. Erythropoiesis-Stimulating Agent (ESA) Therapy and Chronic Kidney Disease (CKD). https://www.nshealth.ca/sites/default/files/documents/pamphlets/1493.pdf. Accessed 22 August 2024. Gauthier-Loiselle M, Michalopoulos SN, Cloutier M, Serra E, Bungay R, Szabo E, et al. Costs associated with the administration of erythropoiesis-stimulating agents for the treatment of anemia in patients with non-dialysis-dependent chronic kidney disease: a US societal perspective. J Manag Care Spec Pharm 2021;27:1703-13. Bonomini M, Del Vecchio L, Sirolli V, Locatelli F. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67:133-42. Maxwell PH, Eckardt K-U. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12(3):157. Chertow GM, Pergola PE, Farag YMK, Agarwal R, Arnold S, Bako G, et al; PRO 2 TECT Study Group. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med. 2021;384(17):1589-1600. Eckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384(17):1601-12. Markham A. Vadadustat: first approval. Drugs. 2020;80;1365-71. Akebia Therapeutics, Inc. Akebia Therapeutics announces approval of vadadustat in Japan for the treatment of anemia due to chronic kidney disease in dialysis-dependent and non-dialysis dependent adult patients. Press release 29 June 2020. https://ir.akebia.com/news-releases/news-release-details/akebia-therapeutics-announces-approval-vadadustat-japan (2020). Accessed 19 August 2024. Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016;90(5):1115-22. Haase VH, Chertow GM, Block GA, et al. Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents. Nephrol Dial Transplant. 2019;34(1):90-9. Koury MJ, Agarwal R, Chertow GM, Eckardt KU, Fishbane S, Ganz T, et al. Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease. Am J Hematol. 2022;97(9):1178-88. Chavan A, Burke L, Sawant R, Navarro-Gonzales P, Vargo D, Paulson SK. Effect of moderate hepatic impairment on the pharmacokinetics of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. Clin Pharmacol Drug Dev. 2021;10(8):950-8. Navarro-Gonzales P, Ganz T, Pergola PE, Zuk A, Dykstra K. Pharmacokinetics, pharmacodynamics, and safety of vadadustat in healthy volunteers and patients with chronic kidney disease. Clin Pharmacol Ther. 2024;116(4):1052-1061. doi: 10.1002/cpt.3342. Epub 2024 Jun 25. Martin ER, Smith MT, Maroni BJ, Zuraw QC, deGoma EM. Clinical trial of vadadustat in patients with anemia secondary to stage 3 or 4 chronic kidney disease. Am J Nephrol. 2017;45(5):380-8. Tables Table 1. Summary of demographic characteristics (randomized population) a One time per week. b Three times per week. IV ESA: darbepoetin alfa or epoetin alfa; 6 patients were dosed with epoetin alfa, and 1 patient was dosed with darbepoetin alfa. ESA, erythropoiesis-stimulating agent; IV, intravenous. Table 2. Summary of pharmacokinetic parameters for plasma vadadustat concentration for vadadustat treatment groups Parameter (Unit) Statistic Vadadustat 600 mg N=12 Vadadustat 750 mg N=10 Vadadustat 900 mg N=13 Day 1 Day 8 Day 1 Day 8 Day 1 Day 8 C max , (μg/mL) Mean (SD) 62.9 (21.5) 80.9 (38.1) 67.5 (27.0) 85.5 (24.7) 88.7 (31.2) 129 (65.9) AUC 0-24 , (h·μg/mL) Mean (SD) 679 (174.0) 947 (440.1) 779 (398.7) 1099 (263.5) 968 (331.6) 1781 (1197) t 1/2 (h) Mean (SD) 10.4 (2.3) 12.2 (3.8) 9.9 (2.8) 16.4 (8.6) 12.6 (5.1) 21.7 (26.0) T max (h) Median (min, max) 3.0 (1.0, 5.0) 2.0 (1.0, 5.0) 3.0 (1.0, 23.8) 3.0 (1.0, 8.0) 3.1 (1.0, 8.0) 3.0 (1.0, 4.1) CL/F (L/h) Mean (SD) 0.8 (0.2) 0.7 (0.3) 1.3 (0.6) 0.7 (0.2) 1.0 (0.1) 0.8 (0.5) Vd/F (L) Mean (SD) 9.8 (1.6) 11.8 (5.4) 14.0 (6.8) 16.9 (7.8) 12.8 (2.2) 13.2 (6.0) Day 8 included samples collected from pre-dose to 11 hours post-dose of Day 8 to calculate C max and T max . In addition, Day 8 pre-dose was considered as a result for the 24-hour time point to calculate AUC 0-24 , t 1/2 , CL/F, and Vd/F. AUC 0-24 , area under concentration-time curve from time 0 to 24 hours; CL/F, oral clearance; C max , maximum observed plasma concentration; t 1/2 , half-life; T max , time to maximum concentration; Vd/F, volume of distribution. Table 3. Summary of pharmacokinetic parameters for plasma vadadustat-OG concentration for vadadustat treatment groups Parameter (Unit) Statistic Vadadustat 600 mg N=12 Vadadustat 750 mg N=10 Vadadustat 900 mg N=13 Day 1 Day 8 Day 1 Day 8 Day 1 Day 8 C max (μg/mL) n 12 12 10 10 13 13 Mean (SD) 23.2 (16.1) 53.6 (43.5) 25.5 (12.7) 68.1 (37.3) 23.5 (6.7) 72.3 (42.7) AUC 0-24 (h·μg/mL) n 12 12 10 10 13 13 Mean (SD) 357 (180.5) 1050 (960.0) 362 (132.2) 1143 (525.0) 382 (85.1) 1196 (604.9) T max (h) n 12 12 10 10 13 13 Median 23.1 0.0 23.7 0.0 11.0 0.0 Min, Max 10.0, 23.8 0.0, 10.8 5.0, 23.9 0.0, 10.6 10.0, 23.9 0.0, 11.0 Day 1 included the entire 24-hour sampling period. Day 8 included samples collected from pre-dose to 11 hours post-dose of Day 8 to calculate C max and T max . In addition, Day 8 pre-dose was considered as result for the 24-hour time point to calculate AUC 0-24 , and t 1/2 . AUC 0-24 corresponded to AUC tau , AUC last , and AUC inf on Day 8. AUC 0-24 , area under concentration-time curve from time 0 to 24 hours; AUC inf , AUC from dosing to infinity; AUC last , AUC from dosing to last quantifiable concentration; AUC tau , AUC to end of the dosing period; C max , maximum observed plasma concentration; T max , time to maximum concentration. Table 4. Overall summary of treatment-emergent adverse events Category Vadadustat 600 mg N=12 n (%) Vadadustat 750 mg N=12 n (%) Vadadustat 900 mg N=13 n (%) Vadadustat Total N=37 n (%) IV ESA N=7 n (%) Number of TEAEs 8 6 6 20 0 Patients with any TEAEs 3 (25.0) 3 (25.0) 5 (38.5) 11 (29.7) 0 Patients with any drug-related TEAEs 1 (8.3) 1 (8.3) 1 (7.7) 3 (8.1) 0 Patients with any severe TEAEs 0 0 0 0 0 Patients with any treatment‑emergent SAEs 1 (8.3) 1 (8.3) 0 2 (5.4) 0 Patients with any TEAEs leading to study treatment discontinuation 0 0 0 0 0 Patients with any TEAEs leading to death 0 0 0 0 0 IV ESA: darbepoetin alfa or epoetin alfa. A TEAE was an AE that began (or a pre-existing AE that worsened) after receiving study drug and within 30 days of the last dose. ESA, erythropoiesis-stimulating agent; IV, intravenous; SAEs, serious adverse events; TEAEs, treatment-emergent adverse events. Additional Declarations Competing interest reported. P.N.G., D.W., S.B., and K.D. are employees of Akebia Therapeutics, Inc., and A.C. is a former employee of Akebia Therapeutics, Inc. Cite Share Download PDF Status: Published Journal Publication published 11 Aug, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 13 Jan, 2025 Editor assigned by journal 13 Jan, 2025 Submission checks completed at journal 13 Jan, 2025 First submitted to journal 05 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-5396906","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":401532845,"identity":"f9bd6fb7-8f7c-42d2-83d8-10ce258f5348","order_by":0,"name":"Pamela Navarro-Gonzales","email":"","orcid":"","institution":"Akebia Therapeutics, Inc","correspondingAuthor":false,"prefix":"","firstName":"Pamela","middleName":"","lastName":"Navarro-Gonzales","suffix":""},{"id":401532846,"identity":"3e5b3d79-dec2-453f-b4d0-3953f9af054a","order_by":1,"name":"Ajit