Pharmacokinetic-pharmacodynamic modelling of artesunate in patients with drug resistant and sensitive malaria
Richard M. Hoglund (1,2), Elizabeth Ashley (1,2), Arjen Dondorp (1,2), Markus Winterberg (1,2), Nicholas P.J. Day (1,2), Nicholas J. White (1,2), Joel Tarning (1,2)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (2) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Objectives: Today our current arsenal of antimalarial drugs are quickly becoming obsolete with the emergence of antimalarial drug resistance [1]. Multi-drug resistant malaria is now emerging and spreading quickly in Southeast Asia [1,2]. It is therefore crucial to optimise the treatment of currently available drugs to contain the spread of resistance and maximise therapeutic efficacy. The objective of this project was to develop a pharmacokinetic-pharmacodynamic model for artesunate and its active metabolite, dihydroartemisinin, and investigate the impact of drug resistance.
Methods: A total of 1,151 patients with uncomplicated falciparum malaria in 10 different countries in Africa and Asia were enrolled and received standard oral artesunate treatment (NCT01350856). Hitherto, this is the largest study conducted, investigating the pharmacokinetic and pharmacodynamic properties of artesunate and the influence of antimalarial drug resistance. Densely collected plasma concentrations of artesunate and dihydroartemisinin, microscopy parasite counts and molecular markers for drug resistance were collected in all patients. Pharmacokinetic and pharmacodynamic data were analysed using nonlinear mixed-effect modelling (NONMEM v.7).
Results: The pharmacokinetics of artesunate and dihydroartemisinin were well-described by a joint parent-metabolite model, assuming 100% in-vivo conversion of artesunate into dihydroartemisinin. One-compartment disposition models for both artesunate and dihydroartemisinin were sufficient with no further improvement of additional peripheral compartments. Parasitemia at enrolment, sex, and body weight were found to influence the pharmacokinetic properties significantly.
Total parasite biomass was modelled by a parasite compartment with a fixed 10-fold multiplication rate per parasite life-cycle (i.e. 48 hours). The drug-dependent elimination of parasites was dependent on the concentration of dihydroartemisinin and was incorporated with an EMAX model. Molecular markers, associated with reduced drug susceptibility, had a significant impact on the EMAX-value, resulting in a slower killing of parasites in patients with drug resistant infections.
Conclusions: A pharmacokinetic-pharmacodynamic model describing artesunate and dihydroartemisinin concentrations and their relationship to the elimination of malaria parasites were successfully developed. This model quantified the impact of molecular markers associated with drug resistant malaria infections.
References:
[1] Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014 Jul 31;371(5):411–23.
[2] Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, et al. Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016 Mar;16(3):357–65.