Safety, Pharmacokinetic, and Pharmacodynamic Evaluation After Single and Multiple Ascending Doses of a Novel Selective Androgen Receptor Modulator in Healthy Subjects

Purpose: Tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of single ascending doses (SADs) and multiple ascending doses (MADs) of PF-06260414, a novel selective androgen receptor modulator, were assessed after oral administration in healthy subjects. Methods: Range of SAD and MAD levels tested were 1 to 400 mg and 3 to 100 mg BID, respectively (n = 8 per cohort). In addition, a 60-mg once-daily (n = 8) cohort and a Japanese cohort receiving 30 mg BID (n = 7) also received PF-06260414. Plasma was collected to study PK properties and hypothalamic-pituitary gonadal (HPG) axis hormones. Tolerability was evaluated from adverse events (AEs), physical examinations, vital signs, ECGs, and clinical laboratory results. Findings: PF-06260414 was well tolerated with no serious AEs. The most frequently reported AEs were increase in alanine aminotransferase and headache, which were reported by 7 and 3 subjects, respectively. PF-06260414 had fast absorption (median T-max, approximately 1-2 hours), a mean t1/2. of approximately 6.9 to 12.8 hours, time-independent PK properties and dose proportionality. C-max and AUC(iota), geometric means in Japanese subjects were 98.6% and 79.5% higher than in Western subjects, respectively, but had similar HPG axis modulation. Changes in HPG axis hormones monitored in SADs were similar to placebo. Maximum placebo-corrected modulations were observed for total testosterone and sex hormone binding globulin in the MAD 100-mg BID regimen. Implications: This study was the first to compare a number of different factors of PF-06260414, including tolerability, PK and PD properties, and ethnic differences between Japanese and Western healthy subjects. PF-06260414 had favorable PK properties and found that sex hormone binding globulin, total testosterone, and HDL were most sensitive to modulation. ClinicalTrials.gov identifier: NCT02070939. (C) 2016 Elsevier HS Journals, Inc. All rights reserved.