{"paper_id":"6a2371b9-b91f-4fe4-ae2d-51cd1fe9b578","body_text":"Open Journal of Obstetrics and Gynecology, 2024, 14, 779-789 \nhttps://www.scirp.org/journal/ojog \nISSN Online: 2160-8806 \nISSN Print: 2160-8792 \n \nDOI: 10.4236/ojog.2024.145064  May 24, 2024 779 Open Journal of Obstetrics and Gynecology \n \n \n \n \nPharmacokinetics and Bioequivalence of \nDienogest in Healthy Bangladeshi Female \nVolunteers: An Open-Label, Single-Dose, \nRandomized, Two-Way Crossover Study \nNusrat Mahmud1, Nafisa Ahamed2, Uttom Kumar Bhowmik3, Sabrina Akter Tushi3,  \nNayan Ghosh3, Nithon Chandra Sahana3, Arifa Akram4, Md. Alimur Reza3* \n1BIRDEM General Hospital, Dhaka, Bangladesh \n2Medical College for Women & Hospital, Dhaka, Bangladesh  \n3Novus Clinical Research Services Ltd., Dhaka, Bangladesh \n4National Institute of Laboratory Medicine & Referral Centre (NILMRC), Dhaka, Bangladesh \n \n \n \nAbstract \nBackground:  Dienogest is a potential treatment for pelvic pain associated \nwith endometriosis, a condition of significant concern in gynaecology. The \ncurrent study was conducted as a crossover -randomized bioequivalence as-\nsessment of two oral Dienogest 2 mg formulations, aiming to provide valu a-\nble insights for healthcare professionals and researchers in this field.  Objec-\ntive:  The primary aim of this research was to evaluate and compare the \npharmacokinetic characteristics of Dienogest 2 mg tablets. Dinogest (D i-\nenogest 2 mg) tablets, manufactured by Nuvista Pharma Limited in Bangl a-\ndesh, and Visanne (Dienogest 2 mg) tablets, manufactured by Bayer Pharma \nin Germany, w ere the test and reference formulations, respectively. \nMaterials \nand Method: The study was an open -label, balanced, randomized, two treat-\nments, two sequences, two periods, two-way crossover, laboratory blind, single \noral dose bioequivalence study conducted in healthy adult females under fast-\ning conditions. The study was carried out on 13 healthy, non -pregnant \nfemale \nsubjects, and all the subjects completed both study periods with a 15 -day wa-\nshout in between. Randomization was used to assign the test and reference \nformulations to the subjects.\n Following each oral administration, a series of \nblood samples were ob tained at different time intervals from pre -dose to 72 \nhours post-dose and analyzed for Dienogest concentrations using a validated \nbio-analytical method. A standard non- compartmental model was used to \nanalyze the pharmacokinetic parameters. The primary pharmacokinetic p a-\nrameters were peak plasma drug concentration (C max), the area under the \nHow to cite this paper: Mahmud, N., \nAhamed, N., Bhowmik , U.K., Tushi , S.A., \nGhosh, N., Sahana,  N.C., Akram , A. and \nReza, M.A. (2024) Pharmacokinetics and \nBioequivalence of Dienogest in Healthy Ban-\ngladeshi Female Volunteers: An Open-Label, \nSingle-Dose, Randomized, Two -Way Cro s-\nsover Study. Open Journal of Obstetrics and \nGynecology, 14, 779-789. \nhttps://doi.org/10.4236/ojog.2024.145064 \n \nReceived:  April 12, 2024 \nAccepted: May 21, 2024 \nPublished: May 24, 2024 \n \nCopyright © 2024 by author(s) and  \nScientific Research Publishing Inc. \nThis work is licensed under the Creative \nCommons Attribution International  \nLicense (CC BY 4.0). \nhttp://creativecommons.org/licenses/by/4.0/  \n  \nOpen Access\n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 780 Open Journal of Obstetrics and Gynecology \n \nplasma concentration-time curve from time zero to time t (AUC0–t), and AUC \nfrom t  = 0 to infinity (AUC 0–∞ ). The other PK parameters included time to \nreach Cmax (Tmax), terminal