Sofia Birgersson
University of Gothenburg
Objectives: Malaria is still a major health problem in the poorest parts of the world. The highly effective first line treatment recommended by the WHO is artemisinin-based combination therapy. However, the emergence of multidrug-resistant Plasmodium falciparum parasites has started to diminish the efficacy of these available drugs (1, 2). A new combination of artemisinin with the long acting drug piperaquine has shown high efficacy and tolerability in patients with uncomplicated Plasmodium falciparum infections (3). The aim of this study was to characterize the population pharmacokinetics of single doses of artemisinin in various formulations in healthy male Vietnamese volunteers and to evaluate specifically the relative bioavailability of two different formulations.
Methods: Fifteen subjects received four different dose regimens of a single dose of artemisinin; the micronized test formulation, 160 mg (T1), the conventional formulation, 160 mg (T2), the conventional formulation, 250 mg (T3), and the micronized test formulation, 160 mg, in combination with piperaquine, 360 mg, (T4). Between each period there was a washout period of three weeks (i.e. four-way cross-over). Venous plasma samples were collected frequently up to twelve hours after dose in each period. Artemisinin was quantified in plasma using liquid chromatography coupled with tandem mass spectrometry. A nonlinear mixed-effects modeling 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. 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.
Conclusions: In conclusion, this is the first population pharmacokinetic characterization of artemisinin in healthy volunteers. The new micronized formulation, dose or concomitant piperaquine administration did not affect the pharmacokinetic properties of artemisinin. The developed final model may be an important tool to investigate new dosing regimens in silico and to be implemented in clinical trial simulations for informative design of future clinical trials.
References:
[1] WHO World Malaria Report 2014.
[2] Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. 2009. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 2009/07/31 ed. 361:455–467.
[3] Trung TN, Tan B, Van Phuc D, Song JP. 2009. A randomized, controlled trial of artemisinin-piperaquine vs dihydroartemisinin-piperaquine phosphate in treatment of falciparum malaria. Chin J Integr Med, 2009/07/02 ed. 15:189–192.
Reference: PAGE 24 (2015) Abstr 3446 [www.page-meeting.org/?abstract=3446]
Poster: Methodology - Covariate/Variability Models