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Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis

Author:
WRING, STEPHEN, GAUKEL, ERIC, NARE, BAKELA, JACOBS, ROBERT, BEAUDET, BETH, BOWLING, TANA, MERCER, LUKE, BACCHI, CYRUS, YARLETT, NIGEL, RANDOLPH, RYAN, PARHAM, ROBIN, REWERTS, CINDY, PLATNER, JACOB, DON, ROBERT, Barrett, Michael P., Croft, Simon L.
Source:
Parasitology 2014 v.141 no.1 pp. 104-118
ISSN:
1469-8161
Subject:
African trypanosomiasis, animal tissues, drugs, humans, models, oral administration, permeability, pharmacokinetics
Abstract:
This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic–pharmacodynamic (PK–PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic–pharmacodyamic studies in animal infection models.
Agid:
5172580