Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria

Abstract

The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria. Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) microgram/ml after regimen A, 9. 0 (1.1 and 19.8) microgram/ml after regimen B, and 8 (1.4 and 17.4) microgram/ml after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 microgram/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.

FIG. 1

Model-based median population profile of plasma lumefantrine concentrations for regimens A (four doses of four tablets) (solid line), B (six doses of four tablets, 60 h) (dotted line), and C (six doses of four tablets, 96 h) (dashed line). Four tablets equalled 80 mg of artemether and 480 mg of lumefantrine. (a) Bangkok (16, 18, and 17 patients for regimens A, B, and C, respectively). (b) Mae La (74, 72, and 69 patients for regimens A, B, and C, respectively).

FIG. 2

Model-based median population profile of plasma lumefantrine concentrations for regimen B (six doses of four tablets, 60 h), superimposed on a box plot (minimum, lower quartile, median, upper quartile, and maximum) of the observed plasma drug concentrations derived from frequent sampling (dense data) in 18 patients to illustrate goodness of fit.

FIG. 3

Relationship between the interpatient deviation (η) in F₁ and the log parasite count on admission.

FIG. 4

Relationship between the interpatient deviation (η) in F₁ and body temperature on admission.

FIG. 5

Relationship between the interpatient deviation (η) in estimated CL and age on admission.

FIG. 6

Relationship between the log parasite count on admission and the time to fall below a plasma lumefantrine concentration of 280 ng/ml. Horizontal line, median log parasite count; vertical line, median time to reach 280 ng/ml. The closed circles represent patients whose infections subsequently recrudesced, and the open squares represent patients who were treated successfully.

FIG. 7

Relationship between the EKG QTc and the estimated plasma lumefantrine concentrations on days 3 to 29. Horizontal line, median QTc.