Modeling the potential effect of cabamiquine-pyronaridine for chemoprevention against Plasmodium falciparum malaria

ABSTRACT Preventive treatment (chemoprevention) is a key intervention for reducing the burden of Plasmodium falciparum malaria in children. The impact of the current widely used drug combination, sulfadoxine-pyrimethamine-amodiaquine (SP-AQ), is challenged by emerging drug resistance and adherence to multi-day dosing. Cabamiquine is a novel antimalarial with activity against liver- and blood-stage malaria parasites, administered as a single dose, and under development in combination with pyronaridine. We used mathematical modeling to translate early phase 1 clinical results into estimates of its potential impact as malaria chemoprevention. Pharmacokinetic-pharmacodynamic (PKPD) models of cabamiquine and pyronaridine were combined, assuming Bliss independence, to estimate time-varying protection against infection. PKPD results were incorporated into an established individual-based malaria transmission model to estimate the impact of seasonal malaria chemoprevention (SMC) across settings with differing transmission and seasonality. Cabamiquine-pyronaridine was predicted to provide protection of >95% for approximately 4 weeks, slightly outperforming SP-AQ even in children who fully adhere to SP-AQ treatment. Six weeks after treatment, cabamiquine-pyronaridine protection dropped for the regimens containing <200 mg cabamiquine, but the combination could still outperform SP-AQ at doses ≥200 mg. If deployed as SMC, a longer duration of protection may enable fewer, more widely spaced treatment cycles while maintaining impact, improving projected cost-effectiveness. Cabamiquine-pyronaridine shows strong potential as a next-generation single-dose chemoprevention regimen, supporting continued clinical development and evaluation.