Torcetrapib for animal and human pharmacokinetic studies: applicability of chiral and achiral methodologies

Abstract

The emergence of bioanalysis as a key tool in the drug-discovery and -development process has enabled the development of sensitive, precise and specific bioanalytical methods in recent years. These methods have enabled the progress of novel chemical entities through the life cycle of drug discovery and development. The focus of this review article is on a well-known cholesteryl ester transfer protein (CETP) inhibitor known as torcetrapib. Although torcetrapib was withdrawn from clinical development, it is important to understand the various bioanalytical methodologies (chiral and achiral) that are readily available for the pharmacokinetic/pharmacodynamic characterization of the drug. Additionally, these methodologies may be applicable to the bioanalysis of the next-generation CETP inhibitors. This review covers the development and validation of assay methods that were used to obtain preclinical and clinical pharmacokinetic parameters of torcetrapib. Accordingly, methods are available for the determination of torcetrapib in various species, namely dogs, hamsters, rats, mice, monkeys and humans. Since torcetrapib is a chiral compound, methods have been developed for stereoselective bioanalysis to evaluate in vivo chiral inversion phenomena. Interestingly, torcetrapib can be analyzed by various bioanalytical options (e.g., HPLC–UV, LC–MS, LC–MS/MS and GC–MS assays) depending on the type of species under consideration with the associated sensitivity requirements. This review covers all the available methodologies for torcetrapib, providing both assay-development and -optimization strategies. It also tabulates validation parameters and enumerates the difficulties, challenges and nuances of the various published assays for torcetrapib.