Chavan","email":"","orcid":"","institution":"Akebia Therapeutics, Inc","correspondingAuthor":false,"prefix":"","firstName":"Ajit","middleName":"","lastName":"Chavan","suffix":""},{"id":401532847,"identity":"e4ebbd44-81ad-47f2-af1e-431075a818ef","order_by":2,"name":"Don Wang","email":"","orcid":"","institution":"Akebia Therapeutics, Inc","correspondingAuthor":false,"prefix":"","firstName":"Don","middleName":"","lastName":"Wang","suffix":""},{"id":401532848,"identity":"5accae51-e80f-446f-9dda-526ceddea70c","order_by":3,"name":"Steven Burke","email":"","orcid":"","institution":"Akebia Therapeutics, Inc","correspondingAuthor":false,"prefix":"","firstName":"Steven","middleName":"","lastName":"Burke","suffix":""},{"id":401532849,"identity":"668f5344-2926-47b9-813f-4b0eab42d8f9","order_by":4,"name":"Kevin Dykstra","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBACCYYEZjCDn5mNgZnBgGgtCQwMku1tpGoxOHOMgZkoh0m25xgb/vxxT974Rlri44ICOwb+9u4EvFqked4YJ/MkFBtuu5F22HiGQTKDxJmzG/BqkZPIMT7MkJDAuO1Geps0jwHQOxK5hLUc/JGQYL95/vP23zwG9YS1SAO1JPAkJCRukEg7xsxjcJiwFsmeZ8XGPGkJyTNupCVLzzA4zkPQLxLHkzdL/rBJsO2fkWb4ueBPtRx/ey9+LQwMHKjRx0NAOQiwPyBC0SgYBaNgFIxoAAAeTUR6oxik3AAAAABJRU5ErkJggg==","orcid":"","institution":"Akebia Therapeutics, Inc","correspondingAuthor":true,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Dykstra","suffix":""}],"badges":[],"createdAt":"2024-11-05 16:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5396906/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5396906/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04367-x","type":"published","date":"2025-08-11T15:57:55+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73870118,"identity":"9454bc08-e667-4dee-bbd1-a8639cc0f51a","added_by":"auto","created_at":"2025-01-15 12:13:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90583,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003ePatients in the vadadustat groups did not receive a dose of ESA following randomization or for the duration of the 10-day treatment period. The ESA washout period started from the time of the last ESA dose prior to randomization, which may have included day of randomization. \u003csup\u003eb\u003c/sup\u003ePatients began their 10-day treatment period within 36 days of initiating screening. Day 1 occurred after a short interdialytic period at the earliest in-clinic visit following randomization. \u003csup\u003ec\u003c/sup\u003ePatients who completed the 10-day treatment period had a follow-up visit 2 days (+3) after Day 10. Patients who discontinued treatment early had a follow-up visit 2 days (+3) after their end-of-treatment visit.\u003cbr\u003e\nESA, erythropoiesis-stimulating agent.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/ad6ac28482593bd447f4e0dd.png"},{"id":73870120,"identity":"e4649bd5-ae7c-422a-97a6-2f5d9dc7e0de","added_by":"auto","created_at":"2025-01-15 12:13:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":210868,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean plasma concentration-time profile for vadadustat (µg/mL) on Day 1 and Day 8\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eError bars indicate 95% CI; geometric mean values were used for vadadustat concentration calculations.\u003c/p\u003e\n\u003cp\u003eh, hours.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/96820210bbea2393303ebea4.png"},{"id":73870748,"identity":"58513228-dbff-42cd-a1eb-7c77ce2c542f","added_by":"auto","created_at":"2025-01-15 12:21:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":191946,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean plasma concentration-time profile for vadadustat-OG (µg/mL) on Day 1 and Day 8\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eError bars indicate 95% CI; geometric mean values were used for vadadustat concentration calculations.\u003c/p\u003e\n\u003cp\u003eh, hours.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/6a4699cf79d73b002bd0814a.png"},{"id":73870749,"identity":"f9be98a6-1e3b-415a-a2e9-3cc2d1032324","added_by":"auto","created_at":"2025-01-15 12:21:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":461450,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean and fold-change EPO concentration-time profile (mU/mL) in the vadadustat treatment group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eError bars indicate 95% CI.\u003c/p\u003e\n\u003cp\u003eEPO, erythropoietin; h, hours.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/7950f5f1cc9bbbc0438616a0.png"},{"id":73870121,"identity":"e684b48d-59f6-483b-a93b-e9eaf8e93259","added_by":"auto","created_at":"2025-01-15 12:13:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":214866,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean and fold-change EPO concentration (mU/mL) in the ESA treatment group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eError bars indicate 95% CI.\u003c/p\u003e\n\u003cp\u003eEPO, erythropoietin; ESA, erythropoiesis-stimulating agent; h, hours.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/7fbe6daaa10fc107b1cb7f09.png"},{"id":73870750,"identity":"8a4ee2a7-9714-4006-982f-0930f035ce9f","added_by":"auto","created_at":"2025-01-15 12:21:36","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":834912,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean and fold-change reticulocytes, hemoglobin, and RBC concentrations in the vadadustat and ESA treatment groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eError bars indicate 95% CI.\u003c/p\u003e\n\u003cp\u003eESA, erythropoiesis-stimulating agent; h, hours; RBC, red blood cell.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/696cc1129de987d5ccfdb53a.png"},{"id":89310571,"identity":"18be1891-f436-4a26-ab13-459c7f569bc4","added_by":"auto","created_at":"2025-08-18 16:08:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3150810,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5396906/v1/22657f81-34ed-47e8-a2f3-48c82304ec35.pdf"}],"financialInterests":"Competing interest reported. P.N.G., D.W., S.B., and K.D. are employees of Akebia Therapeutics, Inc., and A.C. is a former employee of Akebia Therapeutics, Inc.","formattedTitle":"Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Patients With Anemia Associated With Chronic Kidney Disease Receiving Hemodialysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnemia is a frequent complication in patients with chronic kidney disease (CKD). Anemia may develop early in the course of CKD but its severity increases with the decline of renal function [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although the pathogenesis of anemia in CKD is multifactorial, deficiency of erythropoietin (EPO) production is a predominant cause, as the kidneys are unable to secrete sufficient EPO to support erythropoiesis and maintain hemoglobin within normal ranges [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The current standard of care for the treatment of anemia in CKD is use of erythropoiesis-stimulating agents (ESAs) alone or in combination with iron supplementation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, ESAs