Summary of bioequivalence study for PERINDOPRES TRIO, 4 mg perindopril tert-butylamine / 1.25 mg indapamide / 5 mg amlodipine tablets; 4 mg perindopril tert-butylamine / 1.25 mg indapamide / 10 mg amlodipine tablets; 8 mg perindopril tert-butylamine / 2.5 mg indapamide / 5 mg amlodipine tablets; 8 mg perindopril tert-butylamine / 2.5 mg indapamide / 10 mg amlodipine tablets

09 January 2023

Purpose. To prove the bioequivalence (BE) of the test investigational medicinal product (IMP) PERINDOPRES TRIO, 8 mg perindopril tert-butylamine / 2.5 mg indapamide / 10 mg amlodipine tablets, manufactured by PrJSC “Pharmaceutical Firm “Darnitsa” to the reference IMP TRIPLIXAM^®, 10 mg/2.5 mg/10 mg film-coated tablets containing 10 mg perindopril arginine / 2.5 mg indapamide / 10 mg amlodipine manufactured by Servier (Ireland) Industries Ltd in a randomized, open-label, single-dose, two-sequence, two-period, crossover, comparative, oral bioequivalence study in 52 healthy volunteers under fasting conditions.

Objects and methods of the study. In each study period, healthy male and female volunteers took under fasting conditions a single oral dose of test or reference IMPs, i.e., either 8 mg perindopril tert-butylamine or 10 mg perindopril arginine, 2.5 mg indapamide, and 10 mg amlodipine (i.e., 13,466 mg of perindopril, 5 mg indapamide, and 20 mg amlodipine throughout the study). Data of forty-eight (48) healthy volunteers fully completed the study according to the protocol and taken IMP in both periods were included in pharmacokinetic and statistical analysis.

Results. Pharmacokinetic results demonstrate that perindopril geometric least squares mean (LSM) ratios and corresponding 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the plasma concentration curve from administration to last observed concentration at time (t) (AUC0-t) were 97.43% (91.55 to 103.69%) and 101.40% (97.63 to 105.32%), respectively. For indapamide, geometric LSM ratios and corresponding 90% CIs for Cmax and AUC0-t were 105.62% (101.87 to 109.50%) and 103.46% (100.68 to 106.33%), respectively. For amlodipine, geometric LSM ratios and corresponding 90% CIs for Cmax and area under the plasma concentration curve from administration to last observed concentration at 72 hours (AUC0-72h) were 97.94% (94.29 to 101.74%) and 99.06% (96.01 to 102.20%), respectively.

The criteria used to assess bioequivalence between the test and reference IMPs were all fulfilled since the Test to Reference ratio of geometric LSM and corresponding 90% CI for Cmax, AUC0-t and AUC0-72h were all within the acceptance range of 80.00 to 125.00%.

During the study, no clinically significant and drug-related changes were detected in healthy volunteers based on the assessment of vital signs, physical examination, electrocardiography and laboratory tests.

Conclusions. The bioequivalence of the test IMP (PERINDOPRES TRIO, 8 mg perindopril tert-butylamine / 2.5 mg indapamide / 10 mg amlodipine tablets) to the reference IMP (TRIPLIXAM^®, 10 mg/2.5 mg/10 mg film-coated tablets containing 10 mg perindopril arginine / 2.5 mg indapamide / 10 mg amlodipine) was demonstrated in this study. Both IMPs were characterized to have good tolerability after single (within each period) oral administration under fasting conditions.

The Sponsor of the study, PrJSC “Pharmaceutical Firm “Darnitsa”, expresses its gratitude to the employees of contract research organization (CRO) International Pharmaceutical Research Center (IPRC) in Amman, Jordan, for conducting this study and processing its results.