Mechanism-based population modelling of dihydoartemisinin pharmacodynamics in murine malaria

Background: Murine models are powerful tools for studying erythrocytic stages of malaria infection, because parasite morphology and development are similar to that in human malaria. However, mechanism-based pharmacodynamic (PD) models for antimalarials are generally lacking, and are required to optimise dosing.
Objectives: To describe the growth cycle for Plasmodium berghei and the parasitocidal effect of dihydroartemisinin (DHA) in murine malaria.
Methods: Parasite count data were obtained from male Swiss mice receiving a single dose of intraperitoneal DHA (0 – 100 mg/kg). Mice were inoculated with parasitised erythrocytes at time = 0, and then received DHA at 56 h post-inoculation. Measured parasite counts were classified into four erythrocytic maturation stages (ring, early trophozoite, late trophozoite and schizont). Initially, a model describing P. berghei growth in untreated mice was developed in S-ADAPT. The structural growth model was then linked to an independently developed pharmacokinetic (PK) model to simultaneously describe parasite growth and DHA killing in untreated and treatment mice. Predicted DHA plasma concentrations were utilised to drive the ‘kill’ function for parasite elimination.
Results: A mechanism-based model reflecting all stages of the P. berghei life-cycle adequately described parasite growth and DHA PD. The estimate for mean time (MT) through one life-cycle was 25.1 h. Merozoite infection of erythrocytes to rings was described by a first-order process that declined with increasing merozoite count. The estimated number of merozoites per schizont was 20 (between-subject variability, BSV 21%). Saturable schizont efflux with first-order return through 3 transit compartments was additionally required to adequately fit the schizont data. This pathway is to represent schizont trapping in the microvasculature, with subsequent return to the central circulation. Plasma PK of DHA was described by a 1-compartment model with zero order absorption. The estimates for clearance and central volume of distribution were 1.95 L/h (BSV 48%) and 0.851 L (BSV 8%), respectively. Parasite killing was described by a turnover model, with DHA inhibiting the production of physiological processes (IC50 0.78 μg/L; BSV 28%). This parasitocidal effect of DHA was required for all four maturation stages of the P. berghei life-cycle. 
Conclusions: This new mechanism-based model described the rise in parasitaemia after murine inoculation, the nadir following DHA dosing, and subsequent parasite resurgence. This model holds great promise to serve as a basis for other malaria parasites, to optimise antimalarial combination therapy and for ultimate translation from mice to man.