Richard M. Hoglund (1,2), Chanaki Amaratunga (3), Sokunthea Sreng (4), Pharath Lim (3), Seila Suon (4), Nicholas P. J. Day (1,2), Nicholas J. White (1,2), Rick Fairhurst (3), Joel Tarning (1,2)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (2) Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK, (3) Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA, (4) National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia
Objectives: Artemisinin-based combination therapy is the recommended first-line treatment for malaria. However, recent data report emerging multi-drug resistant falciparum malaria in western Cambodia and South-East Asia [1]. This threaten our ability to treat and control malaria in the region and it would have severe consequences if spread globally. The fixed-dose oral combination therapy of dihydroartemisinin-piperaquine administered once daily for three days has previously shown good efficacy, but decreased efficacy of this combination has been reported over the last couple of years [2]. The aim of the study was to evaluate the pharmacokinetic and pharmacodynamic properties of the standard treatment of dihydroartemisinin-piperaquine in Cambodia and evaluate the impact of different molecular markers on the risk of therapeutic failure (i.e. recrudescence malaria).
Methods: Capillary plasma samples were collected at three different sites in Cambodia over two seasons after a standard treatment dose of dihydroartemisinin-piperaquine. Piperaquine drug concentrations were measured in these samples and malaria reinfections during the 63 days of follow-up were characterised as new infections or therapeutic failures (recrudescent malaria) using PCR genotyping. Genotyping was also performed to identify mutations associated with resistance. Piperaquine drug measurements and time to recrudescent malaria were evaluated with nonlinear mixed-effects modelling (NONMEM 7.3). Due to the sparse nature of the collected pharmacokinetic samples, a prior approach were utilized to describe the pharmacokinetic properties of piperaquine. The prior model was a previously published pooled analysis, including 728 patients and a conversion factor between venous and capillary concentrations [3]. The pharmacodynamic data were evaluated with an interval-censored time-to-event model.
Results: The pharmacokinetic properties of piperaquine were described successfully with a prior approach, which consisted of a three-compartment disposition model with a transit compartment model describing the absorption. The outcome time-to-event data was successfully characterised by a Gompez hazard model, linking piperaquine plasma concentration to the baseline hazard with a sigmoidal effect model. Plasmepsin copy number amplification and K13-gene mutation were found to have a significant and substantial impact on the risk of therapeutic failure. Simulations were carried out to determine the clinical impact of different levels of resistance.
Conclusions: Unacceptably high failure rates of 38.5% and 16.9% were seen in sites in western and northern Cambodia, respectively, compared to 3.03% in eastern Cambodia. This was successfully described by a pharmacokinetic-pharmacodynamic nonlinear mixed-effects model for piperaquine, identifying that both the molecular marker for artemisinin resistance (mutation of the K13-propeller) and for piperaquine resistance (increase in plasmepsin copy number) had a substantial impact on therapeutic outcome. Simulations demonstrated that even a quite moderate frequency of K13-mutation and increased plasmepsin copy number resulted in unacceptable therapeutic efficacy (<90%).
References:
[1] C. Amaratunga, P. Lim, S. Suon, S. Sreng, S. Mao, C. Sopha, et al., “Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study,” Lancet Infect. Dis., Jan. 2016.
[2] 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., 31;371(5):411–23., Jul. 2014.
[3] R. M. Hoglund, L. Workman, M. D. Edstein, N. X. Thanh, N. N. Quang, I. Zongo, et al., “Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.,” PLoS Med., vol. 14, no. 1, p. e1002212, Jan. 2017.
Reference: PAGE 28 (2019) Abstr 9035 [www.page-meeting.org/?abstract=9035]
Poster: Drug/Disease Modelling - Infection