The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent

• Published in: European journal of clinical pharmacology Vol. 69; no. 3; pp. 423 - 430
• Main Authors: Stringer, Frances, Scott, Graham, Valbuena, Marian, Kinley, Judith, Nishihara, Mitsuhiro, Urquhart, Richard
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2013; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Analysis of Variance; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotransformation; Cross-Over Studies; Demography; Diabetes; Double-Blind Method; Female; Genetics; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Half-Life; Heterozygote; Homozygote; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacokinetics; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Pharmacogenetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phenotype; Polymorphism; Polymorphism, Genetic; Propionates - administration & dosage; Propionates - blood; Propionates - pharmacokinetics; Thiazoles - administration & dosage; Thiazoles - blood; Thiazoles - pharmacokinetics; United Kingdom; Young Adult; Genotype; Pharmacogenetics; Sipoglitazar; Pharmacokinetics; Polymorphism; Human; Agonist; Hypoglycemic agent; Genetic variability; Genetics; Peroxisome proliferator activated receptor
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-012-1382-7

Purpose Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. Methods Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. Results Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration–time curve from time 0 to infinity (AUC 0-∞ ) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC 0-∞ explained by UGT2B15 was 66.7 % ( P  < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant ( UGT2B15*2/*2 ) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). Conclusions These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.