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

Author:

Körnicke Thomas1,Arora Deepa2,Samad Abdus2,Kaplan Sigal3,Domahidy Mónika4,de Voogd Hanka5,Böhmert Stella6,Ramos Rita Silveira7,Jain Shashank2

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.

Publisher

Georg Thieme Verlag KG

Subject

Drug Discovery,General Medicine

Reference9 articles.

1. Identification of trimetazidine metabolites in human urine and plasma;P J Jackson;Xenobiotica,1996

2. Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure;J Barré;Biopharm Drug Dispos,2003

3. Modified-release formulation of trimetazidine for exceptional control of angina pectoris: Fact or fiction;U Thadani;Am J Cardiovasc Drugs,2005

4. Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study;N Nenchev;Drug Dev Res,2020

5. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation;A S Levey;Ann Intern Med,1999

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