Palang Chotsiri(1), Ingrid Chen(2), Alassane Dicko(3), Joelle M Brown(4), Halimatou Diawara(3), Ibrahima Baber(3), Almahamoudou Mahamar(3), Harouma M Soumare(3), Koualy Sanogo(3), Fanta Koita(3), Sekouba Keita(3), Sekou F Traore(3), Eugenie Poirot(2,4), Jimee Hwang(2,4,5), Charles McCulloch(4), Kjerstin Lanke(6), Helmi Pett(6,8), Mikko Niemi(8), Francois Nosten(9,10), Teun Bousema(6,7), Roly Gosling(2), and Joel Tarning(1,10)
(1) Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (2) Malaria Elimination Initiative, Global Health Group, University of California San Francisco, San Francisco, Washington, DC, USA (3) Malaria Research and Training Center, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Science, Techniques and Technologies of Bamako, Bamako, Mali (4) Department of Epidermiology and Biostatistic, University of California San Francisco, San Francisco, Washington, DC, USA (5) Malaria Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA (6) Department of Medical Microbiology, Radboud University Medical Center,Nijmegan, Netherlands (7) Department of Immunology & Infection, London School of Hygiene & Tropical Medicine, London, UK (8) Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland (9) Shoklo Malaria Research Unit, Mae Sot, Thailand (10) Centre for Trop
Objective: Primaquine is the only antimalarial drug targeting the sexual stage of Plasmodium falciparum, gametocytes, which are responsible for the transmission of malaria. WHO suggests to add a single low dose of primaquine (0.25 mg/kg) to the normal artemisinin-based combination therapy (ACT) in order to reduce malaria transmission in low transmission areas [1]. However, the mechanism of gametocyte reduction and the reduction of malaria transmission after primaquine administration is still unknown. This study aimed to characterize the pharmacokinetic properties of primaquine and its metabolite, carboxyprimaquine, and to develop a mechanistic model for gametocyte clearance in patients and link this model to mosquito infectivity.
Methods: Eighty-one G6PD normal males with uncomplicated falciparum malaria with a detectable gametocytemia received a standard dose of dihydroartemisinin-piperaquine (DHA-PQ) [2]. In addition, each patient was randomly assigned to receive a single low dose of primaquine on day one (placebo, n = 16; 0.0625 mg/kg, n = 16; 0.125 mg/kg, n = 17; 0.25 mg/kg, n = 15; or 0.5 mg/kg, n = 17). Primaquine and carboxyprimaquine concentrations, gametocytemia, and mosquito infectivity were quantified. Pharmacokinetic and pharmacodynamic properties of primaquine were investigated using nonlinear mixed-effects modelling (NONMEM v.7.4).
Results: Primaquine and carboxyprimaquine plasma concentration-time profiles were modelled simultaneously using a linear drug-metabolite model, assuming 100% conversion of parent drug to metabolite. The absorption properties of primaquine were explained by a transit-compartment absorption model (n = 6) with an estimated fraction of a first-pass metabolism. A mechanistic model of gametocyte maturation was implemented as the pharmacodynamic model, consisting of five gametocyte compartments (GI – GV) representing the five gametocyte development stages. The first four stages (GI – GIV) represents undetectable immature and sequestered gametocytes, and the fifth stage (GV) represents the observed circulating gametocytes. Transit rates between these gametocyte stages were fixed to two days, based on literature values. The co-administered antimalarial combination therapy (DHA-PQ) was assumed to be highly effective against asexual blood stage parasites, resulting in no additional gametocyte proliferation after start of treatment. Higher primaquine doses were associated with a higher gametocyte clearance, described by an EMAX relationship between primaquine concentrations and gametocyte death rate. The substantially delayed gametocyte killing effect of primaquine was characterized using a series of transit-compartments and an effect compartment. A combined EMAX function, based on gametocyte density and primaquine concentrations, was used to explain the observed probability of mosquito infectivity.
Conclusion: The pharmacokinetic properties of primaquine and caboxyprimaquine were described successfully by a simultaneous drug-metabolite model. A mechanistic pharmacodynamic model quantified the relationship between primaquine exposure and gametocyte killing, resulting in increased killing of the sexual parasites at higher doses of primaquine. Both gametocyte density and primaquine exposure determined the probability of mosquito infectivity. Thus, the developed model described the pharmacokinetic properties of primaquine and its transmission blocking effects, demonstrating highly effective transmission blocking properties by a direct gametocyte killing effect and an additional drug effect most likely due to its sterilizing effects on the sexual form of the parasite.
References:
[1] World Health Organization (WHO). Guidelines for the treatment of malaria. Third ed. Geneva, Switzerland: World Health Organization (WHO), 2015.
[2] Dicko A, Brown JM, Diawara H, et al. Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial. Lancet Infect Dis 2016; 16(6): 674-84.
Reference: PAGE 28 (2019) Abstr 8926 [www.page-meeting.org/?abstract=8926]
Poster: Drug/Disease Modelling - Infection