Title |
Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose–response analysis
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Published in |
Journal of Pharmacokinetics and Pharmacodynamics, May 2016
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DOI | 10.1007/s10928-016-9475-z |
Pubmed ID | |
Authors |
Daniela J. Conrado, Sriram Krishnaswami, Satoshi Shoji, Sheela Kolluri, Judith Hey-Hadavi, Dorothy McCabe, Ricardo Rojo, Brinda K. Tammara |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 47 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 14 | 30% |
Student > Master | 6 | 13% |
Student > Ph. D. Student | 5 | 11% |
Student > Bachelor | 4 | 9% |
Other | 3 | 6% |
Other | 5 | 11% |
Unknown | 10 | 21% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 15 | 32% |
Pharmacology, Toxicology and Pharmaceutical Science | 8 | 17% |
Biochemistry, Genetics and Molecular Biology | 2 | 4% |
Psychology | 2 | 4% |
Nursing and Health Professions | 2 | 4% |
Other | 7 | 15% |
Unknown | 11 | 23% |