Pharmacokinetics-Pharmacodynamics Driven Approach for Lead Optimization in Anti-Mycobacterial and Anti-Malarial Drug Discovery

Abstract

Establishing in silico ? in vitro ? in vivo correlations (ISIVIVC) and understanding pharmacokinetic-pharmacodynamic (PK-PD) relationships contributes to minimize lengthy and resource intensive animal studies. The work presented in this thesis focuses on drug candidates for the treatment of tuberculosis and malaria, including Part 1: Investigation of ISIVIVC for standard anti-mycobacterials; Part 2: PK-PD relationship analysis for nitroimidazoles; and Part 3: PK-PD relationship analysis for spiroindolones. Most anti-mycobacterials with favorable pharmacokinetic properties complied with various empirical rules. The lung drug distribution studies could potentially be exploited to guide the selection of new nitroimidazole analogs. For KAE609, the dosing regimens covering T>TRE of 100%, AUC0-48/TRE of 587 and a Cmax/TRE of 30 result in maximum reduction in parasitemia in the P. berghei malaria mouse model. The outcome of this work could serve as guidance to prioritize new drug candidates, thereby facilitating the lead optimization and possibly expediting the drug discovery process.