Pharmacometric modelling of antimalarial drugs in development: from challenge to clinics

Aims: guide the dose finding in clinical studies based on the Induced Blood Stage Malaria (IBSM) challenge studies and population pharmacokinetic-pharmacodynamic (PKPD) modeling.

Methods: Two compounds (OZ439 and DSM265) were tested in IBSM challenge studies1. In these studies, P. falciparum was inoculated to healthy volunteers. When parasitemia had developed to a level detectable by real-time quantitative polymerase chain reaction (qPCR) but below the level of detection by microscopy, the treatment was administered. PK concentrations were measured and parasite densities were assessed by qPCR. Typically, each cohort comprised of 8 subjects. OZ439 was tested at 3 single doses (100, 200 and 500 mg) in one challenge study. DSM265 was tested at 2 single doses (150 and 400 mg) in two challenge studies. A population PKPD model was built based on the generated PK and PD data. For DSM265, PK concentrations from First-In-Human studies were added, allowing coverage of a wider range of dose levels. Based on the developed model, parasitemia profiles in patients were predicted for a number of dose level combinations. The underlying assumption was that the model, developed based on IBSM data is valid also for patients, when using higher baseline parasitemia values. The model was then used to predict the parasitemia profiles in patients assuming the parameters of the model are similar as those estimated with the IBSM data, except the baseline parasitemia which was set higher for the patients. The predictions were compared with Phase 2a data in uncomplicated P.falciparum patients. Modelling and simulation were performed in Monolix (version 4.3.3) using the IQM Tool (version 1.2) as an interface.

Results: A population PKPD model was obtained for each compound with a similar approach: first a population PK model was developed. Then, the PD parameters in a PKPD model were estimated whilst the individual PK parameters were fixed to the values estimated by the population PK model obtained in the first step. The PD model assumed the parasites dynamics resulted from a constant net growth rate estimated with the parasitemia measured prior to drug administration and from a concentration-dependent killing rate described by a sigmoidal Emax relationship. The population PKPD model described the challenge data quite well, although the DSM265 PKPD model had a greater uncertainty due to the reduced information avaialable – only two doses were tested and DSM265 being a slowly cleared compound, the range of concentrations investigated was more limited than for OZ439. Predictions of the parasitemia profiles in patients obtained with the combined PKPD models provided a reasonable indication of the clinical effect of the compounds and have been used to guide the dose selection of later stage trials.

Conclusion: IBSM challenge studies offer the opportunity to investigate sub-therapeutic doses in a well controlled and safe environment. Combined with PKPD modelling, they guide the selection of doses for the phase 2 trials in patients. The advantages and limitations of the approach will be discussed.

1. McCarthy JS, et al. (2011) A Pilot Randomised Trial of Induced Blood-Stage Plasmodium falciparum Infections in Healthy Volunteers for Testing Efficacy of New Antimalarial Drugs. PLoS ONE 6(8)