title: Metabolism, excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration.
abstract: 1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 μCi [14C]glasdegib to six healthy male volunteers (NCT02110342). 2. The peak concentrations of glasdegib (890.3 ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75 hours post-dose. The AUCinfwere 8469 ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity. 3. Mean recovery of [14C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0-120 hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites. 4. Elimination of [14C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.
authors.affiliation: a Department of Pharmacokinetics , Dynamics and Metabolism, Pfizer Inc , San Diego , CA , USA.
authors.forename: Justine L
authors.initials: JL
authors.lastname: Lam
authors.affiliation: b Department of Pharmacokinetics , Dynamics and Metabolism, Pfizer Inc , Groton , CT , USA.
authors.forename: Alfin
authors.initials: A
authors.lastname: Vaz
authors.affiliation: c Department of Clinical Pharmacology, Pfizer Inc , San Diego , CA , USA , and.
authors.forename: Brian
authors.initials: B
authors.lastname: Hee
authors.affiliation: d Department of Clinical Pharmacology, Pfizer Inc , Groton , CT , USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Liang
authors.affiliation: b Department of Pharmacokinetics , Dynamics and Metabolism, Pfizer Inc , Groton , CT , USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: c Department of Clinical Pharmacology, Pfizer Inc , San Diego , CA , USA , and.
authors.forename: M Naveed
authors.initials: MN
authors.lastname: Shaik
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D001711:Biotransformation; D020719:Glucuronides / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; D020719:Glucuronides; D010671:Phenylurea Compounds; C000592580:glasdegib
keywords: ADME; Glasdegib; mass balance, PF-04449913; smoothened inhibitor