elimination rate constant (K el), and half -life (t1/2). \nResult:  The ratios and 90% CI for the geometric mean test/reference were \n95.53% (86.70% - 105.26%) for Cmax, 101.75% (95.42% - 108.49%) for AUC0−t, \nand 101.54% (95.59% % - 107.87%) for AUC 0−∞ . The formulations were bio e-\nquivalent sin ce the 90% CIs for the geometric mean test/reference ratios were \n80% to 125%, according to the predetermined range of US Food and Drug Ad-\nministration (FDA) requirements. Conclusion:  This single-dose investigation \nshows that the Dienogest test and reference formulations exhibited a rate and \ndegree of absorption that met the regulatory requirements for bioequivalence. \n \nKeywords \nDienogest, Bioequivalence Study, Endometriosis, Novus CRSL \n \n1. Introduction \nEndometriosis is a chronic, neuro -inflammatory condition defined as the deve l-\nopment of endometrial glands and stroma- like lesions outside of the uterus [1]  \n[2]. Endometriosis frequently exhibits symptoms (dysmenorrhea, deep dysp a-\nreunia, chronic pelvic pain, etc.) that overlap with other gastrointestinal and g y-\nnecologic conditions, making diagnosis m ore difficult [3] . Consequently, for \nmany of these women, the diagnosis of endometriosis can be difficult and leng-\nthy, and often, the delay results in a reduced qu ality of life [4] . Treatment co n-\nsists of the surgical removal of lesions and hormonal medication [5] . Endome-\ntriosis is estimated to affect 6%  - 10% of women of reproductive age [6]. Treat-\nment of endometriosis consists of either medical or surgical management [7] . \nThe surgical management of endometriosis is effective but has several contr o-\nversial features [8] . Endometriosis must be regarded as a chronic pain disorder \nwith a high recurrence rate, even after surgical removal [9]. \nSince endometriosis is essentially a hormonal disease, hormonal drug therapy \nis currently considered an essential and effective therapy [10] . Endometriosis has \nbeen treated with various hormones and medicines [11] . Specific medical ther a-\npies that are approved for the treatment of endometriosis include gonadotr o-\npin-releasing hormone (GnRH) agonists, danazol, the Combined Oral Contr a-\nceptive Pill (COCP), and certain progestins [12]. \nDienogest is a new generation of progestin that has become one of the most \nused drugs in all endometriosis phenotypes for long -term treatment [13]  [14]. \nAccording to the ESHRE (European Society of Human Reproduction and Embry-\nology) guidelines, progestins are primarily used as a first-line, long-term treatment \nthat is highly effective and acts on multiple sites of action [15]. Dienogest is almost \ncompletely absorbed and has a high oral bioavailability of more than 90% [16]. As \nit has a relatively short half- life of 10 hours, there is no risk of accumulation of \n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 781 Open Journal of Obstetrics and Gynecology \n \nthe drug in the body even after multiple dosages. Orally administered Dienogest \nis excreted through urine within 24 hours [17] . Its molecular formula is \nC20H25NO2, with a molecular weight of 311.4 g/mol [18] . Chemically, Dienogest \nis described as (17 α-cyanomethyl-17β-hydroxy-estra-4,9-dien-3-one [19]. Its \nstructural formula is displayed in Figure 1  [20].  \nPeak serum concentrations of approximately 47 nanograms per mL are \nreached about 1.5 hours after single ingestion [21]. \nBioequivalence studies play a crucial role in evaluating a drug ’s efficacy by \nproviding scientific evidence of therapeutic equivalence between different fo r-\nmulations. If two drugs are bioequivalent, they are expected to be the same for \nall intents. This study aims to investigate the bioequivalence of test formulations \nto reference formulations of Dienogest in healthy Bangladeshi female volunteers \nunder fasting conditions [22] . Demonstrating bioequivalence ensures the safety, \nefficacy, and affordability of generic medications, ultimately benefiting patients, \nhealthcare providers, and healthcare systems alike. \n2. Methods \n2.1. Study Centre and Study Period/Duration \nThe bioequivalence trial was conducted in 2023 at Novus Clinical Research Se r-\nvices Limited, a DGDA -approved Contract Research Organization (CRO) in \nDhaka, Bangladesh. The clinical stage of the study was performed from August \n29 to September 18, 2023, and the analytical stage from October 17 to October \n31, 2023. \n2.2. Ethical Consideration \nThe Bangladesh Medical Research Council (BMRC) of the National Research \nEthics Committee (NREC) reviewed and a pproved the study protocol and all \nstudy documentation on January 22, 2023 (Registration No.: 50730102022). The \nstudy was also approved by the Directorate General of Drug Administration \n(DGDA) on April 13, 2023 (Reference No.: DGDA/CTP-04/2016/8688). \nGood Clinical Practice, Good Laboratory Practice, Pharmaceutical Admini s-\ntration Law, and the Declaration of Helsinki (and its amendments) were all fo l-\nlowed during the experiment. \n \n \nFigure 1. Chemical structure of Dienogest. \n\n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 782 Open Journal of Obstetrics and Gynecology \n \n2.3. Identity of Investigational Products \nTable 1  summarises the investigational products that were used in the research \nprocedure. The doses of Dienogest used in this study were determined based on \nthe recommended dose for endometriosis [23]. \n2.4. Study Subjects \nA total of 27 healthy, adult, registered female volunteers were randomly selected \nfor screening from the registered volunteers of Novus Clinical Research Services \nLimited. Among them, 13 eligible subjects aged 18 to 45 years with a body mass \nindex between 18.5 and 29.99 kg/m 2 were included in the study. To confirm the \neligibility of volunteers, chest radiography, electrocardiography, and laboratory \ninvestigations su ch as CBC, Blood glucose, HbA1C, serum creatinine, SGPT, \nSGOT, Uric Acid, Urea, Lipid profile, routine urine examination, etc., were ca r-\nried out before 12 days of the first dosing. \nSubjects were excluded from the study if any abnormalities were found in \nclinical investigations. It was confirmed that the subjects recruited for the study \nmet inclusion and exclusion criteria. Each participant gave written informed \nconsent before the screening, and study -specific informed consent was obtained \nfrom each participating subject before check-in. \n2.5. Study Design \nThis study was performed under fasting conditions using a single -centre, ra n-\ndomized-sequence, single-dose, two-period, two-treatment crossover design. E l-\nigible subjects were randomized to one of the two dosi ng-order subgroups, T /R \nand R/T. SAS® (SAS Institute Inc., USA) was used to randomise. The subjects in \none sequence group were administered a single tablet of the test formulation \nwith 240 mL of water in the first period, and after a washout period, individuals \nreceived a single tablet of the  reference formulation in the second phase. The \nparticipants in the alternative sequence group received a reference tablet in the \nfirst period and a test tablet in the second period. The randomisation code was \nunder controlled access till the completion of  the