Background/Purpose:

PF-04171327 is a prodrug of PF-00251802, a dissociated agonist of the glucocorticoid receptor (DAGR) and being developed as treatment for Rheumatoid Arthritis. The objective of the study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of PF-00251802 following multiple doses of PF-04171327.

Methods:

This was a randomized, placebo-controlled Phase 1 study of multiple doses of PF-04171327 in healthy adult Japanese subjects (N=8). PF-04171327 tablet (20 mg) or matching placebo once daily were administered in the morning for 12 days in a fasted state. The subjects were randomized in a 3:1 ratio to PF-04171327 or placebo, respectively. Blood samples for PK and PD analysis were collected at pre specified time points and analyzed using validated assay methods. Standard non-compartmental analyses methods were used to estimate PK parameters. PD effects were assessed using bone biomarkers (serum P1NP, serum CTX, osteocalcin, urine NTX), carbohydrate markers (fasting glucose, insulin, adiponectin) and HPA axis marker (plasma cortisol).

Results:

The geometric mean summary of the plasma PK parameters of PF-00251802 and its metabolite PF-04015475 on Day 1 and Day 12 are shown in Table 1. The median percent change from baseline on Day 12 for the bone PD markers are shown in Table 2.  

The mean observed accumulation ratios of exposure were 2.23 and 2.50 for PF-00251802 and PF-04015475, respectively. There was no change in the carbohydrate markers with treatment and complete suppression of cortisol levels was observed. There were no deaths, serious adverse events, severe AEs, subject discontinuations, in this multiple dose part of the study.

Conclusion:

Following multiple dosing steady state concentrations of PF-00251802 were achieved by Day 9. There was a trend for greater suppression of bone formation markers osteocalcin and P1NP compared to placebo and increase in bone resorption marker urine-NTX, but not serum CTx. Overall, the treatments administered in this study were well tolerated with an acceptable safety profile.