Effect of high-dose or split-dose artesunate on parasite clearance in artemisinin-resistant falciparum malaria

Abstract

Background: The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions.

Methods: In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009-2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed.

Results: A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89-7.28) hours in Pailin versus 3.42 (2.20-4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68).

Conclusions: Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum. Clinical Trials Registration. ISRCTN15351875.

Figure 1.

Enrollment, randomization, and follow-up of the patients in the 2 study sites. Please see the Methods section for a description of the study arms. Abbreviations: AS, artesunate; f-up, follow-up.

Figure 2.

Log-linear parasite clearance curves expressed as percentage of admission parasitemia. A, Compares the 4 treatment arms between the 2 study sites in Pailin in western Cambodia and Wang Pha in northwestern Thailand. B, Compares single versus twice-daily dosing between the 2 study sites. Please see the Methods section for a description of the study arms.

Figure 3.

A, Parasitemia half-life according to study arm and study site. B, Parasite clearance time according to study arm and study site. Abbreviation: IQR, interquartile range.

Figure 4.

Total artesunate (A) and dihydroartemisinin (B) exposure and maximum artesunate (C) and dihydroartemisinin (D) concentrations in Pailin (filled squares) and Wang Pha (open circles) after the first dose in the different treatment arms (3 mg/kg and 4 mg/kg are twice-daily dose groups and 6 mg/kg and 8 mg/kg are once-daily dose groups). All exposure measurements are dose (mg) normalized. Abbreviations: AUC_0-∞, predicted area under the plasma concentration time curve after the first dose from zero time to infinity; C_max, maximum observed plasma concentration after oral administration.