The population pharmacokinetics of OZ439 in healthy volunteers and patients with falciparum and vivax malaria

Aims: Artemisinin-based combination therapies are the recommended first-line treatment for falciparum malaria. Artemisinin derivatives, containing the peroxide pharmacophore, are the most potent and rapidly acting antimalarial drugs available. OZ439 is a novel synthetic trioxolane with a similar pharmacophore but with improved pharmacokinetic (PK) properties of prolonged elimination half-life and therefore prolonged antimalarial activity [1]. The aim of this work was to characterise the population PK properties of OZ439 in patients with falciparum and vivax malaria in Thailand.


Methods: Data were obtained from a phase 2a exploratory, open-label trial in 81 adult patients with acute, uncomplicated falciparum or vivax malaria. Patients were assigned to receive OZ439 as a single oral dose of 200 mg (n=20), 400 mg (n=20), 800 mg (n=20) or 1200 mg (n=21). Blood samples of OZ439 and its metabolites were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 168 hours post-dose. A population analysis was performed using NONMEM v.7.3. Concentrations measured to be below the lower limit of quantification were accounted for using the M3-method. One-, two- and three-compartment disposition models were evaluated. Zero-order, first-order with and without lag time and transit compartments were explored as absorption models. Covariates tested included total body weight, lean body weight, age, sex, dose and infection (falciparum vs vivax). Model evaluation was performed using likelihood ratio testing (OFV) and visual predictive checks (VPCs).


Results: The PK properties of OZ439 were best described by three transit compartments in the absorption phase followed by two distribution compartments with first-order elimination. Total body weight was a significant covariate on clearance and volume of distribution parameters. Dose was found to be a significant covariate resulting in a decreased mean transit time with increasing doses.


Conclusion: The PK properties of OZ439 were well described by the developed population PK model. Final PK parameter estimates had high precision and the final model showed a high predictive performance, suggesting it to be suitable for further optimal trial design simulations. This will be a crucial tool in the further development of the antimalarial drug OZ439. The developed model will also be expanded to include all measured OZ439 metabolites. 




1.  Phyo P et al. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2016;16(1):61-9.