Population pharmacokinetic and pharmacodynamic properties of OZ439 in healthy volunteers and patients with falciparum and vivax malaria

Background: Increased deployment of artemisinin-based combination therapies (ACTs) has been an important contributor to the recent reductions in malaria, but control and elimination goals are now threatened by the emergence of artemisinin resistance in the Greater Mekong sub-region [1]. New drugs with efficacy and safety profiles which are comparable to the ACTs are needed. OZ439 or artefenomel is a new synthetic trioxolane antimalarial drug with a similar peroxide pharmacophore to the artemisinins [2].             


Aim: To characterise the population pharmacokinetic-pharmacodynamic properties of OZ439 in healthy volunteers and patients with falciparum and vivax malaria.


Methods: Data from healthy volunteers (n=52) and patients with acute uncomplicated falciparum or vivax malaria (n=81) were available from two separate clinical trials. Subjects were assigned to receive 50, 100, 200, 400, 800, 1200 or 1600 mg of OZ439 as multiple single oral doses for healthy volunteers and as a single oral dose for patients. Two different formulations were administered. Drug concentration-time data were pooled and parasite count data were used to estimate the drug-dependent parasite killing. A population analysis was conducted using NONMEM 7.3.


Results: A two-compartment transit absorption model followed by a two-compartment disposition model with first-order elimination provided the best description of the observed concentration-time data. The final model was allometrically scaled for fat free mass. Oral bioavailability of OZ439 was substantially reduced in Asian patients with acute malaria infections compared to non-Asian healthy volunteers, and absorption was markedly different between the suspension and capsule formulation. Drug-dependent killing was best described by a delayed exposure-response relationship (implemented as an EMAX-model), resulting in a potent antimalarial effect of OZ439.      


Discussion: The pharmacokinetic properties of OZ439 in healthy volunteers and patients with malaria were well described by the developed population model. OZ439 showed a potent antimalarial effect.    



1. Ashley et al, N Engl J Med 2014; 371: 411-23

2. Charman et al, Proc Natl Acad Sci 2011; 108: 4400-5