Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

Abstract

AIMSBMS-823778 is an inhibitor of 11β-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism and pharmacokinetics of BMS-823778 to understand its pharmacokinetic variations in early clinical trials. METHODSThe metabolism of BMS-823778 was characterized in multiple in vitro assays. Pharmacokinetics were evaluated in healthy volunteers, prescreened as CYP2C19 extensive metabolizers (EM) or poor metabolizers (PM), with a single oral dose of [ 14 C]BMS-823778 (10 mg, 80 μCi). RESULTSThree metabolites (<5%) were identified in human hepatocytes and liver microsomes (HLM) incubations, including two hydroxylated metabolites (M1 and M2) and one glucuronide conjugate (M3). As the most abundant metabolite, M1 was formed mainly through CYP2C19. M1 formation was also correlated with CYP2C19 activities in genotyped HLM. In humans, urinary excretion of dosed radioactivity was significantly higher in EM (68.8%; 95% confidence interval 61.3%, 76.3%) than in PM (47.0%; 43.5%, 50.6%); only small portions (<2%) were present in faeces or bile from both genotypes. In plasma, BMS-823778 exposure in PM was significantly (5.3-fold, P = 0.0097) higher than in EM. Furthermore, total radioactivity exposure was significantly higher (P < 0.01) than BMS-823778 exposure in all groups, indicating the presence of metabolites. M1 was the only metabolite observed in plasma, and much lower in PM. In urine, the amount of M1 and its oxidative metabolite in EM was 7-fold of that in PM, while more glucuronide conjugates of BMS-823778 and M1 were excreted in PM. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• BMS-823778 is a potent inhibitor of 11β-hydroxysteroid dehydrogenase type-1 and developed for the treatment of Type 2 diabetes.• In early clinical trials, the plasma concentration profiles of BMS-823778 were highly variable among individual subjects.• Preliminary analysis indicated that BMS-823778 had a higher exposure in one CYP2C19 poor metabolizer. WHAT THIS STUDY ADDS• In vitro assays demonstrated that CYP2C19 was a major enzyme involved in BMS-823778 metabolism.• The plasma exposure of BMS-823778 was significantly higher in CYP2C19 poor metabolizers than in extensive metabolizers.• In vitro to in vivo extrapolation under predicted the difference of BMS-823778 plasma exposure between CYP2C19 poor metabolizers and extensive metabolizers.

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

“…Genotyping for CYP2C19, CYP3A5, and UGT1A4 was performed on the drug metabolism enzymes and transporters microarray using the DMET Plus Premier pack kits as described previously (Cheng et al, 2018). Plasma and urine concentrations of BMS-8237778 were determined with validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods reported previously (Furlong et al, 2016).…”

“…Human ADME Study with [ 14 C]BMS-823778. Details of the human ADME study with genotyping have been described previously (Cheng et al, 2018). Briefly, 14 healthy male subjects were placed into three groups based on their predicted CYP2C19 phenotype: group 1 (EMs, n = 7), group 2 (PMs, n = 3,), and group 3 with bile collection 3-8 hours postdose (two EMs and one PM).…”

“…Blood, urine, feces, and bile samples were collected for PK and metabolite analysis. Methods for radioactivity measurement and metabolite analysis have been reported previously (Cheng et al, 2018).…”

“…On completion of the study, it was evident that PK variability across subjects was large, indicating potential involvement of polymorphic metabolizing enzymes. This prompted a reaction phenotyping study that demonstrated that the metabolism of BMS-823778 was catalyzed mainly by cytochrome P450 2C19 (CYP2C19), with minor contribution from CYP3A4/5 and UGT1A4 (Cheng et al, 2018).…”

“…A single-dose human absorption, disposition, metabolism, and excretion (ADME) study with [ 14 C]BMS-823778 in CYP2C19 EM and PM subjects was reported previously in which greater exposure of BMS-823778 was observed in PMs than in EMs (Cheng et al, 2018). The current studies describe the PK of BMS-823778 in healthy volunteers after single or multiple ascending doses, as well as further assessment of polymorphic impact in healthy Chinese and Japanese subjects with various genotypes of CYP2C19, UGT1A4, and CYP3A5.…”