Abstract
BMS-823778 is a potent and selective inhibitor of 11beta-HSD1, an enzyme that regulates tissue specific intracellular glucocorticoid metabolism and a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mainly mediated by polymorphic CYP2C19 with minor contribution from CYP3A3/5 and UGT1A4. Clinical PK of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after oral dose, and systemic exposure at steady state increased proportionally to the dose. Large inter-subject variability in BMS-823778 exposure was likely due to polymorphism of metabolic enzymes. The impact of genetic polymorphism of CYP2C19, UGT1A4 and CYP3A5 on BMS-823778 PK was assessed in healthy Chinese and Japanese subjects as well as in human ADME study, where all subjects were genotyped either before or post treatment. There was a clear trend of high exposure and low clearance in CYP2C19 PMs comparing to EM or IM subjects. Polymorphism of UGT1A4 or CYP3A5 did not appear to impact significantly BMS-823778 PK in CYP2C19 EM or IM subjects. However in a subject who was devoid of CYP2C19 activity, the PK of BMS-823778 appeared to be affected significantly by UGT1A4 polymorphism. Overall, BMS-823778 was safe and well tolerated in healthy subjects following single or multiple oral doses. The PK of BMS-823778 was characterized with rapid absorption and the systemic clearance was directly correlated with the genetic polymorphism of CYP2C19 where poor metabolizers generally had highest exposure and slowest clearance.
- The American Society for Pharmacology and Experimental Therapeutics