Seeking an optimal dosing regimen for OZ439-DSM265 combination therapy for treating uncomplicated falciparum malaria

Abstract

The efficacy of Artemisinin-based Combination Therapies (ACTs), the first- line treatments of uncomplicated falciparum malaria, has been declining in malaria endemic countries due to the emergence of malaria parasites resistant to these com- pounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model that accounts for the pharmacodynamic interaction between the two drugs. Model parameters were estimated using data from healthy volunteers infected with falciparum malaria collected from four trials: three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439-DSM265. Posterior predictive simulations of the model were performed to determine efficacious dosing regimens. One such regimen that predicted at least 90% of infected individuals cured 42 days after the administration of the drugs, while within the tolerable dose range, is 800 mg of OZ439 and 450 mg of DSM265. Our model can be used to inform future phase 2 and 3 clinical trials of OZ439-DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing.