2026-10-14T06:29:59Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34025285 2026-09-29T17:05:07Z category_915 category_7 category_8 category_13 category_46 category_734 category_811 portal_63 item_type_6 month_year_09_2026

Translational Pharmacokinetic and Pharmacodynamic Evaluation of Mefloquine Against Plasmodium falciparum Using a Hollow Fiber Infection Model Sabiha R. Mim (25138037) Kiana Pica (25138040) Lili Liu (111724) Yanan Zang (25138043) Yinzhi Lang (11423653) Jürgen B. Bulitta (1647445) Francine Johansson Azeredo (22751078) Physical Sciences not elsewhere classified Medicine Microbiology Genetics Immunology Biological Sciences not elsewhere classified Mathematical Sciences not elsewhere classified observed parasitemia dynamics guided regimen design adult malaria patients flow culture conditions quantify antimalarial pharmacodynamics improve clinical relevance dynamic exposure conditions plasmodium falciparum </ commonly used plastic 100 mg intravenous simulation study based stage 3d7 parasites like mefloquine exposure falciparum </ control conditions dynamic drug clinical concordance 03 mg study established study demonstrated intravenous mefloquine vitro assays subsequently implemented reproduce human rational evaluation promising framework programmed dilution pharmacodynamic evaluation order elimination mimic first future studies free controls extracapillary space estimated ic50 dosing simulated based hfim asynchronized ring animal models addresses limitations 3 days 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 <i>Plasmodium falciparum</i>. 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 <i>P. falciparum</i>. 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. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/acsptsci.6c00482.s001 https://figshare.com/articles/journal_contribution/Translational_Pharmacokinetic_and_Pharmacodynamic_Evaluation_of_Mefloquine_Against_Plasmodium_falciparum_Using_a_Hollow_Fiber_Infection_Model/34025285 CC BY-NC 4.0