Studies on the pharmacokinetics and metabolism of a γ-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction

BMS-299897 is a γ-secretase inhibitor that was effective in reducing amyloid β-peptide (Aβ) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24–100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited.BMS-299897 was distributed into extravascular space (Vss ≥ 1.3 l kg−1), including brain (brain-to-plasma ratio = 0.13–0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type.Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Inducti...