are associated with increased risk of cardiovascular and thromboembolic events [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, ESAs require parenteral administration and refrigeration. Thus, oral treatment modalities for anemia associated with CKD may be beneficial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are an oral treatment alternative for patients with CKD-related anemia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. HIF-PHIs have been shown to stabilize HIF, a transcription factor that regulates hypoxia-sensitive genes, stimulating EPO production, with a resultant increase in red blood cell (RBC) production as well as improved iron uptake and utilization [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e Vadadustat, an orally bioavailable HIF-PHI, is approved in 37 countries globally for the treatment of CKD-related anemia in dialysis-dependent (DD) patients. It has a starting dose of 300 mg once daily and dose titration in increments or decrements of 150 mg within the range of 150 to 600 mg to achieve or maintain hemoglobin levels within the clinical target range [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In Japan, vadadustat is approved in both non\u0026ndash;DD (NDD)-CKD and DD-CKD populations [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn previous clinical studies, vadadustat has been shown to maintain and increase mean hemoglobin levels within prespecified physiological target ranges [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In addition, vadadustat has been shown to increase endogenous EPO production, improve iron availability, and increase circulating reticulocytes in patients with CKD and anemia [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEarly clinical studies have shown that vadadustat is primarily metabolized through glucuronidation, resulting in vadadustat-O-glucuronide. In healthy individuals, vadadustat and its main metabolite are eliminated from the body through both renal and fecal routes. Vadadustat has also exhibited dose-proportional kinetics and rapid absorption, with a median time to maximum concentration (T\u003csub\u003emax\u003c/sub\u003e) of 3 to 4 hours for doses ranging from 80 to 1200 mg. Vadadustat plasma half-life (t\u003csub\u003e1/2\u003c/sub\u003e) is around 4 to 5 hours [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, in patients with CKD stages 3 and 4 who are not yet on dialysis, there was a modest increase in t\u003csub\u003e1/2\u003c/sub\u003e from 4.2 hours to 7.9 hours, and a decrease in oral clearance (CL/F) from 1.5 L/h to 1.0 L/h [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Here, we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher daily doses of vadadustat (600, 750, and 900 mg) in patients with CKD who are receiving dialysis. Treatment with vadadustat was compared with an active control group in which patients continued their current ESA treatments of either intravenous (IV) darbepoetin alfa or epoetin alfa.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eTrial design\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis was a phase 1b, randomized, open-label study to evaluate the pharmacokinetics and pharmacodynamics of vadadustat 600, 750, or 900 mg daily in patients with CKD-related anemia receiving hemodialysis conducted in the United States between June 2019 and May 2020. The study included a 28-day Screening and Randomization period, a 10-day Treatment Period, and a 30-day Safety Follow-up Period after the last dose of study drug. Eligible patients were randomized 2:2:2:1 to vadadustat 600, 750, 900 mg daily, or IV ESA, respectively. For patients randomized to vadadustat, study duration also included a minimum 5- or 9-day ESA washout period prior to dosing on Day 1 (\u003cstrong\u003eFig. 1\u003c/strong\u003e). Vadadustat was provided as 150 mg white or off-white round bi-convex film-coated tablets for oral administration.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy population \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients eligible for this study were aged \u0026ge;18 years at the time of informed consent confirmation and had stable baseline hemoglobin values between 8.5 and 10.5 g/dL based on 2 average values obtained within 28 days prior to randomization. Study participants were required to be on a stable 3 times weekly hemodialysis regimen, with adequate dialysis clearance defined as a single-pool Kt/Vurea of \u0026ge;1.2 for at least 12 weeks prior to screening. \u0026ldquo;K\u0026rdquo; is dialyzer urea clearance, \u0026ldquo;t\u0026rdquo; is total dialysis session time, and \u0026ldquo;V\u0026rdquo; is volume of distribution of urea, which is approximately equal to total body water. Study participants were also required to be maintained on IV ESA therapy with a mean dose of \u0026lt;1.5 \u0026mu;g/kg/week for darbepoetin alfa, or mean dose of \u0026lt;300 U/kg/week for epoetin alfa) for 8 weeks prior to randomization. Patients were ineligible for the study if they had an RBC transfusion within 8 weeks prior to randomization. Patients with low values of ferritin (\u0026lt;100\u0026thinsp;ng/mL) or transferrin saturation (\u0026lt;20%) were also ineligible. Additional exclusion criteria included a planned change in dialysis modality or renal transplant within the study period; significant cardiovascular, hematologic, hepatic, or chronic inflammatory disease; active or recent gastrointestinal (GI) bleeding, history of new or recurrent malignancy within 2 years prior to screening, or currently receiving treatment or suppressive therapy for cancer.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVadadustat pharmacokinetic assessments\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor each vadadustat treatment group, blood samples for vadadustat PK analysis were collected pre-dose and at 1, 2, 3, 4, 5, 8, 11, and 24 hours post-dose on Day 1 and at pre-dose and at 1, 2, 3, 4, 5, 8, and 11 hours post-dose on Day 8. Primary endpoints were area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration (AUC\u003csub\u003e0-last\u003c/sub\u003e) and to infinity (AUC\u003csub\u003e0-inf\u003c/sub\u003e), as well as maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e). Additional PK parameters included T\u003csub\u003emax\u003c/sub\u003e, clearance (CL), volume of distribution (Vd), and elimination half-life (t\u003csub\u003e\u0026frac12;\u003c/sub\u003e).\u003c/p\u003e\n\u003cp\u003ePK parameters were calculated using an SAS\u0026reg; program (SAS Institute Inc.), which followed the same algorithm as that implemented in WinNonlin\u0026reg; Professional (Version 7.0, Pharsight Corporation, a Certara Company) using the PK population (all patients completing the study without any protocol deviation[s] that would impact the PK profile characterization). Additionally, the SAS results were validated using the parameters generated from WinNonlin 7.0. C\u003csub\u003emax\u003c/sub\u003e and T\u003csub\u003emax\u003c/sub\u003e were determined directly from the concentration time profiles. For AUC calculations, the entire 24-hour sampling period was included for calculating PK parameters on Day 1 using the linear up log down calculation method. AUC\u003csub\u003e0-last\u003c/sub\u003e is equivalent to AUC from time 0 to 24 hours (AUC\u003csub\u003e0-24\u003c/sub\u003e) on Day 1. The pre-dose sample obtained on Day 8 was used as the 24-hour time point on the same day for calculating the AUC\u003csub\u003e0-24\u0026nbsp;\u003c/sub\u003e(which is equivalent to AUC\u003csub\u003einf\u003c/sub\u003e) under the assumption that vadadustat had reached steady state by that day.