Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose–response analysis

  • Daniela J. Conrado
  • Sriram Krishnaswami
  • Satoshi Shoji
  • Sheela Kolluri
  • Judith Hey-Hadavi
  • Dorothy McCabe
  • Ricardo Rojo
  • Brinda K. Tammara
Original Paper

DOI: 10.1007/s10928-016-9475-z

Cite this article as:
Conrado, D.J., Krishnaswami, S., Shoji, S. et al. J Pharmacokinet Pharmacodyn (2016) 43: 325. doi:10.1007/s10928-016-9475-z

Abstract

PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose–response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose–response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be −1.2 points (95 % CI −1.7, −0.84), and the evaluated dose range provided 31–87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were −0.27 (95 % CI −0.55, 0.006) and −0.94 point (95 % CI −1.3, −0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.

Keywords

Dissociated agonist of glucocorticoid receptor (DAGR) Rheumatoid arthritis (RA) Longitudinal dose–response Stochastic simulations Disease activity score 28-4 C-reactive protein (DAS28-4 CRP) Phase 2 randomized double-blind clinical trial 

Supplementary material

10928_2016_9475_MOESM1_ESM.docx (199 kb)
Supplementary material 1 (DOCX 199 kb)

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Daniela J. Conrado
    • 1
    • 5
  • Sriram Krishnaswami
    • 1
  • Satoshi Shoji
    • 2
  • Sheela Kolluri
    • 3
  • Judith Hey-Hadavi
    • 3
  • Dorothy McCabe
    • 3
  • Ricardo Rojo
    • 1
  • Brinda K. Tammara
    • 4
  1. 1.Pfizer Global Innovative Pharma BusinessGrotonUSA
  2. 2.Pfizer Japan Inc. Development JapanTokyoJapan
  3. 3.Pfizer Global Innovative Pharma BusinessPfizerUSA
  4. 4.Pfizer Global Innovative Pharma BusinessCollegevilleUSA
  5. 5.Metrum Research Group LLCWellesleyUSA

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