title: Evaluation of the impact of UGT polymorphism on the pharmacokinetics and pharmacodynamics of the novel PPAR agonist sipoglitazar.
abstract: Sipoglitazar is a peroxisome proliferator-activated receptor α, δ, and γ agonist. During phase I, a wide distribution of clearance between individuals was observed. Hypothesized to result from a polymorphism in the uridine 5'-diphospate-glucuronosyltransferase (UGT)2B15 enzyme, pharmacogenetic samples were collected from each individual for genotyping UGT2B15 in a subsequent phase I trial in healthy subjects (n = 524) and in 2 phase II trials in type 2 diabetes subjects (n = 627), total genotype frequency was as follows: *1/*1 (22%), *1/*2 (51%), and *2/*2 (27%). The impact of genotype on exposure was assessed using a pharmacokinetic modeling approach; the influence of genotype on efficacy was evaluated using 12-week HbA1c change from baseline. Model analysis demonstrated UGT2B15 genotype accounted significantly for the variability in sipoglitazar clearance; however, a small fraction of subjects had a clearance that could not be explained entirely by genotype. HbA1c drop increased with daily drug dose. When stratified by both dose and genotype, HbA1c drop was larger in the UGT2B15*2/*2 compared with UGT2B15*1/*1 and UGT2B15*1/*2 genotypes (P < .05). In summary, UGT2B15 genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the UGT2B15*2/*2 genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype.
authors: Takeda Pharmaceutical Company, Osaka, Japan. fran.stringer@takeda.com
authors: Frances
authors: F
authors: Stringer
authors: Bart A
authors: BA
authors: Ploeger
authors: Joost
authors: J
authors: DeJongh
authors: Graham
authors: G
authors: Scott
authors: Richard
authors: R
authors: Urquhart
authors: Aziz
authors: A
authors: Karim
authors: Meindert
authors: M
authors: Danhof
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D011110:Polymorphism, Genetic; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D014453:Glucuronosyltransferase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D011422:Propionates; D013844:Thiazoles; C517652:hemoglobin A1c protein, human; C572168:sipoglitazar