Mechanism of Action
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), 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 and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (Cmin and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily.
The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following the administration of a single 250 mg oral dose.
A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. XALKORI can be administered with or without food [see DOSAGE AND ADMINISTRATION].
The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.
Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.
In vitro studies demonstrated that crizotinib is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites.
In vitro studies in human liver microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP3A.
Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients.
Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.
The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/hr) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
Coadministration of Crizotinib and CYP3A Substrates
Crizotinib inhibits CYP3A both in vitro and in vivo. Coadministration of crizotinib (250 mg twice daily for 28 days) in patients resulted in a geometric mean oral midazolam AUC that was 3.7-fold that observed when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3 A [see DRUG INTERACTIONS].
Coadministration of Crizotinib and CYP3A Inhibitors
Coadministration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUCinf and Cmax values that were approximately 3.2-fold and 1.4-fold, respectively, those seen when crizotinib was administered alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated [see DRUG INTERACTIONS].
Coadministration of Crizotinib and CYP3A Inducers
Coadministration of a single 250 mg crizotinib dose with rifampin (600 mg QD), a strong CYP3A inducer, decreased crizotinib AUCinf and Cmax by 82% and 69%, respectively, compared to crizotinib alone. However, the effect of CYP3A inducers on steady-state crizotinib exposure has not been evaluated [see DRUG INTERACTIONS].
Coadministration of Crizotinib and Antacids
The aqueous solubility of crizotinib is pH dependent, with higher pH resulting in lower solubility. Drugs that elevate the gastric pH (such as proton pump inhibitors, H2 blockers, or antacids) may decrease the solubility of crizotinib and subsequently reduce its bioavailability. However, no formal studies have been conducted.
Coadministration With Other CYP Substrates
In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
An in vitro study in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2 or CYP3A.
Coadministration With Substrates of Transporters
Crizotinib is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered substrates of P-gp.
In vitro, crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3 at therapeutic concentrations. Therefore, clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the hepatic uptake of substrates for these transporters.
Pharmacokinetics in Special Populations
Hepatic Impairment: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, XALKORI has not been studied in patients with hepatic impairment. Clinical studies excluded patients with ALT or AST greater than 2.5 x ULN or greater than 5 x ULN if due to liver metastases. Patients with total bilirubin greater than 1.5 x ULN were also excluded [see Use In Specific Populations].
Renal Impairment: No dedicated renal impairment trial for XALKORI has been conducted. In Study B, steady-state trough concentrations in patients with mild (CLcr 60 to 90 mL/min, N=47) and moderate renal impairment (CLcr 30 to 60 mL/min, N=27) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, N=33). Limited data (N=l) are available in patients with severe renal impairment, and no data are available in patients with end-stage renal disease [see Use In Specific Populations].
Ethnicity: After 250 mg twice daily dosing, steady-state crizotinib Cmax and AUCτ in Asian patients were 1.57-and 1.50-fold those seen in non-Asian patients, respectively.
The QT interval prolongation potential of crizotinib was assessed in all patients who received XALKORI 250 mg twice daily. Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the effect of crizotinib on QT intervals. Four of 308 patients (1.3%) were found to have QTcF (corrected QT by the Fridericia method) greater than or equal to 500 msec, and 10 of 289 patients (3.5%) had an increase from baseline QTcF greater than or equal to 60 msec by automated machine-read evaluation of ECG. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent increase in QTcF [see WARNINGS AND PRECAUTIONS].
The use of single-agent XALKORI in the treatment of locally advanced or metastatic ALK-positive NSCLC was investigated in 2 multi-center, single-arm studies (Studies A and B). Patients enrolled into these studies had received prior systemic therapy, with the exception of 15 patients in Study B who had no prior systemic treatment for locally advanced or metastatic disease. In Study A, ALK-positive NSCLC was identified using the Vysis ALK Break-Apart FISH Probe Kit. In Study B, ALK-positive NSCLC was identified using a number of local clinical trial assays. The primary efficacy endpoint in both studies was Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Response was evaluated by the investigator and by an independent radiology review panel. Duration of Response (DR) was also evaluated. Patients received 250 mg of XALKORI orally twice daily. Demographic and disease characteristics for Studies A and B are provided in Table 4.
Table 4: Demographic and Disease Characteristics in Studies
A and B
|Characteristics|| Study A
| Study B
|Sex, n (%)|
|Male||64 (47)||59 (50)|
|Female||72 (53)||60 (50)|
|Median (range)||52 (29-82)||51 (21-79)|
|Race, n (%)|
|Asian||43 (32)||34 (29)|
|ECOG PS at baseline, n (%)|
|0||37 (27)||41 (35)|
|1||74 (54)||63 (53)|
|Smoking status, n (%)|
|Never smoked||92 (68)||86 (72)|
|Former smoker||39 (29)||32 (27)|
|Disease stage, n (%)|
|Histological classification, n (%)|
|Large cell carcinoma||1(1)||1(1)|
|Squamous cell carcinoma||0||1(1)|
|Prior systemic therapy for locally advanced or metastatic disease — number of regimens, n (%)|
|1||13 (10)||34 (29)|
|2||37 (27)||20 (17)|
|≥ 4||49 (36)||33 (28)|
|a Includes 1 patient with an ECOG PS of 1 at screening but was 3 at baseline.|
One hundred thirty-six patients with locally advanced or metastatic ALK-positive NSCLC from Study A were analyzed at the time of data cutoff. The median duration of treatment was 22 weeks. Based on investigator assessments, there was 1 complete and 67 partial responses for an ORR of 50% (95% CI: 42%, 59%). Seventy-nine percent of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 41.9 weeks.
One hundred nineteen patients with locally advanced or metastatic ALK-positive NSCLC were enrolled into Study B at the time of data cutoff. The median duration of treatment was 32 weeks. Based on investigator assessments, there were 2 complete and 69 partial responses for an ORR of 61% (95% CI: 52%, 70%). Fifty-five percent of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 48.1 weeks.
Efficacy data from Studies A and B are provided in Table 5.
Table 5: Locally Advanced or Metastatic ALK-Positive NSCLC
Efficacv Results from Studies A and Ba
|Efficacy Parameter|| Study A
| Study B
|Objective Response Rate (CR+PR)b [% (95% CI)]||50% (42%, 59%)||61% (52%, 70%)|
|Number of Responders||68||71|
|Duration of Responsec [Median (range) weeks]||41.9(6.1+, 42.1+)||48. 1(4.1+, 76.6+)|
|a Response as assessed by the Investigator.
b One patient was not evaluable for response in Study A; 3 patients were not evaluable for response in Study B.
c Preliminary estimate using Kaplan-Meier method. +Censored values
Last reviewed on RxList: 3/15/2012
This monograph has been modified to include the generic and brand name in many instances.
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