Affiliation:
1. Parexel International GmbH, Berlin, Germany
2. Drug Safety and Risk Management, Lupin Limited (India), Mumbai,
India
3. Teva Pharmaceutical Industries LTD, Petach Tikva, Israel
4. Department of Clinical Research, Gedeon Richter Plc. Budapest,
Hungary
5. Clinical Development Mylan EPD, Amstelveen, the
Netherlands
6. Sandoz International GmbH, Holzkirchen, Germany
7. Generis® Farmacêutica, Amadora, Portugal
Abstract
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.
Subject
Drug Discovery,General Medicine