Lumefantrine

/ALTERNATIVE IN VITRO TESTS/ Using a continuous in vitro culture system, the sensitivity of Plasmodium falciparum to artemether and a new antimalarial drug, benflumetol (lumefantrine), alone and in combination, was investigated with a multiresistant strain (T-996) from Thailand and a chloroquine-resistant strain (LS-21) from India. Both strains showed similar 50% inhibitory concentration (IC50) levels with artemether alone or benflumetol alone, but the IC90 was higher in strain T-996 compared with strain LS-21: for artemether, 34.45 and 7.11 nmol/L (10.28 and 2.12 ng/mL of erythrocyte-medium mixture [EMM]), and for benflumetol, 293.03 and 95.61 nmol/L (154.69 and 50.47 ng/mL of EMM). When tested in association at artemether:benflumetol (mol: mol) ratios between 100:1 and 1:100, substantial synergism was seen in both strains, especially at the IC90 and IC99 levels.

Lumefantrine

22.4

94.7

Lumefantrine is given in combination with artemether as COARTEM tablets. COARTEM tablets should be administered over 3 days for a total of 6 doses: an initial dose, second dose after 8 hours, and then twice-daily (morning and evening) for the following 2 days. The adult dosage for patients with bodyweight of 35 kg and above is 4 COARTEM tablets per dose for a total of 6 doses over 3 days. COARTEM tablets are scored and contain 20 mg artemether and 120 mg lumefantrine.

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 960 mg/day, Lowest Therapeutic Dose (LTD): 12.0 mg/kg-day, and Screening Dose: 0.004 mg/kg-day.

7-Jun-22

Food increases absorption.

The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. ... The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria.

The pharmacokinetics of benflumetol as a fixed combination, artemether-benflumetol (CGP 56697), following three regimens (regimen A: four tablets at 0, 8, 24 and 48 hr (320 mg artemether, 1,920 mg benflumetol); regimen B: two tablets at 0, 8, 24 and 48 hr (160 mg artemether, 960 mg benflumetol); regimen C: four tablets at 0, 8 and 24 hr (240 mg artemether, 1,440 mg benflumetol)) were investigated in 39 patients with acute uncomplicated falciparum malaria. All patients showed a rapid initial response with a median parasite clearance time of 40, 41 and 39.5 hr and a fever clearance time of 27.8, 32 and 24.5 hr for regimens A, B and C, respectively. In nine patients (two, four and three patients in regimens A, B and C, respectively), however, parasitemia reappeared in the peripheral blood smear between days 9 and 23. The pharmacokinetics of benflumetol were highly variable, with coefficients of variation in pharmacokinetic parameters ranging from 14.9% to 144%. Absorption and elimination of benflumetol were relatively slow. Median Cmax per dose (first dose) was significantly higher in regimen B (6.29 ng/ml/mg dose) than in regimen A (2.6 ng/ml/mg dose) and regimen C (3.06 ng/ml/mg dose). Mean T1/2z in regimen C (2.65 hr) was significantly shorter than in regimen A (4.5 hr) and regimen B (3.89 hr). In patients on regimens A and B who showed a sensitive response, plasma concentrations of benflumetol were significantly higher than in those with treatment failure.

...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 hr. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) ug/mL after regimen A, 9. 0 (1.1 and 19.8) ug/mL after regimen B, and 8 (1.4 and 17.4) ug/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 ug/mL (median for regimen B, 252 hr; that for regimen C, 298 hr; that for regimen A, 204 hr [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.