b or low-dose cytarabine alone.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of glasdegib administration on corrected QT interval (QTc) was eva luated in a randomized,single-dose, double-blind, 4-way crossover, placebo- and open-label moxifloxacin-controlled study in36 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 QTcprolongation.
12.3 Pharmacokinetics
DAURISMO at 5 mg to 600 mg once daily (0.05 to 6 times the recommended dose) result in a doseproportional 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 ofglasdegib 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) ofglasdegib 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, glasdegibmedian 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 carbohydratecalories and 150 protein calories) reduced area under the curve over time to infinity (AUCinf) by 16% and Cmaxby 31%.
Distribution
Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume ofdistribution (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 of6.45 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 andUGT1A9. 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 dosewas 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 x ULN and any AST) or mild to moderate renalimpairment (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 x ULN and any AST) and severe(total bilirubin > 3 x 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 |