analysis. The analysts were \nblinded to the sequence of administration of test and reference formulations \nthroughout the analysis procedures. \n \nTable 1. Identification of the experimental product (s). \nIMP details  Test product (T)  Reference product (R)  \nTrade Name Dinogest Visanne \nGeneric Name Dienogest Dienogest \nSpecification 2 mg/tablet 2 mg/tablet \nBatch/Lot No. 104223002 WEU6CF \nExpiry Date Dec’ 2024 Dec’ 2023 \nManufacturer Nuvista Pharma Ltd., Dhaka, Bangladesh Bayer Pharma, Germany \n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 783 Open Journal of Obstetrics and Gynecology \n \nSubjects were checked in the facility the day before the investigation ’s medica-\ntion was administered in each period to ensure an overnight fast of at least 10 \nhours. There was a 15 -day washout period between two consecutive dosing p e-\nriods of the study, which was conside red appropriate as per requirements by the \nFDA and the EMA [24]. \n2.6. Standard Meal and Fluid \nThe standard meal plan was identical for both study periods, and all in- house \nsubjects received it at 04.00 hours following dosing. Except for one hour before \nand one hour after dosage, subjects were allowed to drink any amount of water \nthey desired [25]. \n2.7. Blood Sampling \nVenous blood samples (5 mL) were collected from each subject approximately \n22 times through an indwelling cannula to assay. Dienogest from predo se to 72 \nhours postdose at preset time points (0.00 (pre -dose), 0.25, 0.50, 0.75, 1.00, 1.25, \n1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, \n48.00, and 72.00 hours) and placed in a K 2EDTA tube. Every plasma sample was \ncentrifuged for 10 minutes at 5 ˚C ± 3˚C at 3500 rpm. Two duplicate tubes co n-\ntaining evenly divided plasma were frozen at − 60˚C, one for testing and the ot h-\ner for backup. \n2.8. Safety Assessment \nClinical examination and vital sign measurements were carri ed out to monitor \nthe subjects’ safety at baseline and 1.00, 3.00, 5.00, 7.00, 9.00, 13.00, 26.00, 35.00, \n48.00, and 72.00 hours after the dose, as specified in the protocol. However, i n-\nvestigations such as CBC, Blood glucose, HbA1C, serum creatinine, SGPT, \nSGOT, Uric Acid, Urea, Lipid profile, routine urine examination, etc and phys i-\ncal examinations, including 12 -lead ECG and X -rays, were carried out at the \ntime of screening and after the trial. Any adverse effects (AEs) that happened \nduring the trial were tracked. Throughout the study, adverse events were ev a-\nluated for their severity, duration, and correlation with the study medication.  \n2.9. Analytical Method \nDienogest plasma concentrations were determined using a previously validated \nliquid chromatography-tandem mass spectrometry (LC -MS/MS) method. Pr o-\ntein precipitation was used to pretreat plasma samples. Chromatographic sep a-\nration was done at 40 ˚C using a Thermo Scientific Hypersil Gold column (4.6 ×  \n50 mm, 5.0 µm). The plasma linearity ranges from 1.000 ng/mL to 200.000 \nng/mL. The intra- assay %CV and accuracy (relative error) for Dienogest were \n1.30% to 6.22% and 99.5% to 110.2%, respectively, while the inter -assay %CV \nand accuracy were 3.34% to 4.87% and 103.6% to 107.4%. \nThe assay sequenc e was as follows: calibration standards of 1.000, 2.000, \n10.000, 20.000, 40.000, 80.000, 160.000, and 200.000 ng/L, volunteers ’ plasma \n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 784 Open Journal of Obstetrics and Gynecology \n \nsamples, and quality -control samples of 3.000, 25.000, 100.0, and 150.00 ng/L \nthroughout all sequences. \n2.10. Pharmacokinetic and Statistical