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

28 Jun 2021

Dini S, Zaloumis SG, Price DJ, Gobeau N, Kümmel A, Cherkaoui M, Moehrle JJ, McCarthy JS, Simpson JA

The Journal of antimicrobial chemotherapy
PMID: 34179977

Doi: 10.1093/jac/dkab181

Photo: BrianAJackson/iStock

BACKGROUND

The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs.

OBJECTIVES

This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model.

METHODS

A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite's life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework.

RESULTS

The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration.

CONCLUSIONS

Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. 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. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.

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