Fran Stringer (1), Joost DeJongh (2), Graham Scott (3) and Meindert Danhof (4)
(1) Clinical Pharmacology Dept, Takeda Pharmaceutical Company, Osaka, Japan; (2) LAP&P Consultants BV, Leiden, The Netherlands; (3) Clinical Pharmacology, Takeda Global Research & Development Centre Ltd. Europe, London, United Kingdom; (4) Leiden-Amsterdam Centre for Drug Research, Division of Pharmacology, Leiden, The Netherlands
Objectives: Sipoglitazar, a pan-PPAR agonist was targeted for treating type 2 diabetes (T2D). Sipoglitazar undergoes conjugation catalyzed by UGT.1 UGT2B15 genotype is a covariate for clearance in individual patients as reported previously from a PK analysis.2 The objectives of this analysis were to evaluate the role of UGT (UGT2B15*1/*1, UGT2B15*1/*2, and UGT2B15*2/*2) driven exposure differences on the pharmacodynamic response for sipoglitazar in both FPG and HbA1c.
Methods: Efficacy of sipoglitazar was assessed in T2D patients in 2 Phase II studies (sipoglitazar QD: 8, 16, 32, 64 mg; BID: 16 or 32 mg, placebo or rosiglitazone 8mg). FPG and HbA1c samples were collected throughout (-1, 0, 2, 4, 6, 8, 10 and 12 weeks). Changes in FPG and HbA1c levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure.3
Results: The effects on FPG and HbA1c could successfully be described for placebo, rosiglitazone and sipoglitazar treated groups in all three UGT2B15 genotypes.4 The Emax for sipoglitazar was estimated at 49% and AUC50 was 1.2 mg.day/L. Rosiglitzone treatment effect was estimated at 28% for the studied dose level.
The simulated mean change from baseline in FPG at 6 months for 64mg sipoglitazar was -1.2 mmol/L, -1.6 mmol/L and -2.1 mmol/L for UGT2B15*1/*1, UGT2B15*1/*2 and UGT2B15*2/*2 genotypes respectively (rosiglitazone 8mg, -2.0 mmol/L).
A simulation study was performed evaluating genotype-based dosing vs. single treatment approach. Using a single treatment approach, a comparable result to rosiglitazone was achieved in all genotype groups at a dose of 96mg. However for genotyped-based dose assignment a comparable result was achieved with lower doses for UGT2B15*1/*2 and UGT2B15*2/*2 groups.
FPG time profiles for genotyped and titration-based dosing were simulated. Genotype-based dosing can achieve glycemic control in a shorter duration. The difference in time to 90% of FPG steady state between genotyped and titration-based dosing was approx. 1-2 months. However, the magnitude of FPG reduction achieved for the 2 approaches would be expected to be the same.
Conclusions: In summary the genotype effect on the PK of the drug does translate to differences in FPG and HbA1c response. The application of genotyped-based dosing could be utilized to normalize clinical response between individuals. However when comparing genotyped-based dosing with a titration approach, the magnitude of response would be comparable with only a 1-2 month difference in reaching the maximum effect.
References:
[1] Stringer F, Scott G, Valbuena M, Kinley J, Nishihara M, Urquhart R. The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent. Eur J Clin Pharmacol. 2013 Mar;69(3):423-30.
[2] Stringer F, Ploeger BA, DeJongh J et al. Evaluation of the Impact of UGT Polymorphism on the Pharmacokinetics and Pharmacodynamics of the Novel PPAR Agonist Sipoglitazar. J Clin Pharmacol. 2013 Mar;53(3):256-63.
[3] de Winter WA et al. Mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying type 2 diabetes mellitus. J. Pharmacokinet Pharmacodyn. 2006;33:313-343.
[4] Stringer F, DeJongh J, Scott G, Danhof M. A Model Based Approach to Analyze the Influence of UGT2B15 Polymorphism Driven Pharmacokinetic Differences on the Pharmacodynamic Response of the PPAR Agonist Sipoglitazar J Clin Pharmacol. 2013 Nov 11. doi: 10.1002/jcph.227.
Reference: PAGE 23 (2014) Abstr 3033 [www.page-meeting.org/?abstract=3033]
Poster: Drug/Disease modeling - Endocrine