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DAURISMO™ (glasdegib) Clinical Pharmacology

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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

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.

12.3 Pharmacokinetics

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 (AUCtau). 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 AUCtau was 17210 ng*hr/mL (54%) in patients with cancer.

Absorption

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.

Effect of Food: A high-fat, high-calorie meal (total 800–1000 calories: 500–600 fat calories, 250 carbohydrate calories and 150 protein calories) reduced area under the curve over time to infinity (AUCinf) by 16% and Cmax by 31%.

Distribution

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.

Elimination

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.

Metabolism

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.

Excretion

Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces.

Specific Populations

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) or mild to moderate renal impairment (creatinine clearance [CLcr] 30–89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib. The effect of moderate (total bilirubin 1.5–3 × ULN and any AST) and severe (total bilirubin > 3 × ULN and any AST) hepatic impairment or severe renal impairment (CLcr 15–29 mL/min) on glasdegib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A4 Inhibitors on Glasdegib:

Coadminstration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUCinf by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone [see Drug Interactions (7)].

Effect of Strong CYP3A4 Inducers on Glasdegib:

Coadminstration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUCinf by 70% and Cmax by 35% [see Drug Interactions (7)].

Effect of Gastric Acid Reducing Agents on Glasdegib:

Coadministration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUCinf but decreased Cmax by 20%.

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).

Effect of Glasdegib on Transporters:

Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro.

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