Population pharmacokinetics of mefloquine given as a 3-day artesunate–mefloquine in patients with acute uncomplicated Plasmodium falciparum malaria in a multidrug-resistant area along the Thai–Myanmar border

Abstract

BackgroundLow mefloquine exposure has been shown to contribute to treatment failure in patients with uncomplicated falciparum malaria following a 3-day artesunate–mefloquine combination. The present study aimed to develop a population pharmacokinetic model for mefloquine based on whole blood concentration–time profiles of this target population for further dose optimization.MethodsA total of 129 Burmese patients aged above 15 years who presented with typical symptoms of malaria and had a blood smear positive for Plasmodium falciparum were included in the study. All were treated with the standard 3-day combination regimen of artesunate and mefloquine consisting of mefloquine for 2 days and artesunate for 3 days. Blood samples were collected before and at different time points after drug administration from different sub-groups of patients. Mefloquine concentrations were quantified in whole blood using high-performance liquid chromatography. A non-linear mixed-effect modelling approach was applied for population pharmacokinetic analysis using the NONMEM v7.3 software. Covariates investigated (body weight, gender, admission parasitaemia, and molecular markers of mefloquine resistance) were investigated in a step-wise manner using the SCM functionality in Perl-Speaks-NONMEM.ResultsPopulation pharmacokinetic analysis of mefloquine was performed in all patients with a total of 653 samples. Whole blood mefloquine concentration–time profiles were described by a two-compartment disposition model. Of the covariates investigated, none was found to have a significant impact on the pharmacokinetics of mefloquine. Significant differences in maximum concentration (Cmax) and elimination half-life (t1/2) were found in patients who had treatment failure (36 cases) compared to patients with successful treatment (107 cases).ConclusionThe study successfully describes the pharmacokinetics of mefloquine following a 2-day treatment of mefloquine as a part of a 3-day artesunate–mefloquine in patients with uncomplicated falciparum malaria from Thailand. A model has been developed which adequately describes the pharmacokinetics of mefloquine. More extensive clinical studies including both adults and children are needed to fully characterize the pharmacokinetics of mefloquine.

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

“…A higher dose of 25 mg/kg is finally recommended to account for the decline in mefloquine sensitivity 95 . The population PK of a 2‐day course of mefloquine (15 and 10 mg/kg on the first and second days) in artesunate‐mefloquine was also developed for optimization of mefloquine in Burmese patients with MDR P falciparum on the Thai‐Myanmar border 96 . It is critical that the artesunate dose and frequency of administration are carefully assessed and optimized in the event of emerging drug resistance and dose‐dependent toxicity (increased risk of neutropenia with a high dose of 6 mg/kg) 97,98 .…”

“…95 The population PK of a 2-day course of mefloquine (15 and 10 mg/kg on the first and second days) in artesunate-mefloquine was also developed for optimization of mefloquine in Burmese patients with MDR P falciparum on the Thai-Myanmar border. 96 It is critical that the artesunate dose and frequency of administration are carefully assessed and optimized in the event of emerging drug resistance and dose-dependent toxicity (increased risk of neutropenia with a high dose of 6 mg/kg). 97,98 Analysis of the parasite clearance time of artesunate-mefloquine from clinical trials in Thailand suggested the 2-mg/kg oral artesunate be the minimum dose that produces maximum effect, 99 but the 4-mg/kg target dose was selected for use in artesunatemefloquine to account for the marked interindividual variation in drug exposure.…”

Identification and characterization of novel chemical scaffolds to overcome drug resistance in malaria

“…Thailand similarly began using artesunate-mefloquine, until resistance to artemisinin and later mefloquine meant that even the adoption of a prolonged treatment regime was no longer effective [103,114]. Dihydroartemisinin-piperaquine was then introduced in 2015, but a failure rate of almost 93% in the north-eastern region of Thailand was observed in 2017, possibly due to imported cases from the Cambodian border [113].…”