Analyses \nPharmacokinetic parameters were calculated using WinNonlin software, and \nstatistical comparisons of pharmacokinetic parameters were carried out using \nSAS® statistical software (Version 9.4; SAS Institute Inc., USA). Pharmacoki netic \nprimary parameters like C max, AUC 0−t, and AUC 0−∞  and secondary parameters \nlike Tmax, t1/2, Kel, and AUCExtrapolation were determined for all the subjects who had \ncompleted both study periods. The two preparations will be bioequivalent if 90% \nConfidence Intervals (CI) for test/reference ratios of Cmax, AUC(0−t), and AUC(0−∞)  \nfall between the range of 80% and 125% [26] [27]. \n3. Results \n3.1. General Characteristics of the Subjects \nA total of 13 participants were enro lled from 27 screened volunteers, and all fi-\nnished the clinical phase of the study. Table 2 displays the demographic info r-\nmation of all enrolled subjects. \n3.2. Method Validation \nAll Dienogest calibration curve standards are within the acceptance limit (1 - 200 \nng/mL). The correlation coefficient was higher than 0.999. There were no visible \ninterferences, and the chromatograms produced were entirely distinct from each \nother. The method validation followed international guidelines of the Food and \nDrug Administration (FDA) [28] and the European Medicines Agency (EMA) [29]. \n3.3. Tolerability and Safety Assessment \nAll Adverse Events (AEs) were closely observed and monitored throughout the \nstudy. During the clinical stage, mild forms of AEs were observed (subjects 4, 8, \nand 9 experienced vomiting, and subject 9 had diarrhoea) and resolved spont a-\nneously under medical supervision. \n3.4. Pharmacokinetic Parameters \nFigure  2 and Figure  3 show the mean plasma concentration- time curves of the  \n \nTable 2. Demographic Characteristics of the Subjects (n-13). \nCharacteristic  Values  \nAge, mean (SD), range, years 26 (5.44), 18 - 35 \nWeight, mean (SD), range, kg 57.04 (12.54), 40.70 - 77.80 \nHeight, mean (SD), range, cm 152.80 (8.29), 143 - 168 \nBMI, mean (SD), range, kg/m2 24.30 (4.27), 18.80 - 29.99 \nBMI = Body mass index; SD = Standard deviation. \n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 785 Open Journal of Obstetrics and Gynecology \n \n \nFigure 2. Linear Plot of Mean Plasma Concentration (ng) versus Time (hr). \n \n \nFigure 3. Semilog Plot of Mean Plasma Concentration (ng) versus Time (hr). \n \ntwo formulations. The superimposable figures suggest that the two formulations \nhave equivalent mean plasma concentration-time curves. \nTable  3 reports the pharmacokinetic results, and Table 4  shows the geometric \nmeans, geometric mean ratios, and 90% CIs for the pharmacokinetic parameters \nof the Dienogest 2 mg tablet. \nThe impact of formulations, sequences, and periods on log -transformed phar-\nmacokinetic variables was evaluated using the analysis of variance (ANOVA) [30]  \n\n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 786 Open Journal of Obstetrics and Gynecology \n \nTable 3. Pharmacokinetic parameters (N = 13). \nVisanne (Dienogest 2 mg) tablets ( Reference Product ) \nVariable  Arithmetic  \nMean SD CV% Min Median  Max \nPrimary Variable  \nCmax (ng/mL) 55.0587 12.02436 21.8 39.105 51.127 78.118 \nAUC0− t (hr*ng/mL) 694.8138 194.88638 28.0 408.241 696.563 1100.844 \nAUC0− ∞  (hr*ng/mL) 727.4534 203.11283 27.9 434.141 729.589 1162.059 \nTmax (hr) 1.6346 0.93883 57.4 0.750 1.250 4.000 \nAUC_% Extrap_obs (%) 4.5198 1.37358 30.4 1.945 4.527 6.452 \nT½ (hr) 12.8260 3.04074 23.7 8.436 12.320 17.699 \nKel (hr− 1) 0.0570 0.01379 24.2 0.039 0.056 0.082 \nDienogest 2  mg Tablets ( Test Product ) \nSecondary