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

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

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 (AUC0-∞) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC0-∞ 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.

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Acknowledgments

The authors would like to thank Judith Wallace for her editorial assistance and Anil Sekhari and Diana Stuart for their support and expertise on the production of the graphical displays.

Conflict of interest

F.S, R.U, and M.N are employees of Takeda Pharmaceutical Company, and G.S, M.V, and J.K are employees of Takeda Global Research & Development, Inc.

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Authors and Affiliations

  1. Takeda Pharmaceutical Company, 1-1, Doshomachi 4-Chome, Chuo-Ku, Osaka, 540-8645, Japan

    Frances Stringer

  2. Takeda Global Research & Development, London, UK

    Graham Scott, Marian Valbuena & Judith Kinley

  3. Takeda Global Research & Development, 26-1, Muraoka-Higashi 2-chome, Fujisawa, 251-8555, Japan

    Mitsuhiro Nishihara & Richard Urquhart

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  1. Frances Stringer
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  2. Graham Scott
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  3. Marian Valbuena
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  4. Judith Kinley
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  5. Mitsuhiro Nishihara
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  6. Richard Urquhart
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Correspondence to Frances Stringer.

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Stringer, F., Scott, G., Valbuena, M. et al. The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent. Eur J Clin Pharmacol 69, 423–430 (2013). https://doi.org/10.1007/s00228-012-1382-7

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  • DOI: https://doi.org/10.1007/s00228-012-1382-7

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