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Drug Res (Stuttg) 2020; 70(10): 472-477
DOI: 10.1055/a-1180-4357
Original Article

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

Thomas Körnicke
1   Parexel International GmbH, Berlin, Germany
,
Deepa Arora
2   Drug Safety and Risk Management, Lupin Limited (India), Mumbai, India
,
Abdus Samad
2   Drug Safety and Risk Management, Lupin Limited (India), Mumbai, India
,
Sigal Kaplan
3   Teva Pharmaceutical Industries LTD, Petach Tikva, Israel
,
Mónika Domahidy
4   Department of Clinical Research, Gedeon Richter Plc. Budapest, Hungary
,
Hanka de Voogd
5   Clinical Development Mylan EPD, Amstelveen, the Netherlands
,
Stella Böhmert
6   Sandoz International GmbH, Holzkirchen, Germany
,
Rita Silveira Ramos
7   Generis® Farmacêutica, Amadora, Portugal
,
Shashank Jain
2   Drug Safety and Risk Management, Lupin Limited (India), Mumbai, India
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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.

Key words

pharmacokinetics - drug delivery - drug research - clinical trials - cardiovascular pharmacology


Publication History

Received: 25 February 2020

Accepted: 27 March 2020

Article published online:
04 September 2020

© 2020. Thieme. All rights reserved.

© Georg Thieme Verlag KG
Stuttgart · New York

 

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