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePharmacodynamic assessments\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor each vadadustat treatment group, blood samples for EPO analysis were collected at pre-dose and at 1, 2, 3, 4, 5, 8, 11, and 24 hours post-dose on Day 1 and at pre-dose and at 1, 2, 3, 4, 5, 8, and 11 hours post-dose on Day 8. Blood samples for other PD biomarkers, hemoglobin, and RBC were collected at pre-dose on Days 1, 6, 8, 10, and 12 (follow-up visit). Reticulocyte samples were collected on Days 1, 6, 8, and 10. PD biomarker concentrations were summarized by dose level and by dosing day using descriptive statistics and graphical displays citing the PK population. For the ESA treatment group, blood samples for analysis of EPO were collected at Day 1 at pre-dose, and 0.25, 1, 2, 3, 4, 5, 8, 11, and 24 hours post-dose.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBioanalysis of samples\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe concentration measurements of vadadustat were performed by a validated liquid chromatography-mass spectrometry/mass spectrometry method at Syneos Health Clinic (Quebec, Canada). The EPO measurements were performed by the enzyme-linked immunosorbent assay method at Q2 Solutions (Marietta, GA). Other PD endpoints (reticulocytes, RBC, and hemoglobin) were tested at the central lab facility (ACM Medical Laboratory, Rochester, NY) using existing validated methods. All study samples were analyzed within analytical runs that complied with the acceptance ranges for the quality control samples and were completed within the known period of analyte stability.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSafety assessment\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSafety assessments included adverse events (AEs), vital signs, clinical laboratory values, and physical examinations in the safety population (all patients who received at least 1 dose of study drug). An AE that started during the treatment period or up to 30 days after the last dose of study drug was considered a treatment-emergent AE (TEAE) if it was not present prior to the first dose of study drug, or it was present prior to the first dose of study drug but increased in severity during the treatment period or up to 30 days after the last dose of study drug. AEs of special interest were also assessed, including, but not limited to, malignancy, elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver enzymes greater than 3 times the upper limit of normal, and pulmonary hypertension. All AEs were coded using Medical Dictionary for Regulatory Activities Version 23.0.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eTrial population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA summary of patient demographic characteristics is provided for the randomized population in \u003cstrong\u003eTable 1\u003c/strong\u003e. The treatment groups were well balanced regarding mean age, ethnicity, race, sex, height, and weight, among all vadadustat groups and IV ESA treatment groups. This was similar for the safety and PK populations (data not shown). In the 750-mg dose group, 1 patient had inadvertent ESA administration and another patient had the entire concentration profile below quantitation limit for every vadadustat PK sample and therefore, these 2 patients were excluded from the PK population.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePharmacokineti\u003c/em\u003e\u003cem\u003ec results\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePlasma concentration-time profiles of vadadustat after oral administration are shown in \u003cstrong\u003eFig. 2.\u003c/strong\u003e After the first day of dosing, a rise in vadadustat exposure was observed, measured by AUC, that corresponded with an increase in dose. This dose-dependent increase was consistently seen on both Day 1 and Day 8, as evidenced by the elevated C\u003csub\u003emax\u003c/sub\u003e and AUC values. Mean values of C\u003csub\u003emax\u003c/sub\u003e and AUC\u003csub\u003e0-24\u0026nbsp;\u003c/sub\u003ewere higher on Day 8 compared with Day 1, indicating minimal accumulation of vadadustat; ratios for Day 8/Day 1 of mean C\u003csub\u003emax\u003c/sub\u003e values ranged from 1.27 to 1.45, and ratios of mean AUC\u003csub\u003e0-24\u0026nbsp;\u003c/sub\u003evalues ranged from 1.39 to 1.84, with the 900-mg dose having the highest ratios. Mean apparent total body clearance (CL/F) values for each dose on Day 8 were similar, indicating dose-proportional pharmacokinetics following multiple doses. The median T\u003csub\u003emax\u003c/sub\u003e of vadadustat was between 2.0 and 3.0 hours, and appeared to be similar across the 600-, 750-, and 900-mg vadadustat treatment groups when measured on Day 1 and Day 8 during dialysis (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMean concentrations of vadadustat-OG (the major vadadustat metabolite which is an inactive and nontoxic) increased with time on Day 1 for all vadadustat groups, but no substantial difference across dose groups was observed (\u003cstrong\u003eFig. 3\u003c/strong\u003e). However, an initial decline in vadadustat-OG concentration was observed at the early time points on Day 8 (\u003cstrong\u003eFig. 3\u003c/strong\u003e). Based on a comparison of mean Day 1, 24-hour post-dose, to pre-dose on Day 8, vadadustat-OG concentrations appeared to have increased 2.5- to 3.5-fold with multiple dosing in patients with DD-CKD (\u003cstrong\u003eFig. 3\u003c/strong\u003e). Vadadustat-OG PK parameters are shown in \u003cstrong\u003eTable 3\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePharmacodynamics results:\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eVadadustat increased plasma EPO concentrations in all participants, but a variable EPO response was observed in each dosing group (\u003cstrong\u003eFig. 4\u003c/strong\u003e). Following Day 1 dosing, the highest EPO increase was observed in the 750-mg vadadustat treatment group. There was a \u0026gt;4-fold increase in peak EPO relative to the baseline in the 600- and 750-mg dosing groups on the first day. This contrasts with the 900-mg dosing group, where the EPO increase was just over 2-fold. EPO levels reached their peak 11 hours post-dose in all dosage groups. Following additional doses of vadadustat on Day 8, there was a \u0026gt;5-fold increase in the 750-mg group, contrasting with the 4-fold increase observed in the 600- and 900-mg groups. As depicted in \u003cstrong\u003eFig. 5\u003c/strong\u003e, there was a 100-fold increase in EPO levels in the ESA group.