Evaluation of the Impact of UGT Polymorphism on the Pharmacokinetics and Pharmacodynamics of the Novel PPAR Agonist Sipoglitazar. (24th January 2013)

• Record Type: Journal Article
• Authors: Stringer, Frances; Ploeger, Bart A.; Jongh, Joost De; Scott, Graham; Urquhart, Richard; Karim, Aziz; Danhof, Meindert
• Is Part Of: Journal of clinical pharmacology. Volume 53:Number 3(2013:Mar.)
• Page Start: 256
• Page End: 263
• Publication Date: 2013-01-24
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1177/0091270012447121
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcp447121-sec-0001" sec-type="section"> <p>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 <italic>UGT2B15</italic> 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 <italic>UGT2B15*2/*2</italic> compared with <italic>UGT2B15*1/*1</italic> and <italic>UGT2B15*1/*2</italic> genotypes (<italic>P</italic> < .05). In summary, <italic>UGT2B15</italic> genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the <italic>UGT2B15*2/*2</italic> genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype.</p> </sec> </abstract>