Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects

Abstract

Aim This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. Methods This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. Results Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h−1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h−1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. Conclusion Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Multisystem effect of cytoprotection

“…Пик концентрации лекарственного препарата в крови составил 79,32±23,08, 153,17±23,08 и 199,67±23,08 нг/мл соответственно, время достижения максимальной концентрации вещества в плазме крови -5,42±0,49, 4,51±1,27 и 4,57±0,96 ч соответственно, период полувыведения составил 7,75±1,62, 6,40±1,23 и 6,50±1,18 ч соответственно, площадь под фармакокинетической кривой -кривой «концентрация-время» -1116,89±378,35, 1838,39±284,50 и 2504,84±348,35 нг.ч/мл соответственно. Были подтверждены хорошая переносимость и безопасность разовой дозы модифицированного высвобождения препарата [26].…”

Evaluation of the pharmacokinetics, bioequivalence, and safety of two preparations of 20 mg trimetazidine

“…After oral administration of TMZ hydrochloride 20 mg tablets, TMZ is quickly absorbed and achieves its peak concentration within 2 hours. Elimination of TMZ is predominantly renal, and most of the unchanged drug is excreted in urine (Jackson et al, 1996;Körnicke et al, 2020). TMZ hydrochloride tablets were originally developed by Les Laboratoires Servier (France) under the name Vasorel.…”