| Research Article |
Open Access |
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| Pharmacokinetics and Comparative Bioavailability of Artesunate and Mefloquine Administered Separately or as
a Fixed Combination Product to Healthy Volunteers and
Patients with Uncomplicated Plasmodium falciparum Malaria |
| Piero Olliaro1*,Surash Ramanathan2,Michel Vaillant3, Stephanie E Reuter4, Allan M Evans4, Srivicha Krudsood5, Sornchai Looareesuwan5§,
Jean-René Kiechel6, Walter RJ Taylor1, 7 and Visweswaran Navaratnam2 |
1UNICEF/UNDP/World Bank/WHO Special Programme for Research & Training in Tropical Diseases (TDR), Geneva, SWITZERLAND
2Centre for Drug Research, Universiti Sains Malaysia, Penang, MALAYSIA
3Clinical Epidemiology and Public Health Unit, Centre for Health Studies, CRP-Santé, LUXEMBOURG
4School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, AUSTRALIA
5Hospital for Tropical Disease, Bangkok, THAILAND
6Drugs for Neglected Diseases initiative (DNDi), Geneva, SWITZERLAND
7Division of International and Humanitarian Medicine, Geneva, SWITZERLAND
§ Deceased |
| *Corresponding author: |
Dr. Piero L Olliaro, MD, PhD,
UNICEF/UNDP/World, Bank/
WHO Special Programme on Research & Training in Tropical Diseases (TDR)
World Health Organization,
Avenue Appia 20, CH-1211 Geneva 27,
SWITZERLAND,
Tel: +41 22 791 3734,
Fax: + 41 22 791 4774,
E-mail: olliarop@who.int |
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| Citation: Olliaro P, Ramanathan S, Vaillant M, Reuter SE, Evans AM, et al. (2010)
Pharmacokinetics and Comparative Bioavailability of Artesunate and Mefloquine
Administered Separately or as a Fixed Combination Product to Healthy Volunteers
and Patients with Uncomplicated Plasmodium falciparum Malaria. J Bioequiv
Availab 2: 059-066. doi: 10.4172/jbb.1000032 |
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| Copyright: © 2010 Olliaro P, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
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| Abstract |
| Purpose: The current World Health Organisation recommendation for the treatment of uncomplicated Plasmodium
falciparum malaria is with artemisinin-based combination therapy. Artesunate and mefloquine combination therapy
has achieved consistently high efficacy rates and reduced malaria morbidity; however, the current standard treatment
regimen is complex and may be difficult to comply with outside of a research setting. Consequently, an artesunate
mefloquine fixed dose oral co-formulation has been developed and is now registered in Brazil. This study was conducted
in order to assess the pharmacokinetics and comparative bioavailabilities of artesunate and mefloquine administered as
separate products and the new co-formulated product. |
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| Methods: The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant
species and mefloquine were assessed in a single-dose, randomised, crossover design study in healthy volunteers and
in a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria. |
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| Results: The two formulations were bioequivalent in terms of mefloquine pharmacokinetics in healthy volunteers
and uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve
(AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% bioequivalence limits.
For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between co-formulated
and separate products extended below the 80% limit; AUC and Cmax values were 15-25% and 25-40% lower
than those observed after administration of the separate products. |
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Conclusions: These differences in the exposure to artesunate/dihydroartemisinin are unlikely to be of clinical
relevance based on in vitro and clinical data. However, the results of this study do emphasise the importance of
evaluating the bioavailability and bioequivalence of new formulations.
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