Combinations of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics

Abstract

Combinations of artemisinin and quinine for uncomplicated falciparum malaria were studied. A total of 268 patients were randomized to 7 days of quinine at 10 mg/kg of body weight three times a day (Q) or to artemisinin at 20 mg/kg of body weight followed by 3 (AQ3) or 5 (AQ5) days of quinine. Recrudescence rates were 16, 38, and 15% for the Q, AQ3, and AQ5 groups, respectively (P < 0.001). Recrudescence was associated with shorter parasite clearance time (PCT) and longer treatment after the blood smear had become negative (eradication time). However, classification of patients to outcome-recrudescence or radical cure-was correct in only 77% of patients. The population kinetics of the parasitemia was estimated with nonlinear mixed-effect models. Several models were tested, but the best model was a monoexponential decline of the parasitemia in which the mean parasite elimination half-life was shorter after artemisinin (5.1 h; 95% confidence interval [CI], 4.9 to 5.2 h) than after quinine (8.0 h [95% CI, 7.5 to 8.3 h]). Attempts to simulate the initial increase of the parasitemia did not result in better models with a biologically plausible interpretation. Recrudescence was associated with slower parasite clearance and a higher simulated terminal parasitemia (P(term)). The classification of patients to outcome groups based on P(term) was correct in 78% of patients. The data suggest that parasite strains with reduced sensitivity to quinine are prevalent in Vietnam, with slower parasite clearance and consequent recrudescence. A single dose of artemisinin induces rapid parasite reduction and lowers the value of P(term), but to prevent recrudescence, this should be followed by quinine for at least 3 days after parasite clearance, or 5 days in total.

Figures

FIG. 1

Kaplan Meier curve of the cumulative recrudescence of P. falciparum after treatment with quinine monotherapy for 7 days (Q [○]) or a single dose of artemisinin followed by either 3 days of quinine (AQ3 [●]) or 5 days of quinine (AQ5 [□]) (P < 0.001; log-rank test).

FIG. 2

P. falciparum parasitemia simulated by an exponential elimination model (see text) during treatment with quinine monotherapy for 7 days (Q) or a single dose of artemisinin followed by either 3 days of quinine (AQ3) or 5 days of quinine (AQ5). The arrow indicates the single dose of 1 g of artemisinin, and the shaded bar indicates the duration of treatment with quinine. L.d., limit of detection. ——, patients with radical cure; ............, patients with late recrudescence; ······, patients with early recrudescence.

FIG. A1

Geometric mean parasitemia of P. falciparum during treatment with quinine monotherapy for 7 days (Q [○]) or a single dose of artemisinin followed by either 3 days of quinine (AQ3 [●]) or 5 days of quinine (AQ5 [□]). The bars indicate the 95% CIs. A parasitemia measurement below the detection level (negative blood smear) was entered as 3 parasites per μl.