sipoglitazar and Diabetes-Mellitus--Type-2

The pharmacokinetics of sipoglitazar, a peroxisome proliferator activated receptor agonist, are subject to high inter-individual variability resulting from a polymorphism of the UGT2B15 genotype. The aim of the current analysis was to apply a PK-PD model-based approach to evaluate the influence of UGT2B15 driven pharmacokinetic differences on the clinical response. Efficacy and safety of sipoglitazar compared to placebo were assessed in Type 2 Diabetes Mellitus patients in two Phase II randomized, double-blind studies (sipoglitazar once daily: 8, 16, 32, or 64 mg; sipoglitazar twice daily: 16 or 32 mg; rosiglitazone 8 mg once daily and placebo for 13 weeks; n = 780). Changes in fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure. The effects on FPG and HbA1c could successfully be described for placebo, rosiglitazone, and sipoglitazar treated groups in all three UGT2B15 genotypes. Differences in drug effects between genotypes were fully explained by differences in drug exposure. The current PK-PD analysis confirms that UGT2B15 genotype is a major determinant for differences in FPG and HbA1c response to sipoglitazar treatment between Type 2 Diabetes mellitus patients, due to related differences in drug exposure.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Genotype; Glucuronosyltransferase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Models, Biological; Peroxisome Proliferator-Activated Receptors; Polymorphism, Genetic; Propionates; Rosiglitazone; Thiazoles; Thiazolidinediones

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.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Female; Genotype; Glucuronosyltransferase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Models, Biological; Peroxisome Proliferator-Activated Receptors; Polymorphism, Genetic; Propionates; Thiazoles; Young Adult