Translational Pharmacokinetic and Pharmacodynamic Evaluation of Mefloquine Against Plasmodium falciparum Using a Hollow Fiber Infection Model

Abstract

This study established a plastic-based hollow fiber infection model (HFIM) to reproduce human-like mefloquine exposure and quantify antimalarial pharmacodynamics (PD) against blood-stage Plasmodium falciparum. Asynchronized ring-stage 3D7 parasites were maintained in the extracapillary space under continuous-flow culture conditions that supported sustained growth across two consecutive 48 h intraerythrocytic life cycles. The observed parasitemia dynamics were comparable in static and dynamic drug-free controls. Target total plasma concentration time profiles for intravenous mefloquine were generated using a pharmacokinetic (PK) simulation study based on previously reported compartmental models from adult malaria patients and subsequently implemented in the HFIM through programmed dilution to mimic first-order elimination, with dosing simulated as a 100 mg intravenous (IV) bolus every 24 h for 3 days. The HFIM exposure profile maintained clinically relevant peak concentrations with the long clinical PK half-life of mefloquine. Under these dynamic exposure conditions, mefloquine produced sustained suppression of parasitemia across successive life cycles relative to both control conditions, consistent with concentration-driven blood-stage activity. The estimated IC50 was 0.03 mg/L. Together, this study demonstrated that the commonly used plastic-based HFIM can simulate clinically relevant PK profiles and characterize the antimalarial PD against blood-stage P. falciparum. This addresses limitations of static in vitro assays and reduces the reliance on animal models, where preclinical-to-clinical concordance can be poor. Thereby, HFIM provides a promising framework for optimizing antimalarial dosing strategies. Future studies will extend this approach to rational evaluation of combination therapies using PK/PD-guided regimen design to improve clinical relevance.