Population modelling of the pharmacokinetics of a mefloquine-artesunate treatment at the Thai-Myanmar border
Richard Höglund (1), Angela Äbelö (1), Kesara Na-Bangchang (2), Michael Ashton (1)
(1) Unit of pharmacokinetics and drug metabolism, Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden; (2) Faculty of Allied Health Science, Thammasat University, Bangkok, Thailand
Background: Malaria is an important health problem in tropical regions of the world. Artesunate-mefloquine is a standard treatment against Plasmodium falciparum malaria in Thailand, but there might be a developing drug resistance against both of the combination partner drugs.
Objectives: The objective of this study was to describe the pharmacokinetic properties of mefloquine, artesunate and dihydroartemisinin, which at a later stage will be used in the development of PK-PD models for different molecular markers and their impact on the outcome and efficacy of the treatment, as well as possible resistance development.
Methods: One hundred thirty Burmese patients with uncomplicated P. falciparum malaria were given a three-day oral dose regimen of artesunate and mefloquine. Details on the study have previously been published . Venous blood samples were drawn from each patient resulting in either a full or sparse concentration-time profile. Whole blood or plasma concentrations of mefloquine, artesunate and dihydroartemisinin were quantified using LC-UV and LC-MS/MS [2,3]. Drug concentrations were analysed with nonlinear mixed-effects modelling in NONMEM VI. Multi-compartment distribution models with different absorption models were evaluated. It was explored whether covariates such as parasite clearance time, weight, age or parasitemia could explain the variability between patients. Baseline measurements of drug concentrations, due to self-medication before the initiation of the study, were modelled as a baseline in the PK model.
Results: : A total of 677 plasma samples were analysed. 11.4 % of the patients had baseline concentrations of mefloquine. None had artesunate or dihydroatemisinin concentrations at enrolment to the study. The concentrations were adequately described by the used modelling approach taking into account the baseline concentrations. For mefloquine a regular two compartment disposition model were used and artesunate-dihydroartemisinin were described by a metabolite model.
Conclusions: The developed model could adequately describe the PK for this mefloquine-artesunate combination treatment.
 Na-Bangchang et al.: Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malaria Journal 2010 9:273.
 Karbwang et al.: Determination of mefloquine in biological fluids using high performance liquid chromatography. Southeast Asian J Trop Med Publich Health 1989 20:55-60.
 Thuy le et al.: Development and validation of a liquid chromatography-mass spectromy method for the simultaneous quantification of artesunate and dihydroartemisinin in human plasma. Southeast Asian J Trop Med Publich Health 2008 39:963-977.