Prediction of improved antimalarial chemotherapy of artesunate-mefloquine in combination with mefloquine sensitive and resistant Plasmodium falciparum malaria

BACKGROUND: Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment. OBJECTIVE: This study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant P. falciparum malaria. METHODS: Data collected during 2008–2009 from 124 patients with uncomplicated P. falciparum malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients’ adherence and parasite biomass. RESULTS: The developed PK/PD models well described with clinically observed data. For mefloquine-resistant P. falciparum, a three-day standard regimen of artesunate-mefloquine is suitable (>50% efficacy) only when the level of parasite sensitivity was < 1.5-fold of the cut-off level (IC(50) < 36 nM). For mefloquine-sensitive parasite with IC(50) < 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC(50) of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C(336h) (>408 ng.mL(-1)) or C(max)/IC(50) (>130.1 g.m/M), and C(max)/IC(50) (>381.2 g.m/M), respectively. CONCLUSIONS: Clinical use of a three-day standard artesunate-mefloquine is suitable only when the IC(50) of P. falciparum isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC(50) is lower than 23.19 nM.