12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
In an ECG substudy conducted in 52 patients with ALK-positive NSCLC, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 12.3 ms (2-sided 90% upper CI: 19.5 ms) following administration of XALKORI 250 mg orally twice daily. An exposure-QT analysis suggested a crizotinib plasma concentration-dependent increase in QTcF [see Warnings and Precautions (5.3)].
Following XALKORI 250 mg twice daily, steady-state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady-state observed minimum concentration (Cmin) 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).
A single crizotinib dose was absorbed with median time to achieve peak concentration of 4 to 6 hours, and the mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%).
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.
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).
No clinically significant difference in crizotinib pharmacokinetics were observed based on age, sex, ethnicity (Asian, non-Asian), or body weight.
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 (2.3) and 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. 4), Use in Specific Populations (8.7)].
Drug Interaction Studies
Gastric Acid Reducing Agents: No clinically significant differences in crizotinib pharmacokinetics were observed when used concomitantly with esomeprazole, a proton pump inhibitor.
Strong CYP3A Inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole, a strong CYP3A inhibitor, increased crizotinib AUC0–INF by 216% and Cmax by 44% compared to crizotinib alone. Coadministration of XALKORI 250 mg orally once daily with itraconazole, a strong CYP3A inhibitor, increased crizotinib steady-state AUC by 57% and Cmax by 33% compared to crizotinib alone [see Drug Interactions (7.1)].
Strong CYP3A Inducers: Coadministration of XALKORI 250 mg orally twice daily with rifampin, a strong CYP3A inducer, decreased crizotinib steady-state AUC0–Tau by 84% and Cmax by 79%, compared to crizotinib alone [see Drug Interactions (7.1)].
CYP3A Substrates: Coadministration of XALKORI 250 mg orally twice daily for 28 days increased AUC0–INF of oral midazolam (CYP3A substrate) 3.7-fold compared to midazolam alone [see Drug Interactions (7.2)].
In Vitro Studies
CYP Enzymes: Crizotinib inhibits CYP2B6 in vitro. Crizotinib does not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Crizotinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A.
UDP-glucuronosyltransferase (UGT): Crizotinib does not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.