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 [C]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 AUC were 8469 ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity. 3. Mean recovery of [C]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 [C]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.

Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers

“…A human mass balance study showed glasdegib to be metabolised primarily by hepatic CYP3A4, and to a lesser extent, by uridine diphosphoglucuronosyltransferase 1A9 . The involvement of CYP3A4 in the glasdegib metabolism was supported by the result of the previous DDI study, in which a known strong inhibitor of CYP3A, ketoconazole, increased glasdegib AUC inf and C max by 140% and 40%, respectively, in healthy volunteers .…”

“…The total study duration was approximately 17 days. Glasdegib 100 mg once daily is the clinical dosage of glasdegib that is under evaluation in Phase 2/3 trials, and was selected based on clinical activity, biomarker modulation, safety and tolerability data from previous studies in patients with haematologic malignancies and healthy volunteers .…”

“…The pharmacokinetics and safety of glasdegib following a single‐dose administration have been evaluated in healthy volunteers in three Phase 1 studies . Additional pharmacokinetics studies to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) have been conducted in patients with advanced solid tumours or select haematological malignancies in the United States and Europe as well as in Japan .…”

“…In vitro and ex vivo studies showed that glasdegib is primarily metabolised by cytochrome P450 (CYP) 3A4/5 ; hence, a strong inhibitor or inducer of CYP3A4/5 may impact glasdegib pharmacokinetics. A previous drug–drug interaction (DDI) study evaluating the effect of a strong CYP3A inhibitor found that co‐administration of ketoconazole increased glasdegib plasma exposure in healthy volunteers .…”

Absolute Oral Bioavailability of Glasdegib (PF‐04449913), a Smoothened Inhibitor, in Randomized Healthy Volunteers

“…Results from the ADME study also indicated that glasdegib major route of elimination is primarily through CYP3A4 oxidation, and that contribution from the glucuronidation pathway via the uridine 5′‐diphospho‐glucuronosyltransferase 1‐9 (UGT1A9) is only minor . In that study, 4.2% of the administered dose was found in the urine as N‐glucuronide metabolite but not in the feces, whereas 19.5% of the administered glasdegib parent dose was recovered in the feces.…”