12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Glasdegib is an inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction.
In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine, inhibited increases in tumor size and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greater extent than glasdegib or low-dose cytarabine alone.
The effect of glasdegib administration on corrected QT interval (QTc) was evaluated in a randomized, single-dose, double-blind, 4-way crossover, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects. At therapeutic plasma concentrations for the recommended dose, achieved with a single dose of 150 mg DAURISMO, the largest placebo and baseline-adjusted QTc interval change was 8 ms (90% CI: 6, 10 ms). At a two-fold therapeutic plasma concentration, achieved with a single dose of 300 mg DAURISMO, the QTc change was 13 ms (90% CI: 11, 16 ms). Glasdegib is associated with concentration-dependent QTc prolongation.
DAURISMO at 5 mg to 600 mg once daily (0.05 to 6 times the recommended dose) result in a dose proportional increase in glasdegib peak concentrations (Cmax) and area under the curve over the dosing interval (AUC0-Tau). Steady-state plasma levels are reached by 8 days of daily dosing. The median accumulation ratio of glasdegib ranged from 1.2 to 2.5 following once-daily dosing.
At DAURISMO 100 mg once daily, the geometric mean (geometric coefficient of variation, % CV) of glasdegib Cmax was 1252 ng/mL (44%) and AUC0-Tau was 17210 ng*hr/mL (54%) in patients with cancer.
The mean absolute bioavailability of DAURISMO is 77%. Following 100 mg once daily dosing, glasdegib median time to peak concentrations (Tmax) at steady-state ranged from 1.3 hours to 1.8 hours.
Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.
Glasdegib has a mean (± SD) half-life of 17.4 h (3.7) and geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies.
Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma.
Age (25 to 92 years), sex, race (White, Black, Asian), body weight (43.5 to 145.6 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1–1.5 × ULN and any AST), and mild renal impairment (creatinine clearance 60–89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib.
Patients with Renal Impairment
Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR ≥90 mL/min). The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis.
Patients with Hepatic Impairment
Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone [see Drug Interactions (7)].
Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35% [see Drug Interactions (7)]. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%.
In Vitro Studies
Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro.
Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).