Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Abstract

h 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. O ral artesunate (AS) is an important drug used in the control of multidrug-resistant Plasmodium falciparum malaria. However, the mechanism of action for this class of drugs, known as the artemisinins, and thus potential mechanisms for development of drug resistance remain poorly understood. Semimechanistic models of parasite dynamics have been proposed to explain the potential effects of drug on parasite sequestration in unmeasurable compartments (16,18). Selective effects of drug on early parasite ring stages were found to explain differences in parasite clearance observed between patients treated in Thailand and Cambodia using intrahost mathematical modeling of pharmacokinetic (PK)-pharmacodynamic (PD) relationships (36). Autoinduction of metabolism has been suggested for drugs in this class (15,17), representing a possible confounder to parasite-based mechanisms of resistance. The current models provide only limited explanations for artesunate resistance, creating an ongoing need for additional empirical data.We recently reported evidence of artesunate resistance in malaria parasites from patient...

How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

“…The results from the sensitivity analysis of PRR 48 and iRBC clearance rates are shown on Table 1. The correlations among the artemisinin killing rate, the partner drug killing rate, the duration of artemisinin killing, and overall drug effectiveness measured as the PRR 48 are high.…”

“…As a reference to interpret these killing rates on an hourly scale, killing rates of 0.19, 0.14, and 0.096 are equivalent to PRR 48 values of 10 Ϫ4 (because e Ϫ48 ϫ 0.19 ϭ 10 Ϫ4 ), 10 Ϫ3 , and 10 Ϫ2 , respectively, assuming that all parasite stages are equally sensitive. In fact, not all stages are equally sensitive, which is why the killing rates for the sensitive stages have to be increased to compensate for the lack of killing in the nonsensitive stages to maintain the same PRR 48 values (see the supplemental material for details).…”

“…Drug killing rates are expressed in units per hour and are obtained from the more familiar parasite reduction ratio at 48 h (PRR 48 ), which is the ratio of the number of parasites present at the start of treatment divided by the number remaining 48 h later, for the methodological reasons explained in the text around Equation S1.1 in the supplemental material. As a reference to interpret these killing rates on an hourly scale, killing rates of 0.19, 0.14, and 0.096 are equivalent to PRR 48 values of 10 Ϫ4 (because e Ϫ48 ϫ 0.19 ϭ 10 Ϫ4 ), 10 Ϫ3 , and 10 Ϫ2 , respectively, assuming that all parasite stages are equally sensitive.…”

“…The correlations among these four factors, drug effectiveness, and iRBC clearance rates were measured. Drug effectiveness was quantified by using the conventional metric of the PRR 48 . More effective treatments will kill more parasites and consequently will result in a higher PRR 48 .…”

Effects of Body Size and Gender on the Population Pharmacokinetics of Artesunate and Its Active Metabolite Dihydroartemisinin in Pediatric Malaria Patients

“…This interval was adopted because, at the time of this analysis, a clear relationship between concentrations and clinical efficacy has remained largely undefined for the artemisinin derivatives (32). However, were such a relationship to be determined, the full covariate modeling in the present analysis could be reinterpreted.…”