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

Abstract

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. 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 20mg 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. 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. 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. .