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Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion‐451840 in an induced blood stage malaria study in healthy subjects
Author(s) -
Krause Andreas,
Dingemanse Jasper,
Mathis Alexandre,
Marquart Louise,
Möhrle Jörg J.,
McCarthy James S.
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12962
Subject(s) - pharmacokinetics , pharmacodynamics , malaria , plasmodium falciparum , dosing , regimen , medicine , pharmacology , biology , immunology
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.