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.

Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy?

“…In a previous study, we showed that extending the duration of quinine monotherapy was equally effective in lowering P term and reducing recrudescence, as was adding a single starting dose of artemisinin before administration of quinine. 12 The critical value of P term to prevent early recrudescence was ϳ 1 parasite/L, comparable to the value found in this study.…”

“…12 In brief, P term is a simulated value, in most cases far below the detection limit. A line connecting P term and the parasite count of patients with a recrudescence represents the replication rate after treatment.…”

Therapeutic Efficacies of Artemisinin-Based Combination Therapies in Nigerian Children with Uncomplicated Falciparum Malaria during Five Years of Adoption as First-Line Treatments

“…38 The parasitemia half-life of 1 hour provides a baseline for which future changes in parasite population in vivo and in vitro susceptibility profiles from this endemic area may be measured or compared, and it may be relevant in the evolution of drug resistance to the adopted ACTs. With an overall parasitemia half-life of 1 hour, it would seem likely that genuine differences occur in the parasitemia kinetics after artemisinin or ACTs administration in children from this endemic area and in patients from Vietnam (8 hours) 39 or Thailand (3 hours), 35 where the half-lives of parasitemia are considerably longer than in the present study. These differences may be related to different sampling times, different pharmacokinetic models, population variations in drug handling, and regional differences in susceptibilities in P. falciparum isolates to artemisinins and the partner drugs 36 in a region where recent data suggest that artemisinin resistance has developed.…”

Plasmodium falciparum Na+/H+ Exchanger (pfnhe-1) Genetic Polymorphism in Indian Ocean Malaria-Endemic Areas

“…1 To date, resistance to QN remains particularly patchy and rare, [2][3][4][5][6][7][8][9][10][11][12] and only few cases of clinical failure have been reported in Asia and South America. The mechanism underlying QN resistance is not well-understood, and it is probably complex and multigenic.…”