Author: Thommis, Jonathan ; Van Leene, Chloé ; Melchers, Diana ; Verhee, Annick ; Houtman, René ; Delhaye, Louis ; Hellemans, Madeleine ; De Bosscher, Karolien ; Van Moortel, Laura ; Gevaert, Kris ; Eyckerman, Sven

Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for the treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the differential transcriptional activity of GR following treatment with the selective GR agonist and modulator dagrocorat compared to classic (ant)agonists, we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that dagrocorat and the antagonist RU486 both reduced GR interaction with CREB-binding protein/p300 and the mediator complex compared to the full GR agonist dexamethasone. Chromatin immunoprecipitation assays revealed that these changes in GR interactome were accompanied by reduced GR chromatin occupancy with dagrocorat and RU486. Our data offer new insights into the role of differential coregulator recruitment in shaping ligand-specific GR-mediated transcriptional responses.

01 Jan 2018·Clinical and translational science

Population Pharmacokinetics of Fosdagrocorat (PF‐04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis

Article

Author: Tammara, Brinda ; Weatherley, Barry ; McFadyen, Lynn

Abstract:

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF‐04171327), with active DAGR metabolite PF‐00251802 (Metabolite‐1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite‐1 and its active metabolite PF‐04015475 (Metabolite‐2) in patients with moderate to severe RA enrolled in a 12‐week, phase II, randomized, double‐blind study (NCT01393639). A simultaneous fit of a two‐compartment model for Metabolite‐1 and a one‐compartment model for Metabolite‐2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite‐1 (∼26%) and Metabolite‐2 (∼33%) compared with males. Age influenced clearance of Metabolite‐1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration–time curve of Metabolite‐1 at the extremes.

01 Dec 2016·International journal of clinical pharmacology and therapeuticsQ4 · MEDICINE

Pharmacokinetics and food-effect of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, in healthy adult Caucasian and Japanese subjects

Q4 · MEDICINE

Article

Author: Tammara, Brinda ; Miyoshi, So ; Nagaoka, Makoto ; Hey-Hadavi, Judith

OBJECTIVE:

Fosdagrocorat (PF-04171327) is a pro-drug form of PF-00251802, a dissociated agonist of the glucocorticoid receptor, under investigation for the treatment of rheumatoid arthritis. This study investigates the pharmacokinetics (PK) of single and multiple doses of fosdagrocorat in healthy Japanese and Western volunteers, the effect of food on fosdagrocorat PK, and the effect of fosdagrocorat on bone biomarkers.

METHODS:

This was a phase 1, randomized, placebo-controlled, dose-escalation study. For single-escalating-dose evaluation, Japanese (n = 9) and Western (n = 9) subjects were randomized (1 : 1 : 1) to treatment sequences including 3 doses of fosdagrocorat (5, 10, or 30 mg) or placebo. For multiple-dose evaluation, Japanese subjects were randomized (3 : 1) to receive fosdagrocorat 20 mg or placebo once daily (QD) for 12 days. Subjects were aged 18 - 55 years; body mass index 17.5 - 30.5 kg/m²; total body weight > 45 kg.

RESULTS:

Following single doses of fosdagrocorat, the PK of PF-00251802 and its metabolite PF-04015475 were similar between Japanese (PF-00251802: mean area under the curve (AUC)_inf (range across doses), 791 - 3,460 ng×h/mL; individual half-life (t_1/2) 14.1 - 28.9 hours; PF-04015475: mean AUC_inf, 395 - 1,740 ng×h/mL; individual t_1/2 21.6 - 40.3 hours) and Western (PF-00251802: mean AUC_inf, 750 - 4,150 ng×h/mL; individual t_1/2 17.7 - 40.4 hours; PF-04015475: mean AUC_inf, 394 - 2,160 ng×h/mL; individual t_1/2 24.5 - 63.7 hours) subjects. Steady-state concentrations were reached within 9 days following multiple doses of fosdagrocorat. Food did not affect total exposure of PF-00251802 and PF-04015475. Multiple-dose administration of fosdagrocorat 20 mg QD resulted in suppression of bone formation markers and cortisol and increased bone resorption markers vs. placebo. Adverse events (AEs) were mild in severity and no serious AEs, deaths, or severe AEs were reported.

CONCLUSIONS:

The PK profile of fosdagrocorat was similar between Japanese and Western subjects, with little effect of food on PK parameters. Fosdagrocorat was well tolerated in both Japanese and Western subjects. .

100 Deals associated with Dagrocorat

External Link

KEGG	Wiki	ATC	Drug Bank
D10617	Dagrocorat	-	DB14676

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 1	US	Pfizer Inc.	-

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