Variable  \nCmax (ng/mL) 52.9390 13.48170 25.5 35.817 51.465 89.783 \nAUC0− t (hr*ng/mL) 707.0434 186.81099 26.4 440.166 736.734 1007.867 \nAUC0− ∞  (hr*ng/mL) 738.9579 194.24527 26.3 459.597 768.867 1041.096 \nTmax (hr) 2.0192 0.59039 29.2 1.000 2.000 3.000 \nAUC_% Extrap_obs (%) 4.3629 1.08353 24.8 2.899 4.179 5.932 \nT½ (hr) 12.6727 2.63849 20.8 9.594 11.491 17.078 \nKel (hr− 1) 0.0568 0.01095 19.3 0.041 0.060 0.072 \nCmax: maximum plasma concentration of the drug, AUC 0− t: area under the plasma co n-\ncentration-time curve from time zero to the time of the last measurable concentration, \nAUC0− ∞ : area under the plasma concentration-time curve from time zero to infinity, Tmax: \ntime to reach maximum plasma Concentration, T 1/2: half-life of the drug, K el: elimination \nrate constant. \n \nTable 4. Summary results. \nParameter  \nGeometric Least \nSquares  \nMeans (GEOLSM)  T/R  \nRatio  \n(%) \n90% Confidence  \nInterval  Intra  \nSubject  \nCV (%)  \nPower \n(%) \nTest  \nProduct  \nReference  \nProduct  \nLower  \nLimit \n(%) \nUpper  \nLimit \n(%) \nCmax \n(ng/mL) 51.368 53.773 95.53 86.70 105.26 13.79 96.01 \nAUC0− t  \n(hr*ng/mL) 680.392 668.707 101.75 95.42 108.49 9.10 99.90 \nAUC0− ∞   \n(hr*ng/mL) 711.497 700.698 101.54 95.59 107.87 8.57 99.95 \n\nN. Mahmud et al. \n \n \nDOI: 10.4236/ojog.2024.145064 787 Open Journal of Obstetrics and Gynecology \n \nTable 5. P-values for sources of variations obtained from the analysis of variance \n(ANOVA). \nANOVA p Values  \nParameters  LCmax LAUC0− t LAUC0− ∞  \nSequence 0.4850 0.6515 0.6743 \nPeriod 0.4148 0.7241 0.6127 \nFormulation 0.7197 0.6374 0.6584 \n \nmodel. No significant period or sequence effects were detected. The ANOVA \nresults are displayed in Table 5 . \n4. Discussion \nFor Cmax, the ratios of least -squares mean (with 90% confidence intervals) were \n95.53% (86.70% - 105.26%). For AUC 0−t and AUC0−∞ , the ratios of least -squares \nmean (with 90% confidence intervals) were 101.75% (95.42% - 108.49%) and \n101.54% (95.59% - 107.87%), respectively. \nAll of the 90% CI of the pharmacokinetic parameters (C max, AUC 0–t, and \nAUC0–∞ ) were within the bioequivalence acceptable range of 80% to 125%. \nMoreover, the C max profile of Dienogest 2  mg was almost identical for the test \nand reference products. The absence of sequence effects in the ANOVA also i n-\ndicated the absence of a carry-over effect. \n5. Limitations \nThere are some limitations in this current study, as with any other bioequiv a-\nlence study. The results were obtained from healthy adult individuals of a d e-\nfined age range who were given a single dose of the formulation in compliance \nwith regulatory criteria. The pharmacokinetics might differ among patients in \ndifferent age groups. The findings of this study may not be general ized to a sp e-\ncific target population. A non- compartmental model was used to calculate the \npharmacokinetic parameters, which are based on certain assumptions about the \npharmacokinetic behaviour of the drug, such as uniform distribution and linear \nkinetics. Any deviations from these presumptions may impact the precision of \nthe model’s predictions. \n6. Conclusion \nThe test product Dinogest (Dienogest 2  mg) tablet was unequivocally bioequiv a-\nlent with the reference product Visanne ® (Dienogest 2  mg) tablet in healt hy \nadult participants under fasting conditions, per regulatory requirements. Both \nformulations were well tolerated. \nConflicts of Interest \nThe authors declare no conflicts of interest regarding the publication of this paper. \n\nN. 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