Animal pharmacokinetics/pharmacodynamics (PK/PD) infection models for clinical development of antibacterial drugs: lessons from selected cases.

In the wake of emerging antimicrobial resistance, antibacterial drug development has become more critical. At the same time, development of antibacterial drugs targeting specific pathogens or resistance phenotypes that may have low prevalence presents challenges because it is difficult to conduct large, randomized controlled trials for such drugs. Animal models have increasingly supported clinical development of antibacterials; however, more work is needed to optimize the design and application of these animal models to ensure clear and actionable translation to further human investigation.

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats.