Population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers

BACKGROUND: Artemisinin-based combination therapy is recommended as first-line anti-malarial treatment worldwide. A combination of artemisinin with the long acting drug piperaquine has shown high efficacy and tolerability in patients with uncomplicated Plasmodium falciparum infections. The aim of this study was to characterize the population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers after two different dose sizes, formulations and in a combination with piperaquine. A secondary aim was to compare two different methods for the evaluation of bioequivalence of the formulations. METHODS: Fifteen subjects received four different dose regimens of a single dose of artemisinin as a conventional formulation (160 and 500 mg) and as a micronized test formulation (160 mg alone and in combination with piperaquine phosphate, 360 mg) with a washout period of 3 weeks between each period (i.e. four-way cross-over). Venous plasma samples were collected frequently up to 12 h after dose in each period. Artemisinin was quantified in plasma using liquid chromatography coupled with tandem mass spectrometry. A nonlinear mixed-effects modelling approach was utilized to evaluate the population pharmacokinetic properties of the drug and to investigate the clinical impact of different formulations. RESULTS: The plasma concentration–time profiles for artemisinin were adequately described by a transit-absorption model with a one-compartment disposition, in all four sequences simultaneously. The mean oral clearance, volume of distribution and terminal elimination half-life was 417 L/h, 1210 L and 1.93 h, respectively. Influence of formulation, dose and possible interaction of piperaquine was evaluated as categorical covariates in full covariate approaches. No clinically significant differences between formulations were shown which was in accordance with the previous results using a non-compartmental bioequivalence approach. CONCLUSIONS: This is the first population pharmacokinetic characterization of artemisinin in healthy volunteers. Increasing the dose resulted in a significant increase in the mean transit-time but the micronized formulation or concomitant piperaquine administration did not affect the pharmacokinetic properties of artemisinin. The results from the traditional bioequivalence evaluation were comparable with results obtained from mixed-effects modelling.