A population pharmacokinetics analysis of OZ439 disposition in patients

OZ439 is a synthetic trioxolane undergoing clinical investigation and being developed by MMV as a potential anti-malarial therapy. OZ439 has shown in vivo a potential for a single dose cure in Plasmodium falciparum malaria while showing in in vitro and in vivo models marked prophylactic potential, extended half-life and oral bioavailability, and increased metabolic stability. Data from Phase I study in healthy volunteers and the on-going Phase IIa have confirmed OZ439 to be safe and tolerable. The pharmacokinetics (PK) of OZ439 will help determine its potential as a single dose cure. PK data from the on-going Phase IIa investigation in patients was analysed using a non-linear mixed effects approach. In this study single doses of OZ439 have been orally administered to patients. The optimal structural model was a 2 compartment model with oral absorption. The oral absorption had a lag time associated with it. Interindividual variability was attributed to the central volume of distribution, clearance and lag time. The observed PK was linear with a clearance of 65.7 L/hr and an elimination half-life of 53 hours; thus the PK supported OZ439's potential as a single dose cure. This population PK model will aid in predicting the time course of OZ439 at different doses and will be updated as more data is collected. This will include determining the covariates of the PK parameters in order to characterise the effects of age, co-administered drugs, and ethnopharmacology. A major benefit of characterising the PK in this manner is the ability to use these parameters in PK/PD models, to make population predictions of OZ439's efficacy as an anti-malarial, to confirm the suitability of OZ439's PK for a single dose cure and to design future clinical trials.