Semi-mechanistic population pharmacokinetic/pharmacodynamic modeling of a Plasmodium elongation factor 2 inhibitor cabamiquine for prevention and cure of malaria

Abstract

ABSTRACT Cabamiquine is a novel antimalarial agent that demonstrates the potential for chemoprevention and treatment of malaria. In this article, the dose–exposure–response relationship of cabamiquine was characterized using a population pharmacokinetic (PK)/pharmacodynamic (PD) model, incorporating the effects of cabamiquine on parasite dynamics at the liver and blood stages of malaria infection. Modeling was performed sequentially. First, a three-compartmental population PK model was developed, comprising linear elimination, a transit absorption model in combination with first-order absorption, and a recirculation model. Second, this model was expanded into a PK/PD model using parasitemia data from an induced blood stage malaria (IBSM) human challenge model. To describe the parasite growth and killing in the blood, a turnover model was used. Finally, the liver stage parasite dynamics were characterized using data from a sporozoite challenge model (SpzCh), and system parameters were fixed based on biological plausibility. Cabamiquine concentration in the central compartment was used to drive parasite killing at the blood and liver stages. Blood stage minimum inhibitory concentrations (MIC b ) were estimated at 7.12 ng/mL [95% confidence interval (CI 95% ): 6.26–7.88 ng/mL] and 1.28 ng/mL (CI 95% : 1.12–1.43 ng/mL) for IBSM and SpzCh populations, respectively, while liver stage MIC l was lower (0.61 ng/mL; CI 95% : 0.24–0.96 ng/mL). In conclusion, a population PK/PD model was developed by incorporating parasite dynamics and drug activity at the blood and liver stages based on clinical data and biological knowledge. This model can potentially facilitate antimalarial agent development by supporting the efficient selection of the optimal dosing regimen.