A new in vitro checkerboard-parasite reduction ratio interaction assay for early de-risk of clinical development of antimalarial combinations

Abstract

The development and spread of drug resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapies parasitological data to predict the parasitological endpoints of the combination. This allows to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel - piperaquine and artefenomel - ferroquine drug combinations. Besides, the predictive performance of our novel in vitro model was equivalent to the humanized mouse model outcome. Lastly, our more granular in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g. a concentration-dependent change in the Emax and the EC50 values of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations in malaria and potentially also in other therapeutic areas.

Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood stagePlasmodium falciparum

“…Dose selection in the phase 2b artefenomel + piperaquine combination was primarily designed to achieve the maximum exposure that would be well tolerated, with minimization of a potential prolongation of the QT interval by high plasma levels of piperaquine a key consideration [13,26]. The value of assessing the pharmacological interaction between antimalarial combinations during in vitro parasite culture, and in the humanized mouse model of malaria, to inform clinical decision making around drug and dose selection has recently been established [27,28]. However, the translatability of these models is likely to be limited by the complex PK/PD interactions that may occur in humans.…”

Drug Combination Modeling: Methods and Applications in Drug Development

“…A recent example of using combination modeling to inform clinical trial development for antimalarial combination therapies used experimental and in silicobased approaches to generate in vitro PD preclinical parameters, which were then used in clinical trial simulations. 66 The study describes an approach to identify PD interactions of 2 antimalarial drugs by using monotherapy data to inform a PK/PD model to predict combination endpoints of optimal parasite killing. To understand the kinetics of parasite killing at different time points, Plasmodium falciparum parasites were cultured in the presence of antimalarial drugs at different concentrations as either monotherapy or combinations.…”

“…A recent example of using combination modeling to inform clinical trial development for antimalarial combination therapies used experimental and in silico–based approaches to generate in vitro PD preclinical parameters, which were then used in clinical trial simulations 66 . The study describes an approach to identify PD interactions of 2 antimalarial drugs by using monotherapy data to inform a PK/PD model to predict combination endpoints of optimal parasite killing.…”