Artemisinin-resistant
malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of
drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral
artesunate monotherapy were explored in a dose-ranging trial in an area of emerging
artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated
Plasmodium falciparum malaria in an open label study of directly observed
artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of
body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in
artesunate and
dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline
parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable
artesunate dose (4 mg/kg/day) and baseline
parasitemia from the two studies. Reduced plasma
drug levels with higher presentation
parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated
malaria. Neither in vitro parasite susceptibility nor plasma
drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral
artesunate on
malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships.