Development of a pharmacodynamic model of murine malaria and antimalarial treatment with dihydroartemisinin.

Antimalarial treatment strategies based on in vitro studies are limited by the paucity of pharmacodynamic information for dosage regimen design. We postulated that a murine model could be used for pre-clinical stages of drug development, especially in dose-response studies and evaluation of combination therapies. Swiss mice infected with Plasmodium berghei parasites (2-5% starting parasitaemia) were given dihydroartemisinin (0-100 mg/kg single dose). Parasite density was regularly determined from thin blood films. A parasite population growth model comprising parasite multiplication, decline in erythrocyte count with increasing parasitaemia and parasite clearance after drug administration was developed. This model described the rise in parasitaemia following inoculation, the nadir following dihydroartemisinin administration, and the subsequent resurgence of parasitaemia (analogous to 'recrudescence'). At doses of 10, 30 and 100 mg/kg dihydroartemisinin, there was a graded response with 2.5+/-1, 5+/-1 and 12+/-4-fold decreases in parasitaemia, respectively. The nadir parasitaemia (at 21-27 h) was also dose-dependent. This study demonstrates that a murine malaria pharmacodynamic model is a valuable tool for understanding how single drugs and their dosing schedules alter the time course and level of infection.