\u003c/p\u003e\n\u003cp\u003eIn relation to other PD parameters (\u003cstrong\u003eFig. 6\u003c/strong\u003e), all vadadustat dose groups showed an approximately 2-fold increase in mean reticulocyte count on Day 5, which continued to rise through the final on-treatment assessment 9 days after the initial dose, yet there was no significant difference observed among the various doses. In contrast, the reticulocyte count exhibited minimal change in the group receiving the ESA treatment (\u003cstrong\u003eFig. 6\u003c/strong\u003e). Mean hemoglobin and RBC levels remained unchanged relative to baseline, and no significant changes were observed in both the vadadustat and ESA treatment groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSafety and tolerability\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the vadadustat treatment groups, 20 TEAEs were reported by 11 patients, while no TEAEs were reported in the ESA treatment group (\u003cstrong\u003eTable 4\u003c/strong\u003e). At least 1 TEAE was experienced by 3 (25.0%), 3 (25.0%), and 5 (38.5%) patients in the vadadustat 600-, 750-, and 900-mg treatment groups, respectively. One patient in each of the groups experienced a drug-related TEAE, and a treatment-emergent serious AE was reported by 1 patient in both the vadadustat 600- and 750-mg treatment groups. In the 600-mg vadadustat treatment group, a TEAE of nausea was considered drug related but nonserious. In the 750-mg vadadustat treatment group, 1 patient experienced decreased appetite and later showed elevations in ALT/AST enzymes, which was considered to be drug related. However, there were no associated symptoms with the elevated liver function tests and no abnormal values of bilirubin or alkaline phosphatase were observed during this period. In the 900-mg group, a TEAE of diarrhea was considered drug related but nonserious. All TEAEs reported in the vadadustat treatment groups were either mild or moderate in intensity, and there were no TEAEs leading to treatment discontinuation or death. Diarrhea was experienced by 3 patients in the vadadustat treatment groups (2 in the 750-mg group and 1 in the 900-mg group). No other TEAE was experienced by \u0026gt;1 patient in the vadadustat treatment group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVadadustat is an orally administered HIF-PHI that has been developed to treat anemia associated with CKD [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Pivotal phase 3 trials included a vadadustat starting dose of 300 mg with a maximum dose of 600 mg [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Here, we report a phase 1b study with a goal to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of vadadustat 600, 750, or 900 mg daily in DD-CKD. An active control group continued prior treatment with IV darbepoetin alfa or epoetin.\u003c/p\u003e \u003cp\u003eVadadustat exhibited a dose-dependent increase in AUC, but consistently similar CL/F values across doses, a result that aligns with prior findings [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The C\u003csub\u003emax\u003c/sub\u003e and AUC ratios for vadadustat on Day 8 vs Day 1 were \u0026lt;\u0026thinsp;2, indicating modest accumulation of the parent drug. An initial decrease in vadadustat-OG concentration was observed on Day 8 in the first 4 hours after dosing. These findings are consistent with the delay of formation of the metabolite and its accumulation in plasma in DD-CKD patients. Previous studies have indicated that vadadustat was detected in the urine as vadadustat-OG in healthy volunteers; however, it appears that there are multiple simultaneous elimination pathways in patients with CKD, aligning with nonclinical absorption, distribution, metabolism, and excretion data that propose a combination of renal and hepatic routes for the elimination of vadadustat.\u003c/p\u003e \u003cp\u003eVadadustat triggered a variable EPO response. After the first day of dosing, the most significant increase in EPO was observed in the group treated with 750 mg of vadadustat, primarily due to a single-patient surge in EPO levels. The data suggest that there was no clear dose-response relationship in EPO levels following vadadustat treatment. As expected, there was a much larger increase in EPO after IV ESA administration.\u003c/p\u003e \u003cp\u003eAll vadadustat dose groups showed a continuous increase in the mean reticulocyte count until the end of treatment; this result is consistent with previous findings [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Despite this trend, there were no significant differences observed among doses due to the variability of the data. Conversely, in the ESA-treated group, there were no significant changes in the reticulocyte count. This can be attributed to the absence of a washout period in this group, which suggests there was no restimulation of reticulocyte production, unlike in the vadadustat treatment groups. Mean hemoglobin and RBC concentrations did not show clinically meaningful changes in any of the vadadustat or ESA groups during the 10-day treatment due to the short treatment duration.\u003c/p\u003e \u003cp\u003eThe primary TEAEs in the vadadustat groups, primarily GI related, could be attributed to the use of an oral dosage form (vadadustat) compared with an injectable ESA. There were no deaths or discontinuations from study treatment due to AEs.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study characterizes the exposure, biomarker response, and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. This marks the first instance of the higher doses, specifically 750 and 900 mg, being explored within a patient population. These findings will contribute to the development of higher-dose regimens for further investigation in clinical studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAEs, adverse events\u003c/p\u003e\n\u003cp\u003eALT, alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eAUC, area under the plasma concentration time curve\u003c/p\u003e\n\u003cp\u003eAUC\u003csub\u003e0-last\u003c/sub\u003e, AUC from dosing to last quantifiable concentration\u003c/p\u003e\n\u003cp\u003eAUC\u003csub\u003e0-inf\u003c/sub\u003e, AUC from dosing to infinity\u003c/p\u003e\n\u003cp\u003eAUC\u003csub\u003e0-24\u003c/sub\u003e, time 0 to 24 hours\u003c/p\u003e\n\u003cp\u003eAUC\u003csub\u003etau\u003c/sub\u003e, AUC to the end of the dosing period\u003c/p\u003e\n\u003cp\u003eAST, aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003eCKD, chronic kidney disease\u003c/p\u003e\n\u003cp\u003eCL/F, oral clearance\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration\u003c/p\u003e\n\u003cp\u003eDD, dialysis-dependent\u003c/p\u003e\n\u003cp\u003eEPO, erythropoietin\u003c/p\u003e\n\u003cp\u003eESA, erythropoiesis-stimulating agent\u003c/p\u003e\n\u003cp\u003eGI, gastrointestinal\u003c/p\u003e\n\u003cp\u003eHIF-PHI, hypoxia-inducible factor prolyl hydroxylase inhibitor\u003c/p\u003e\n\u003cp\u003eIV, intravenous\u003c/p\u003e\n\u003cp\u003eKt/Vurea, \u0026apos;K\u0026apos; is dialyzer urea clearance, \u0026apos;t\u0026apos; is