Following XALKORI 250 mg capsules twice daily, steady-state was reached within 15 days with a median accumulation ratio of 4.8. Steady-state minimum concentration (Cmin.ss) and AUC increased in a greater than dose-proportional manner over the dose range of 200 mg to 300 mg twice daily (0.8 to 1.2 times the approved recommended dosage).
Absorption
A single crizotinib capsule dose was absorbed with median time to achieve peak concentration (Tmax) of 4 to 6 hours, and the mean absolute bioavailability of 43% (range: 32% to 66%).
The oral pellets had a comparable crizotinib bioavailability compared with the capsules.
Effect of Food
A high-fat meal, reduced AUC0-INF and maximum plasma concentration (Cmax) of crizotinib each by 14% for the capsule formulation; reduced AUC0-INF and Cmax of crizotinib by 15% and 23%, respectively, for the pellet formulation as compared to those under fasted conditions.
Distribution
The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following a single intravenous dose. Protein binding of crizotinib is 91% and is independent of drug concentration in vitro. Crizotinib is a substrate for P-glycoprotein (P-gp) in vitro. The blood-to-plasma concentration ratio is approximately 1.
Elimination
The mean apparent plasma terminal half-life of crizotinib was 42 hours following single doses of crizotinib in patients. The mean apparent clearance (CL/F) of crizotinib was lower at steady-state (60 L/h) after 250 mg twice daily than after a single 250 mg oral dose (100 L/h).
Metabolism
Crizotinib is predominantly metabolized by CYP3A.
Excretion
Following administration of a single oral 250 mg dose of radiolabeled crizotinib dose to healthy subjects, 63% (53% as unchanged) of the administered dose was recovered in feces and 22% (2.3% as unchanged) in urine.
Specific Populations
No clinically significant difference in crizotinib pharmacokinetics were observed based on age, sex, or ethnicity (Asian, non-Asian). For patients <18 years of age, body weight has a significant effect on the pharmacokinetics of crizotinib, with lower crizotinib exposures observed in patients with higher body weight.
Pediatric Patients
In pediatric patients, crizotinib steady-state exposure increased proportionally with dose over the dose range of 165 mg/m2 to 280 mg/m2 orally twice daily. At a dosing regimen of 280 mg/m2 (approximately 2 times the recommended adult dose), geometric mean (CV%) steady-state maximum plasma concentrations (Cmax) of crizotinib was 621 (73%) ng/mL and AUC0–tau was 6530 (34%) ng∙hr/mL.
Patients with Hepatic Impairment
Steady-state mean crizotinib AUC and Cmax decreased by 9% in patients with mild hepatic impairment (AST >ULN and total bilirubin ≤1 times ULN or any AST and total bilirubin >1 times ULN but ≤1.5 times ULN) compared to patients with normal hepatic function following XALKORI 250 mg orally twice daily.
Steady-state mean crizotinib AUC increased by 14% and Cmax increased by 9% in patients with moderate hepatic impairment (any AST and total bilirubin >1.5 times ULN and ≤3 times ULN) following XALKORI 200 mg orally twice daily compared with patients with normal hepatic function following XALKORI 250 mg orally twice daily.
Mean crizotinib AUC decreased by 35% and Cmax decreased by 27% in patients with severe hepatic impairment (any AST and total bilirubin >3 times ULN) following XALKORI 250 mg orally once daily compared with patients with normal hepatic function following XALKORI 250 mg orally twice daily [see Dosage and Administration (2.7), Use in Specific Populations (8.6)].
Patients with Renal Impairment
Mild or moderate renal impairment (CLcr of 60–89 ml/min or 30–59 ml/min, respectively, calculated using the modified Cockcroft-Gault equation) has no clinically significant effect on the exposure of crizotinib. Following a single 250 mg dose, the mean AUC0–INF of crizotinib increased by 79% and the mean Cmax increased by 34% in patients with severe renal impairment (CLcr <30 mL/min) who did not require dialysis compared to those with normal renal function (CLcr ≥90 mL/min). Similar changes in AUC0–INF and Cmax were observed for the active metabolite of crizotinib [see Dosage and Administration (2.8), Use in Specific Populations (8.7)].