Population pharmacokinetics of mefloquine, administered as a fixed-dose combination of artesunate-mefloquine in Indian patients for the treatment of acute uncomplicated Plasmodium falciparum malaria

Malaria Journal

Research

Jean-René Kiechel¹  Bhawna Sharma²  Vincent Jullien³  Neena Valecha⁴  Bina Srivastava⁴ 

[1] Drugs for Neglected Diseases initiative, 15 chemin Louis-Dunant, 1202, Geneva, Switzerland;Drugs for Neglected Diseases initiative, F-79 Green Park Main, 110016, New Delhi, India;INSERM U1129, University Paris Descartes, Paris, France;Service de Pharmacologie, Hôpital Européen Georges Pompidou; Assistance Publique - Hôpitaux de Paris, Paris, France;National Institute of Malaria Research, New Delhi, India;

关键词: Mefloquine;    Population pharmacokinetics;    Adults;    Malaria;   

DOI  :  10.1186/1475-2875-13-187

 received in 2014-01-15, accepted in 2014-04-27,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundFixed-dose combinations of artemisinin combination therapy are strongly recommended to facilitate drug administration and compliance. New fixed-dose combinations must nevertheless be evaluated in relevant populations in terms of efficacy and pharmacokinetics.MethodsA single-arm, open-label, clinical trial was performed in Indian patients with acute uncomplicated Plasmodium falciparum malaria to investigate the efficacy and the pharmacokinetics of mefloquine when combined with artesunate in a fixed-dose combination (400/200 mg of mefloquine base/artesunate). The pharmacokinetic analysis was performed using a population approach.ResultsSeventy-seven patients were included in the study. Mefloquine pharmacokinetics obeys a two-compartment model with first-order absorption and elimination. Mean parameter estimates (% inter-individual variability) were as follows: 0.16 h-1 (75%) for the absorption rate constant, 1.13 L/h (30%) for the apparent plasma clearance, 271 L (21%) for the apparent central distribution volume, 344 L (54%) for the apparent peripheral distribution volume, and 1.43 L/h for the apparent distribution clearance. These values were consistent with the pharmacokinetic results described in Thai patients. No significant covariate was found for clearance. Body weight explained the inter-individual variability of the apparent central and peripheral distribution volumes. The PCR-adjusted efficacy of the treatment was 100%.ConclusionsThe lack of significant covariate explaining the inter-individual variability of mefloquine clearance, combined with the excellent efficacy, supports the use of the standard 200/400 mg of artesunate-mefloquine fixed-dose combination in Indian patients with uncomplicated P. falciparum malaria.Trial RegistrationClinical Trial Registration: ISRCTN70618692

【 授权许可】

Unknown   
© Jullien et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.