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

Jiachang Gong,Lisa Iacono,Lars Hansen

doi:10.1124/dmd.117.078824

Jiachang Gong, Lisa Iacono + Show 1 more

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https://doi.org/10.1124/dmd.117.078824

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Abstract

BMS-823778 is a potent and selective inhibitor of 11β-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.

Highlights

BMS-823778 is a potent and selective inhibitor of 11b-HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism and is a compelling target for the treatment of metabolic diseases
Several lines of evidence have indicated that reducing cortisol generation from cortisone in tissues by inhibition of 11b-HSD1 has the potential to be an efficacious treatment of type 2 diabetes, dyslipidemia, and obesity (Morton, 2010; Sooy et al, 2010; Anderson and Walker, 2013; Morentin Gutierrez et al, 2015)
The primary analysis suggested a slightly more than doseproportional increase in exposure based on the data collected in all dose panels, including the 2- and 5-mg doses panels of BMS-823778, in which the percentage of extrapolated area under the concentration-time curve (AUC) was .20% that of the AUC

Summary

Introduction

BMS-823778 is a potent and selective inhibitor of 11b-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 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. On completion of the study, it was evident that PK variability across subjects was large, indicating potential involvement of polymorphic metabolizing enzymes. Genetic polymorphisms of CYP2C19 have the potential to influence significantly the pharmacokinetics (PK) and pharmacodynamics of many drugs in clinical use, which could result in adverse drug effects or therapeutic failure (Desta et al, 2002; Wojnowski and Kamdem, 2006; Jiang et al, 2015)

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