total dialysis session time, and \u0026apos;V\u0026apos; is volume of distribution of urea\u003c/p\u003e\n\u003cp\u003eNDD, non-dialysis-dependent\u003c/p\u003e\n\u003cp\u003ePD, pharmacodynamic\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePK, pharmacokinetic\u003c/p\u003e\n\u003cp\u003eRBC, red blood cell\u003c/p\u003e\n\u003cp\u003et\u003csub\u003e1/2\u003c/sub\u003e,\u003csub\u003e\u0026nbsp;\u003c/sub\u003ehalf-life\u003c/p\u003e\n\u003cp\u003eTEAE, treatment-emergent adverse event\u003c/p\u003e\n\u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e, time to maximum concentration\u003c/p\u003e\n\u003cp\u003eVd, volume of distribution\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the protocol, ethical principles of the Declaration of Helsinki, Good Clinical Practice, and International Conference on Harmonisation guidelines, as well as all other applicable regulations. Prior to study implementation, investigators obtained approval from a central institutional review board (IRB; Advarra IRB, Columbia, MD) except for one site that required a local IRB (Committee on the Protection of Human Subjects, Providence, RI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe purpose and nature of the study, as well as the possibility of adverse effects, were explained to study participants in understandable, plain language terms, and written informed consent was obtained from each participant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProposal requests for access to original data should be sent to [email protected]. Deidentified patient-level data will be available 12 months after US and EU approval to qualified researchers with an appropriate research proposal. The research proposal is subject to review by an IRB with final approval by Akebia Therapeutics, Inc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;P.N.G., D.W., S.B., and K.D. are employees of Akebia Therapeutics, Inc., and A.C. is a former employee of Akebia Therapeutics, Inc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was funded by Akebia Therapeutics, Inc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to data interpretation and manuscript review. A.C. and S.B. were responsible for the study design. D.W. conducted the statistical analysis of the data. K.D. and P.N.G. wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical writing assistance was provided by Syneos Health Medical Communications, LLC, and supported by Akebia Therapeutics, Inc.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS One. 2014;9(1):e84943. \u003c/li\u003e\n\u003cli\u003eH\u0026ouml;rl WH. Anaemia management and mortality risk in chronic kidney disease. Nat Rev Nephrol. 2013;9(5):291.\u003c/li\u003e\n\u003cli\u003eBabitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23:1631-34. https://doi.org/10.1681/ASN.2011111078\u003c/li\u003e\n\u003cli\u003eKDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2(4). \u003c/li\u003e\n\u003cli\u003eMcCullough PA, Barnhart HX, Inrig JK, et al. Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. Am J Nephrol. 2013;37(6):549-58.\u003c/li\u003e\n\u003cli\u003eFishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol. 2007;2(6):1274-82.\u003c/li\u003e\n\u003cli\u003eBonomini M, Del Vecchio L, Sirolli V, Locatelli F. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67(1):133-42.\u003c/li\u003e\n\u003cli\u003eNova Scotia Health Authority. Patient and Family Guide 2020. Erythropoiesis-Stimulating Agent (ESA) Therapy and Chronic Kidney Disease (CKD). https://www.nshealth.ca/sites/default/files/documents/pamphlets/1493.pdf. Accessed 22 August 2024.\u003c/li\u003e\n\u003cli\u003eGauthier-Loiselle M, Michalopoulos SN, Cloutier M, Serra E, Bungay R, Szabo E, et al. Costs associated with the administration of erythropoiesis-stimulating agents for the treatment of anemia in patients with non-dialysis-dependent chronic kidney disease: a US societal perspective. J Manag Care Spec Pharm 2021;27:1703-13. \u003c/li\u003e\n\u003cli\u003eBonomini M, Del Vecchio L, Sirolli V, Locatelli F. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67:133-42.\u003c/li\u003e\n\u003cli\u003eMaxwell PH, Eckardt K-U. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12(3):157.\u003c/li\u003e\n\u003cli\u003eChertow GM, Pergola PE, Farag YMK, Agarwal R, Arnold S, Bako G, et al; PRO\u003csub\u003e2\u003c/sub\u003eTECT Study Group. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med. 2021;384(17):1589-1600. \u003c/li\u003e\n\u003cli\u003eEckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384(17):1601-12. \u003c/li\u003e\n\u003cli\u003eMarkham A. Vadadustat: first approval. Drugs. 2020;80;1365-71. \u003c/li\u003e\n\u003cli\u003eAkebia Therapeutics, Inc. Akebia Therapeutics announces approval of vadadustat in Japan for the treatment of anemia due to chronic kidney disease in dialysis-dependent and non-dialysis dependent adult patients. Press release 29 June 2020. https://ir.akebia.com/news-releases/news-release-details/akebia-therapeutics-announces-approval-vadadustat-japan (2020). Accessed 19 August 2024.\u003c/li\u003e\n\u003cli\u003ePergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016;90(5):1115-22.\u003c/li\u003e\n\u003cli\u003eHaase VH, Chertow GM, Block GA, et al. Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents. Nephrol Dial Transplant. 2019;34(1):90-9. \u003c/li\u003e\n\u003cli\u003eKoury MJ, Agarwal R, Chertow GM, Eckardt KU, Fishbane S, Ganz T, et al. Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease. Am J Hematol. 2022;97(9):1178-88. \u003c/li\u003e\n\u003cli\u003eChavan A, Burke L, Sawant R, Navarro-Gonzales P, Vargo D, Paulson SK. Effect of moderate hepatic impairment on the pharmacokinetics of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. Clin Pharmacol Drug Dev. 2021;10(8):950-8.\u003c/li\u003e\n\u003cli\u003eNavarro-Gonzales P, Ganz T, Pergola PE, Zuk A, Dykstra K. Pharmacokinetics, pharmacodynamics, and safety of vadadustat in healthy volunteers and patients with chronic kidney disease. Clin Pharmacol Ther. 2024;116(4):1052-1061. doi: 10.1002/cpt.3342. Epub 2024 Jun 25.\u003c/li\u003e\n\u003cli\u003eMartin ER, Smith MT, Maroni BJ, Zuraw QC, deGoma EM. Clinical trial of vadadustat in patients with anemia secondary to stage 3 or 4 chronic kidney disease. Am J Nephrol. 2017;45(5):380-8.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Summary of demographic characteristics (randomized population)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" style=\"width: 624px;\" width=\"624\" height=\"808\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eOne time per week. \u003csup\u003eb\u003c/sup\u003eThree times per week.\u003c/p\u003e\n\u003cp\u003eIV ESA: darbepoetin alfa or epoetin alfa; 6 patients were dosed with epoetin alfa, and 1 patient was dosed with darbepoetin alfa.\u0026nbsp;\u003cbr\u003e\u0026nbsp;ESA, erythropoiesis-stimulating agent; IV, intravenous.