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

Abstract

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 Tmax, approximately 1-2 hours), a mean t½ of approximately 6.9 to 12.8 hours, time-independent PK properties and dose proportionality. Cmax and AUCτ 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.

Keywords: first in human; hypothalamic-pituitary-gonadal axis hormones; pharmacodynamic properties; pharmacokinetic properties; selective androgen receptor modulator.