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

Glasdegib (PF-04449913) is an oral small-molecule inhibitor of the Hedgehog signaling pathway under development for treating myeloid malignancies. This was an open-label phase 1, randomized, 2-sequence, 2-treatment, 2-period, crossover study evaluating the absolute bioavailability of glasdegib in healthy volunteers under fasting condition (NCT03270878). In period 1, 12 eligible subjects received either a single oral dose of glasdegib 100 mg (tablet) or a single intravenous (IV) dose of glasdegib 50 mg. Following ≥6-day washout, subjects received the treatment that they did not receive in the first period. Blood samples were collected for up to 96 hours after dosing. Drug plasma concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Glasdegib pharmacokinetic parameters were calculated using noncompartmental analysis. The mean terminal half-life was 14.3 hours for oral tablet treatment vs 13.8 hours for glasdegib IV treatment. The absolute oral bioavailability measured as the ratios (oral/IV) of adjusted geometric mean (90% confidence interval) of dose normalized area under the plasma concentration-time curve was 77.12% (71.83%-82.81%). Two adverse events (1 mild and 1 moderate in severity) were reported by 2 subjects following oral tablet administration; these were fully resolved by the end of the study.