Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon

Abstract

Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated, and potential covariates influencing the pharmacokinetic properties were assessed. A population pharmacokinetic analysis was performed with 264 pregnant women from a randomized controlled trial evaluating a single and a split-dose regimen of two 15-mg/kg mefloquine doses at least 1 month apart versus SP-IPTp. Both enantiomers of mefloquine and its carboxy-metabolite (CMQ), measured in plasma and cord samples, were applied for pharmacokinetic modelling using NONMEM 7.3. Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group, mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r2 0.84) at delivery. With the dosing regimens investigated, prophylactic levels are not constantly achieved. A modeling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens; however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as a valuable tool for researchers and clinicians to develop and optimize alternative dosing regimens for IPTp in pregnant women.