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSummary of pharmacokinetic parameters for plasma vadadustat concentration for vadadustat treatment groups\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 0px;\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003cp\u003e(Unit)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 0px;\"\u003e\n \u003cp\u003eStatistic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 0px;\"\u003e\n \u003cp\u003eVadadustat 600 mg\u003cbr\u003e\u0026nbsp;N=12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 0px;\"\u003e\n \u003cp\u003eVadadustat 750 mg\u003cbr\u003e\u0026nbsp;N=10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 0px;\"\u003e\n \u003cp\u003eVadadustat 900 mg\u003cbr\u003e\u0026nbsp;N=13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC\u003csub\u003emax\u003c/sub\u003e, (\u0026mu;g/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e62.9 (21.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e80.9 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e67.5 (27.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e85.5 (24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e88.7 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e129 (65.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003csub\u003e0-24\u003c/sub\u003e,\u003csub\u003e\u0026nbsp; \u0026nbsp;\u003c/sub\u003e(h\u0026middot;\u0026mu;g/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e679\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(174.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e947\u003c/p\u003e\n \u003cp\u003e(440.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e779\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(398.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1099 (263.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e968 (331.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1781 (1197)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003et\u003csub\u003e1/2\u0026nbsp;\u003c/sub\u003e(h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10.4 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e12.2 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e9.9 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e16.4 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e12.6 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e21.7 (26.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT\u003csub\u003emax\u0026nbsp;\u003c/sub\u003e(h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMedian (min, max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e3.0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.0, 5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2.0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.0, 5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e3.0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.0, 23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e3.0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.0, 8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e3.1\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.0, 8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e3.0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(1.0, 4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCL/F (L/h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.8 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.7 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1.3 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.7 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1.0 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.8 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVd/F (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e9.8 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e11.8 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e14.0 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e16.9 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e12.8 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e13.2 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eDay 8 included samples collected from pre-dose to 11 hours post-dose of Day 8 to calculate C\u003csub\u003emax\u003c/sub\u003e and T\u003csub\u003emax\u003c/sub\u003e. In addition, Day 8 pre-dose was considered as a result for the 24-hour time point to calculate AUC\u003csub\u003e0-24\u003c/sub\u003e, t\u003csub\u003e1/2\u003c/sub\u003e, CL/F, and Vd/F.\u0026nbsp;\u003cbr\u003eAUC\u003csub\u003e0-24\u003c/sub\u003e, area under concentration-time curve from time 0 to 24 hours; CL/F, oral clearance; C\u003csub\u003emax\u003c/sub\u003e, maximum observed plasma concentration; t\u003csub\u003e1/2\u003c/sub\u003e, half-life; T\u003csub\u003emax\u003c/sub\u003e,\u0026nbsp;time to maximum concentration; Vd/F,\u0026nbsp;volume of distribution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSummary of pharmacokinetic parameters for plasma vadadustat-OG concentration for vadadustat treatment groups\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19px;\"\u003e\n \u003cp\u003eParameter (Unit)\u003c/p\u003e\n \u003cp\u003eStatistic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 26px;\"\u003e\n \u003cp\u003eVadadustat 600 mg\u003cbr\u003e\u0026nbsp;N=12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 26px;\"\u003e\n \u003cp\u003eVadadustat 750 mg\u003cbr\u003e\u0026nbsp;N=10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 26px;\"\u003e\n \u003cp\u003eVadadustat 900 mg\u003cbr\u003e\u0026nbsp;N=13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC\u003csub\u003emax\u003c/sub\u003e (\u0026mu;g/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e23.2 (16.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e53.6 (43.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e25.5 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e68.1 (37.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e23.5 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e72.3 (42.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003csub\u003e0-24\u0026nbsp;\u003c/sub\u003e(h\u0026middot;\u0026mu;g/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e357 (180.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1050 (960.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e362 (132.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1143 (525.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e382 (85.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1196 (604.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT\u003csub\u003emax\u0026nbsp;\u003c/sub\u003e(h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e23.1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e23.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e11.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMin, Max\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10.0, 23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.0, 10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e5.0, 23.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.0, 10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10.0, 23.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.0, 11.