Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, in Healthy Subjects

Abstract

BMS-823778 is a potent and selective inhibitor of 11-HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism and is a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mediated mainly by polymorphic CYP2C19, with minor contributions from CYP3A4/5 and UGT1A4. The clinical pharmacokinetics (PK) of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after the oral dose, and systemic exposure at steady state increased proportionally to the dose. Large intersubject variability in BMS-823778 exposure was likely because of the 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 a human absorption, distribution, metabolism, and excretion study in which all subjects were genotyped either before or after treatment. A clear trend of high exposure and low clearance was seen in poor metabolizers (PMs) of CYP2C19 compared with extensive (EM) and intermediate metabolizer (IM) subjects. The impact of UGT1A4 or CYP3A5 polymorphism on BMS-823778 PK was statistically not significant in CYP2C19 EM and IM subjects; however, in a subject with predicted CYP2C19 PM phenotype, the PK of BMS-823778 was affected significantly by UGT1A4 polymorphism. Overall, BMS-823778 was safe and well tolerated in healthy subjects after single or multiple oral doses. The PK of BMS-823778 was characterized by rapid absorption, and the systemic clearance directly correlated with the genetic polymorphism of CYP2C19.

Physiologically‐based pharmacokinetic modelling of a CYP2C19 substrate, BMS‐823778, utilizing pharmacogenetic data

“…The PBPK model over‐predicted day‐1 PK of BMS‐823778 at low doses in both Chinese and Japanese studies. This might be due to the nonlinear PK of BMS‐823778 after the first dose at low dose levels . In the SAD study, there was a greater than dose‐proportional increase in exposure in the dose range of 2–12 mg.…”

“…In the SAD study, there was a greater than dose‐proportional increase in exposure in the dose range of 2–12 mg. However, when exposure has reached steady state after multiple daily‐doses of BMS‐823778, the exposure increased largely proportionally to dose even at low doses . The PBPK model was not able to capture the nonlinear PK because of unknown mechanism for the relatively low exposure of BMS‐823778 after the first dose at low dose levels.…”

“…Steady state volume of distribution (Vss) was predicted based on the individual input K p values in the aforementioned tissues with a global K p scalar of 1, using the Rodgers and Rowland method in Simcyp . The predicted Vss (1.88 l kg –1 ) was in the range of clinically observed values (Vss/F ranged from 1.6–2.1 l kg –1 in SAD/MAD study) .…”

“…By contrast, genetic polymorphism of CYP3A5 and UGT1A4 did not seem to impact PK of BMS‐823778 in subjects who were CYP2C19 EMs or IMs. However, in a CYP2C19 PM subject, genetic polymorphism (*1/*2) of UGT1A4 appeared to further reduce the clearance of BMS‐823778 . Because of limited number of subjects in the study, the impact of UGT1A4 or CYP3A5 polymorphisms on the PK of BMS‐823778 in subjects with predicted CYP2C19 PM phenotype was not fully characterized.…”

“…The impact of polymorphisms on the PK of BMS‐823778 was investigated in clinical studies in Chinese and Japanese subjects, as well as in human mass–balance study with healthy volunteers . A direct correlation between genetic variation of CYP2C19 and BMS‐823778 clearance was observed in all studies.…”