Summary of bioequivalence study for GASTROTEC®, 0,2 mg misoprostol tablets

18 November 2022

Purpose. To prove the bioequivalence (BE) of the test investigational medicinal product (IMP) GASTROTEC^®, 0,2 mg misoprostol tablets, manufactured by PrJSC “Pharmaceutical Firm “Darnitsa” to the reference IMP CYTOTEC_®, 0,2 mg misoprostol tablets, manufactured by Pfizer in a comparative, randomized, crossover, two-sequence, four-period study (according to the TRTR/RTRT scheme) in healthy male volunteers.

Objects and methods of the study. Blood samples were collected in healthy male volunteers after a single oral dose of IMPs at a dose level of 0,2 mg misoprostol in each period (i.e., 0,8 mg of misoprostol throughout the study) under fed conditions. Misoprostol is de-esterified to its active metabolite, misoprostol acid (MSPA), which was used as an analyte in the study. MSPA in human plasma was assayed using validated method of high-performance liquid chromatography with tandem mass-spectrometric detection (HPLC-MS/MS).

Results. All 40 randomised subjects completed the study, and their data were included in pharmacokinetic analysis. 90% confidence interval (CI) limits for the ratio of geometric least square means of maximum plasma concentration (Cmax) and area under the plasma concentration curve from administration to last observed concentration at time t (AUC0-t) of MSPA for GASTROTEC^® and CYTOTEC^® were 98.87% to 128.10% and 98.78% to 106.62%, respectively. Since intra-subject variability of Cmax for the reference IMP was found to be of 48.61% (i.e., above 30%), bioequivalence acceptance range for Cmax was widened to 70.47 to 141.91% according to Guideline on the Investigation of Bioequivalence.

Therefore, the results confirmed that 90% CI for Test to Reference ratios of the geometric least squares means for both main pharmacokinetic parameters met international requirements with 90% CI for AUC0-t of MSPA being within standard bioequivalence acceptance range (80.00% to 125.00%) and 90% CI for Cmax of MSPA being entirely within widened acceptance range (70.47% to 141.91%).

There were no adverse events (AE) observed during the study.

Conclusions. The bioequivalence of the test IMP (GASTROTEC^®, 0.2 mg misoprostol tablets) to the reference IMP (CYTOTEC^®, 0.2 mg misoprostol tablets) was demonstrated in this study. Both IMPs were characterized to have good tolerability with single (within each period) oral dosage in fed conditions.

The sponsor of the study, PrJSC “Pharmaceutical Firm “Darnitsa”, expresses its gratitude to the employees of PHARMBIOTEST Research Centre LLC (Ukraine) and bioanalytical laboratory of QUINTA-ANALYTICA s.r.o. (Czech Republic) for conducting the research and processing its results.

For more details about study design, please see Annex 30 published on the official site of the State Expert Center of the Ministry of Health of Ukraine: https://www.dec.gov.ua/materials/gastrotek/.