Murine models are used to study erythrocytic stages of
malaria infection, because parasite morphology and development are comparable to those in human
malaria infections. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models for
antimalarials are scarce, despite their potential to optimize
antimalarial combination
therapy. The aim of this study was to develop a mechanism-based growth model (MBGM) for Plasmodium berghei and then characterize the parasiticidal effect of
dihydroartemisinin (DHA) in murine
malaria (MBGM-PK-PD). Stage-specific (ring, early trophozoite, late trophozoite, and schizont) parasite density data from Swiss mice inoculated with Plasmodium berghei were used for model development in S-ADAPT. A single dose of intraperitoneal DHA (10 to 100 mg/kg) or vehicle was administered 56 h postinoculation. The MBGM explicitly reflected all four erythrocytic stages of the 24-hour P. berghei life cycle. Merozoite invasion of erythrocytes was described by a first-order process that declined with increasing
parasitemia. An efflux pathway with subsequent return was additionally required to describe the schizont data, thus representing parasite sequestration or trapping in the microvasculature, with a return to circulation. A 1-compartment model with zero-order absorption described the PK of DHA, with an estimated clearance and distribution volume of 1.95 liters h(-1) and 0.851 liter, respectively. Parasite killing was described by a turnover model, with DHA inhibiting the production of physiological intermediates (IC(50), 1.46 ng/ml). Overall, the MBGM-PK-PD described the rise in
parasitemia, the nadir following DHA dosing, and subsequent parasite resurgence. This novel model is a promising tool for studying
malaria infections, identifying the stage specificity of
antimalarials, and providing insight into
antimalarial treatment strategies.