Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects

Andreas Krause, Jasper Dingemanse, Alexandre Mathis, Louise Marquart, Jörg J Möhrle, James S McCarthy, Andreas Krause, Jasper Dingemanse, Alexandre Mathis, Louise Marquart, Jörg J Möhrle, James S McCarthy

Abstract

Aims: The aim of this study was to use data from an experimental induced blood stage malaria clinical trial to characterize the antimalarial activity of the new compound Actelion-451840 using pharmacokinetic/pharmacodynamic (PK/PD) modelling. Then, using simulations from the model, the dose and dosing regimen necessary to achieve cure of infection were derived.

Methods: Eight healthy male subjects were infected with blood stage P. falciparum. After 7 days, a single dose of 500 mg of Actelion-451840 was administered under fed conditions. Parasite and drug concentrations were sampled frequently. Parasite growth and the relation to drug exposure were estimated using PK/PD modelling. Simulations were then undertaken to derive estimates of the likelihood of achieving cure in different scenarios.

Results: Actelion-451840 was safe and well tolerated. Single dose treatment markedly reduced the level of P. falciparum parasitaemia, with a weighted average parasite reduction rate of 73.6 (95% CI 56.1, 96.5) and parasite clearance half-life of 7.7 h (95% CI 7.3, 8.3). A two compartment PK/PD model with a steep concentration-kill effect predicted maximum effect with a sustained concentration of 10-15 ng ml(-1) and cure achieved in 90% of subjects with six once daily doses of 300 mg once daily.

Conclusions: Actelion-451840 shows clinical efficacy against P. falciparum infections. The PK/PD model developed from a single proof-of-concept study with eight healthy subjects enabled prediction of therapeutic effects, with cure rates with seven daily doses predicted to be equivalent to artesunate monotherapy. Larger doses or more frequent dosing are not predicted to achieve more rapid cure.

Keywords: Plasmodium falciparum; challenge model; malaria; pharmacodynamics; pharmacokinetics; proof of concept.

© 2016 The British Pharmacological Society.

Figures

Figure 1
Figure 1
Pharmacokinetics: individual drug concentration–time profiles, linear (A) and semi‐logarithmic scale (B). (R001 R002 R003 R004 R005 R006 R007 R008 )
Figure 2
Figure 2
Pharmacodynamics: parasite concentration over time after inoculum (A) and after treatment start, semi‐logarithmic scale (B). (R001 R002 R003 R004 R005 R006 R007 R008 )
Figure 3
Figure 3
Concentration–effect curve over the observed range of drug concentration
Figure 4
Figure 4
Model visualization PD: observed and model‐predicted parasite count with 10th to 90th percentile
Figure 5
Figure 5
Model‐predicted population typical PK (A) and PD (B) for one to four doses of 500 mg once daily
Figure 6
Figure 6
Simulated parasite concentration, population typical and 80% range for one to six doses of 500 mg once daily

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