New Mathematical Models of Antimalarial Drug Action to Improve Drug Dosing Regimens

Abstract

Plasmodium falciparum malaria remains a major threat to global public health. Artemisinin-based combination therapies—a critical component of current control strategies—are at risk of failure due to the emergence of artemisinin resistance. To extend the life of artemisinin-based therapies, it is crucial that we develop a better understanding of how they act to reduce parasitemia in the host. Recent laboratory-based experiments have demonstrated that parasites respond to the cumulative, rather than instantaneous, drug concentration. This observation directly challenges the standard paradigm of pharmacokinetic–pharmacodynamic (PK–PD) modelling. Here, we introduce a generalisation to the PK–PD model which accounts for cumulative exposure. Parasites accumulate ‘stress’, which translates into an effective killing rate which can vary with both drug concentration and exposure time. Our model indicates how drug-resistant parasites may avoid killing. Through simulation, we explore alternative drug dosing strategies that may overcome drug resistance.