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

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.