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

Abstract

1. 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.

2. BMS-299897 was distributed into extravascular space (V_ss ≥ 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.

3. 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. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250 mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer’s patients.

Keywords::

• Induction
• cytochrome P450 (CYP)
• glucuronidation
• γ-secretase inhibitor
• pharmacokinetics
• metabolism

Acknowledgments

We would like to acknowledge the Lead Profiling group (Bristol-Myers Squibb Research and Development, Wallingford, CT) for the Caco-2 and hPXR transactivation results discussed in this article. We thank the assistance by the department of Veterinary Sciences (Bristol-Myers Squibb Research and Development, Wallingford, CT) in the preclinical pharmacokinetic studies. We would also like to acknowledge the conduct of the clinical SAD study in healthy subjects by the Clinical Pharmacology Unit at Bristol-Myers Squibb (Hamilton, NJ), and the MAD study in probable Alzheimer’s patients by California Clinical Trials (Beverly Hills, CA) and Veterans Affairs Medical Center (San Diego, CA). We also thank Dr David Rodrigues for his valuable comments on the manuscript. This study was sponsored by Bristol-Myers Squibb Company and SIBIA Neurosciences, Inc. (later acquired by Merck & Co., Inc.).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.