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eDay 1 included the entire 24-hour sampling period. Day 8 included samples collected from pre-dose to 11 hours post-dose of Day 8 to calculate C\u003csub\u003emax\u003c/sub\u003e and T\u003csub\u003emax\u003c/sub\u003e. In addition, Day 8 pre-dose was considered as result for the 24-hour time point to calculate AUC\u003csub\u003e0-24\u003c/sub\u003e, and t\u003csub\u003e1/2\u003c/sub\u003e. AUC\u003csub\u003e0-24\u0026nbsp;\u003c/sub\u003ecorresponded to AUC\u003csub\u003etau\u003c/sub\u003e, AUC\u003csub\u003elast\u003c/sub\u003e, and AUC\u003csub\u003einf\u003c/sub\u003e on Day 8.\u0026nbsp;\u003cbr\u003eAUC\u003csub\u003e0-24\u003c/sub\u003e, area under concentration-time curve from time 0 to 24 hours; AUC\u003csub\u003einf\u003c/sub\u003e, AUC from dosing to infinity; AUC\u003csub\u003elast\u003c/sub\u003e, AUC from dosing to last quantifiable concentration; AUC\u003csub\u003etau\u003c/sub\u003e, AUC to end of the dosing period; C\u003csub\u003emax\u003c/sub\u003e, maximum observed plasma concentration; T\u003csub\u003emax\u003c/sub\u003e,\u0026nbsp;time to maximum concentration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Overall summary of treatment-emergent adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003eCategory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eVadadustat 600 mg\u003c/p\u003e\n \u003cp\u003eN=12\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eVadadustat 750 mg\u003c/p\u003e\n \u003cp\u003eN=12\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eVadadustat 900 mg\u003c/p\u003e\n \u003cp\u003eN=13\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eVadadustat Total\u003c/p\u003e\n \u003cp\u003eN=37\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eIV ESA\u003c/p\u003e\n \u003cp\u003eN=7\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003eNumber of TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003ePatients with any TEAEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e3 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e5 (38.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e11 (29.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003ePatients with any drug-related TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e3 (8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003ePatients with any severe TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003ePatients with any treatment‑emergent SAEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e2 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003ePatients with any TEAEs leading to study treatment discontinuation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003ePatients with any TEAEs leading to death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIV ESA: darbepoetin alfa or epoetin alfa. A TEAE was an AE that began (or a pre-existing AE that worsened) after receiving study drug and within 30 days of the last dose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eESA, erythropoiesis-stimulating agent; IV, intravenous; SAEs, serious adverse events; TEAEs, treatment-emergent adverse events.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"vadadustat, HIF-PHI, phase 1, pharmacokinetics, pharmacodynamics, safety","lastPublishedDoi":"10.21203/rs.3.rs-5396906/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5396906/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eVadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia in dialysis-dependent chronic kidney disease (CKD) with a starting dose of 300 mg once daily (dose adjustments up to 600 mg). A recent phase 1b study evaluated the pharmacokinetics, pharmacodynamics, and safety of higher vadadustat doses (500\u0026ndash;900 mg) in healthy volunteers. Here we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher doses of vadadustat in patients with CKD receiving dialysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis phase 1b, randomized, open-label study evaluated the pharmacokinetics and pharmacodynamics of vadadustat (600, 750, or 900 mg) in patients with CKD-related anemia receiving hemodialysis over a 10-day treatment period. Eligible patients were randomized 2:2:2:1 to vadadustat 600, 750, 900 mg daily or an intravenous erythropoiesis-stimulating agent, respectively. For vadadustat groups, blood samples for PK and PD analyses were collected on Day 1 and Day 8. PK analyses included area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration and to infinity, and to maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e). PD analyses measured serum erythropoietin (EPO), hemoglobin, and red blood cells (RBCs). Safety assessments included adverse events in the safety population (patients who received \u0026ge;1 dose of study drug).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the vadadustat groups, a dose-dependent increase in plasma exposure of vadadustat (C\u003csub\u003emax\u003c/sub\u003e and AUC), with modest accumulation, was observed on Day 1 and Day 8. Vadadustat increased plasma EPO concentrations, with a variable EPO response observed in each group. Relative to baseline, mean hemoglobin and RBC levels remained unchanged, with no significant changes observed in any treatment group. Vadadustat was well-tolerated.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe current study characterized the PK and PD response (EPO and reticulocytes) and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. Overall, vadadustat was well tolerated. These findings will contribute to the development of higher-dose regimens for further investigation in phase 3 studies.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov ID NCT03992066; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/study/NCT03992066\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/study/NCT03992066\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; Updated September 9, 2020. Accessed November 22, 2024.\u003c/p\u003e","manuscriptTitle":"Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Vadadustat in Patients With Anemia Associated With Chronic Kidney Disease Receiving Hemodialysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-15 12:13:31","doi":"10.21203/rs.3.rs-5396906/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-13T13:54:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-13T13:28:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-13T13:28:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2024-11-05T16:00:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2dd46bbb-38c4-4ccc-86b5-393bcde8fb8c","owner":[],"postedDate":"January 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-18T16:02:40+00:00","versionOfRecord":{"articleIdentity":"rs-5396906","link":"https://doi.org/10.1186/s12882-025-04367-x","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-08-11 15:57:55","publishedOnDateReadable":"August 11th, 2025"},"versionCreatedAt":"2025-01-15 12:13:31","video":"","vorDoi":"10.1186/s12882-025-04367-x","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04367-x","workflowStages":[]},"version":"v1","identity":"rs-5396906","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5396906","identity":"rs-5396906","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}