Pharmacokinetic properties and safety assessment of the generic vaginal gel progesterone preparation: results of an open-label, randomized, crossover bioequivalence study

Tapilskaya N.I., Gzgzyan А.М., Kоgan I.Yu., Pisarev V.V., Merkulov М.Е., Korneeva I.E.

1) D.O. Ott Research Institute of Obstetrics, Gynecology and Reproduction, St. Petersburg, Russia; 2) Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, St. Petersburg, Russia; 3) Saint Petersburg State University, St. Petersburg, Russia; 4) Medical Center Probiotech LLC, Moscow, Russia; 5) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia

Objective: To assess bioequivalence of the generic (test) progesterone preparation Miragel, vaginal gel 90 mg/dose (WERTEX JSC, Russia) and the branded (reference) vaginal gel progesterone Crinone, 90 mg/dose (Merck Serono Limited, Great Britain).
Materials and methods: Progesterone concentrations in the blood plasma of volunteers (naturally postmenopausal women) were determined after a single intravaginal injection of the generic Miragel, vaginal gel 90 mg/dose (WERTEX JSC, Russia) and branded preparation Crinone, vaginal gel 90 mg/dose (Merck Serono Limited, Great Britain). The study was conducted using an open-label, randomized, a 4-period crossover scheme, with two sequences of medicine administration and with an interval of 14 days. A total of 42 female volunteers who met the inclusion and non-inclusion criteria were selected for participation in the study; all of them provided informed consent. The concentration of progesterone in the blood plasma samples of volunteers was determined using high performance liquid chromatography tandem mass spectrometry.
Results: Progesterone concentration was identified in 3281 blood plasma samples obtained from 42 volunteers during four study periods. The mean values and standard deviations of the pharmacokinetic parameters of progesterone after intravaginal administration of the test and reference drugs were as follows: Cmax 11.497±3.693 ng/ml and 10.912±3.651 ng/ml; AUC0-t 200.114±93.023 ng·h/ml and 225.264±134.477 ng·h/ml, respectively. Two-sided 90% confidence intervals for the ratios of the corresponding geometric mean values of the pharmacokinetic parameters of progesterone Cmax and AUC0-t were 100.45–111.98% and 85.28–101.41%, respectively. A total of 30 adverse events were registered in 20 volunteers of the safety population (47.6%): 18 adverse events in 14 volunteers (33.3%) after administration of the test drug and 12 adverse events in 10 volunteers (23.8%) after administration of the reference drug. No adverse events that would be reliably, probably or possibly associated with the administration of the test or reference preparations have been registered.
Conclusion: The boundaries of the estimated two-sided 90% confidence intervals for the ratio of the geometric mean values of the pharmacokinetic parameters AUC0-t and Cmax range from 80.00 to 125.00%. Therefore, the test preparation Miragel, vaginal gel 90 mg/dose (WERTEX JSC, Russia) and the reference drug Crinone, vaginal gel 90 mg/dose (Merck Serono Limited, Great Britain), are bioequivalent.

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About the Authors

Natalya I. Tapilskaya, MD, PhD, DSci (Medicine), Professor, Leading researcher at the Department of Reproduction, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, 199034, Mendeleyevskaya Line 3, Russia; Professor at the Department of Obstetrics and Gynecology, Saint Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation, Saint Petersburg, 194100, Litovskaya 2, Russia, +7(812)328-98-22,
tapnatalia@yandex.ru, https://orcid.org/0000-0001-5309-0087
Alexander M. Gzgzyan, MD, PhD, DSci (Medicine), Head of the Department of Reproduction, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, 199034, Mendeleyevskaya Line 3, Russia; Professor at the Department of Obstetrics, Gynecology and Reproduction,
Medical Faculty, St. Petersburg State University, Saint Petersburg, 199034, Universitetskaya nab., 7-9, Russia, +7(812)328-98-22, iagmail@ott.ru,
https://orcid.org/0000-0003-3917-9493
Igor Yu. Kogan, MD, PhD, DSci (Medicine), Professor, Corresponding Member of RAS, Director of the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, 199034, Mendeleyevskaya Line 3, Russia; Professor at the Department of Obstetrics, Gynecology and Reproduction,
Medical Faculty, St. Petersburg State University, Saint Petersburg, 199034, Universitetskaya nab., 7-9, Russia, ikogan@mail.ru, https://orcid.org/0000-0002-7351-6900
Vladimir V. Pisarev, MBA, Head of Medical Center Probiotech, 5-ya Kabelnaya str., 2B, Moscow, 111024, Russian Federation, vladimir.pisarev@probiotech.ru,
https://orcid.org/0000-0003-3212-4369
Mikhail E. Merkulov, specialist, Medical Center Probiotek, 5-ya Kabelnaya str., 2B, Moscow, 111024, Russian Federation, mikhail.merkulov@probiotech.ru,
https://orcid.org/0000-0002-1987-992X
Irina E. Korneeva, MD, PhD, DSci (Medicine), Professor, Senior Researcher at the Scientific and Clinical Department of Assisted Reproductive Technology named
after F. Paulsen, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation,
4 Oparin str., Moscow, Russian Federation, 117997, irina.korneeva@inbox.ru

Authors’ contributions: Tapilskaya N.I. – analysis of research documents, selection of material, writing the text; Gzgzyan A.M. – selection of material, writing the text; Kogan I.Yu. – final revision of the article; Pisarev V.V., Merkulov M.E. – selection of literature and statistical processing; Korneeva I.E. – assistance at the stage of drug registration, preparation of instructions and justification for the use of the drug in the clinic, testing of the drug in clinical practice.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The study was sponsored by WERTEX JSC, Russia.
Acknowledgements: The authors express their gratitude to Irina A. Proskurina, PhD, Head of the Department No. 2 in the Effectiveness and Safety of Drugs, Scientific Centre for Expert Evaluation of Medicinal Products, for assistance in preparing the article;
Alexander L. Khokhlov, Dr. Med. Sci., Professor, Head of the Department of Clinical Pharmacology, Yaroslavl State Medical University, Ministry of Health of the Russian Federation, for conducting a clinical trial.
Patient Consent for Publication: All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Tapilskaya N.I., Gzgzyan А.М., Kоgan I.Yu., Pisarev V.V., Merkulov М.Е., Korneeva I.E. Pharmacokinetic properties and safety assessment of the generic vaginal gel progesterone preparation: results of an open-label, randomized, crossover bioequivalence study.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 8: 144-152 (in Russian)
https://dx.doi.org/10.18565/aig.2022.8.144-152

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