title: Safety, Pharmacokinetic, and Pharmacodynamic Evaluation After Single and Multiple Ascending Doses of a Novel Selective Androgen Receptor Modulator in Healthy Subjects.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Pfizer, Cambridge, Massachusetts. Electronic address: neil.bhattacharya@pfizer.com.
authors.forename: Indranil
authors.initials: I
authors.lastname: Bhattacharya
authors.affiliation: Pfizer, New Haven, Connecticut.
authors.forename: Sanela
authors.initials: S
authors.lastname: Tarabar
authors.affiliation: Pfizer, Groton, Massachusetts.
authors.forename: Yali
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Pfizer, Cambridge, Massachusetts.
authors.forename: Vivek
authors.initials: V
authors.lastname: Pradhan
authors.affiliation: Pfizer, Cambridge, Massachusetts.
authors.forename: Jane
authors.initials: J
authors.lastname: Owens
authors.affiliation: Pfizer, Cambridge, Massachusetts.
authors.forename: Barry
authors.initials: B
authors.lastname: Oemar
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001741:Black or African American; D000728:Androgens / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001213:Asian; D004311:Double-Blind Method; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011944:Receptors, Androgen / Q000378:metabolism*; D044465:White People; D055815:Young Adult
chemical_list: C410798:AR protein, human; D000728:Androgens; D007546:Isoquinolines; C000622589:PF-06260414; D011944:Receptors, Androgen
keywords: first in human; hypothalamic-pituitary-gonadal axis hormones; pharmacodynamic properties; pharmacokinetic properties; selective androgen receptor modulator