Mefloquine Pharmacokinetic-Pharmacodynamic Models: Implications for Dosing and Resistance

Abstract

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response <28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

Efficacy of Mefloquine and a Mefloquine-Artesunate Combination Therapy for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Amazon Basin of Peru

“…This recommendation is based on mathematical modeling of pharmacokinetic and pharmacodynamic data from Thailand, which has shown that initial use of a 15 mg/kg dose provides a greater opportunity for selection of resistant mutations and could thus lead more rapidly to resistance than a dose of 25 mg/kg. 12 Different commercial preparations of MQ are known to vary in terms of their bioavailability. 13 A recent study in Thailand comparing Lariam ® (F. Hoffmann La Roche, Basel, Switzerland) with two other commercial preparations, Mephaquin ® and Eloquine ® (Medochemie, Ltd., Limassol, Cyprus) showed that blood levels and the area under the curve with Mephaquin ® were 50% lower that those with Lariam ® .…”

Making the Most of Clinical Data: Reviewing the Role of Pharmacokinetic-Pharmacodynamic Models of Anti-malarial Drugs

“…A number of studies have not attempted formal parameter estimation and simply draw on the existing literature to specify model parameters that are both biologically plausible and result in observed parasite kinetics that mimic experimental observations (5)(6)(7)9,12,13,15,(18)(19)(20) (Table I). Whilst potentially providing useful therapeutic insights, it is possible that an alternative model parameterization may exist that could represent the observed data equally well but provide markedly different conclusions in terms of the magnitude of the killing effect of the drug and the shape of the concentration-effect relationship.…”

“…2. Continuous-time within-host pharmacokinetic-pharmacodynamic models: a Total parasite burden models (5,7,13,15,18,19,20); b Stage-specific models (11). Note, k death was assumed to be determined by the killing action of the anti-malarial and host immunity; c Stage-specific models (10,17,21).…”

“…Some of these mechanistic PK-PD models have been fitted formally to patient parasite-time profiles to obtain parameter estimates (10,11,14,16,17,21,22), whereas others have simply selected parameter values that generate parasitetime profiles that accord well with the profiles from clinical studies (5)(6)(7)9,12,13,15,(18)(19)(20). Both of these approaches are dependent on empirical data defining the dynamics of the parasite burden.…”

“…These models can be incorporated in population-level analyses to predict the selection and spread of drug resistance (8). A variety of within-host PK-PD models have been described for falciparum malaria, and there is a wide variation in the number of biological parameters describing the parasite life cycle and PD effect of the anti-malarial treatment (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The accuracy of these models in predicting the change in parasite burden following treatment depends on many factors.…”