Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria

Abstract

Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation.

FIG. 1

Whole-blood mefloquine concentrations during follow-up in each of the treatment groups. Data points represent the median values, and error bars extend to the 10th and 90th percentiles. (A) Group A, mefloquine (25 mg/kg on day 2) with food; (B) group B, mefloquine (15 mg/kg on day 2 and 10 mg/kg on day 3) with food; (C) group C, mefloquine (25 mg/kg on day 0) with food; (D) group D, mefloquine (25 mg/kg on day 2) without food.