Introduction Mefloquine is 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 its 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.
Materials and Methods A population pharmacokinetic analysis was performed with 264 pregnant women of a randomized controlled trial evaluating a single and split-dose regimen of two 15 mg/kg mefloquine dosings at least one month separated versus SP-IPTp. Both mefloquine enantiomers and its carboxy-metabolite (CMQ), measured in plasma and cord, were applied for pharmacokinetic modelling using NONMEM 7.3.
Results Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group the 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 investigated dosing regimens prophylactic levels are not constantly achieved. A modelling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented.
Discussion 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 valuable tool for researchers and clinicians to develop and optimise alternative dosing regimens for IPTp in pregnant women.
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