Model system identifies kinetic driver of Hsp90 inhibitor activity against African trypanosomes and Plasmodium falciparum [PublishAheadOfPrint]

Hsp90 inhibitors, well-studied in the laboratory and clinic for antitumor indications, have promising activity against protozoan pathogens, including Trypanosoma brucei that causes African sleeping sickness, and malaria parasite Plasmodium falciparum. To progress these experimental drugs toward clinical use we adapted an in vitro dynamic hollow-fiber system and deployed artificial pharmacokinetics to discover the driver of their activity: either concentration or time. Compounds from three major classes of Hsp90 inhibitors in development were evaluated against trypanosomes. In all circumstances tested Hsp90 inhibitors were concentration-driven. By optimally deploying the drug to match kinetic driver, efficacy of a given dose was improved up to five-fold, and maximal efficacy was achieved with a significantly lower drug exposure. The superiority of concentration-driven regimens was evident in vitro over several logs of drug exposure, and was predictive of efficacy in a mouse model of African trypanosomiasis. In studies with P. falciparum, antimalarial activity was similarly concentration-driven. This experimental strategy offers an expedient and versatile translational tool to assess the impact of pharmacokinetics on antiprotozoal activity. Knowing kinetic governance early in drug development provides an additional metric for judging lead compounds and allows incisive design of animal efficacy studies.

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