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

M Zheng; J Wang; J Lubinski; O P Flint; R Krishna; M Yao; J M Pursley; A Thakur; D W Boulton; K S Santone; D M Barten; J J Anderson; K M Felsenstein; S B Hansel

doi:10.1080/00498250902928555

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

Xenobiotica. 2009 Jul;39(7):544-55. doi: 10.1080/00498250902928555.

Authors

M Zheng¹, J Wang, J Lubinski, O P Flint, R Krishna, M Yao, J M Pursley, A Thakur, D W Boulton, K S Santone, D M Barten, J J Anderson, K M Felsenstein, S B Hansel

Affiliation

¹ Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA. Ming.Zheng@bms.com

PMID: 19480557
DOI: 10.1080/00498250902928555

Abstract

BMS-299897 is a gamma-secretase inhibitor that was effective in reducing amyloid beta-peptide (A beta) 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 (V(ss) >or= 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. 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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Adult
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism*
Animals
Antibiotics, Antitubercular / pharmacokinetics
Antibiotics, Antitubercular / pharmacology
Biological Availability
Brain / enzymology
Butyrates / pharmacokinetics*
Butyrates / pharmacology
Cells, Cultured
Cytochrome P-450 CYP3A / biosynthesis*
Cytochrome P-450 Enzyme System / biosynthesis*
Dogs
Enzyme Induction / drug effects
Female
Guinea Pigs
Hepatocytes / cytology
Hepatocytes / enzymology*
Humans
Hydrocarbons, Halogenated / pharmacokinetics*
Hydrocarbons, Halogenated / pharmacology
Male
Mice
Mice, Knockout
Pregnane X Receptor
Rats
Rats, Sprague-Dawley
Receptors, Steroid / metabolism
Rifampin / pharmacokinetics
Rifampin / pharmacology
Species Specificity

Substances

4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid
ATP Binding Cassette Transporter, Subfamily B, Member 1
Amyloid beta-Peptides
Antibiotics, Antitubercular
Butyrates
Hydrocarbons, Halogenated
Pregnane X Receptor
Receptors, Steroid
Cytochrome P-450 Enzyme System
Cyp3a41a protein, mouse
Cyp3a2 protein, rat
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Amyloid Precursor Protein Secretases
Rifampin