Pharmacokinetics and food-effect of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, in healthy adult Caucasian and Japanese subjects
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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 (t1/2) 14.1 - 28.9 hours; PF-04015475: mean AUCinf, 395 - 1,740 ng×h/mL; individual t1/2 21.6 - 40.3 hours) and Western (PF-00251802: mean AUCinf, 750 - 4,150 ng×h/mL; individual t1/2 17.7 - 40.4 hours; PF-04015475: mean AUCinf, 394 - 2,160 ng×h/mL; individual t1/2 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.
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Model-Based Comparison of Dose-Response Profiles of Tofacitinib in Japanese Versus Western Rheumatoid Arthritis Patients.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this analysis was to characterize the relationship between tofacitinib dose and efficacy, as measured by American College of Rheumatology (ACR) response rates, and to compare this between Japanese and Western patients with RA. Efficacy data were pooled from 2 double-blind, dose-ranging phase 2 studies of tofacitinib monotherapy 1-15 mg twice daily in patients with RA with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). NCT00550446 was carried out in mostly Western patients and NCT00687193 in Japanese patients. ACR20, ACR50, and ACR70 response rates in week 12 were analyzed using maximum drug effect (Emax ) models on the logit domain. Both studies showed a dose-response for each end point, supporting the efficacy of tofacitinib in patients with inadequate response to DMARDs. Study-specific differences in Emax were noted, whereas potency (dose providing half the maximum effect [ED50 ]) was similar across studies. After adjustment for study differences in Emax by calculating the fractions of the maximum placebo-adjusted proportion of ACR responses, the estimated locations for the 5- and 10-mg twice-daily doses on the dose-response curves were similar for the 2 patient populations: ACR20, ACR50, andACR70 mean fractional responses for 5 and 10 mg twice daily were 0.78, 0.43, 0.32 and 0.90, 0.69, and 0.56, respectively, for the Japanese study and 0.54, 0.41, and 0.22 and 0.73, 0.61, and 0.40, respectively, for the Western study. This analysis therefore supports the rationale for the same dosing regimen in Japanese patients as in Western patients from an efficacy perspective.

Phase 1 Dose-Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers.

The aim of the study was to characterize the pharmacokinetics, safety, and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in healthy Japanese volunteers, and to compare these outcomes with those of healthy Western volunteers. Twenty-five volunteers (Japanese, n = 16; Western [white], n = 9) were randomized to receive either 3 escalating single doses of tofacitinib (1, 5, and 30 mg), single-dose tofacitinib (15 mg) followed by multiple doses (15 mg twice daily for 5 days), or placebo. No significant differences in systemic exposure to tofacitinib were detected between the 2 ethnicities. Following single tofacitinib 1, 5, and 30 mg doses, mean area under the plasma concentration-time curve from time zero to infinity ratio (Japanese/Western) values were 96.6%, 93.5%, and 95.6%, respectively. Similarly, mean maximum observed plasma concentration ratio values were 99.5%, 118%, and 119%, respectively. Mean renal clearance was also similar, ranging across doses from 134 mL/min (5 mg) to 162 mL/min (1 mg) in Japanese volunteers, and 124 mL/min (30 mg) to 160 mL/min (1 mg) in Western volunteers. In both ethnicities, most adverse events were mild. No serious adverse events or deaths were reported. The pharmacokinetics of tofacitinib were well characterized in healthy Japanese volunteers and were similar to those in Western volunteers.

A Comparison of the Pharmacokinetics and Drug Safety Among East Asian Populations.

Global clinical studies conducted in various countries and regions are increasing. Race and extrinsic ethnic factors are key covariates that may affect the pharmacokinetics (PK), efficacy, and safety of the drug. Genetic similarity among East Asian populations has been confirmed; thus, PK, efficacy, and safety in these populations are expected to be similar, but this has not been confirmed. This study presents a comparison of PK and safety among East Asians from clinical studies sponsored by Pfizer. Four compounds with different characteristics, including mechanism of actions and PK profiles, were selected, and retrospective PK and safety comparisons in East Asians were conducted. No distinct differences were observed in PK and safety across the 4 compounds. These results are consistent with previous reports on PK comparisons and meet the expectations based on genetic similarity among East Asians. Extrapolation of these findings to other compounds should be done with caution, but these results should support the consideration of mutual use of clinical data among East Asian countries.