XALKORI (crizotinib) Action And Clinical Pharmacology

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Mechanism of Action

Crizotinib is a selective small-molecule inhibitor of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (i.e., ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the Hepatocyte Growth Factor Receptor (HGFR, c-Met) RTK, ROS (ROS1, c-ros), and Recepteur d’Origine Nantais (RON) RTKs.


Crizotinib demonstrated concentration-dependent inhibition of the kinase activity of ALK, ROS1, and c‑Met in biochemical assays and inhibited phosphorylation and kinase-dependent phenotypes in cell-based assays. Crizotinib demonstrated potent and selective growth inhibitory activity and induced apoptosis in tumor cell lines exhibiting ALK fusion events (including echinoderm microtubule-associated protein-like 4 [EML4]-ALK and nucleophosmin [NPM]-ALK), ROS1 fusion events, or exhibiting amplification of the ALK or MET gene locus.

Crizotinib demonstrated antitumor efficacy, including marked cytoreductive antitumor activity, in mice bearing tumor xenografts that expressed ALK and ROS1 fusion proteins. The antitumor efficacy of crizotinib was dose-dependent and correlated to pharmacodynamic inhibition of phosphorylation of ALK (EML4-ALK or NPM-ALK) and ROS1 (CD74-ROS1 or EZR-ROS1) fusion proteins in tumors in vivo. Crizotinib also demonstrated marked antitumor activity in mouse xenograft studies, where tumors were generated using a panel of NIH 3T3 cell lines engineered to express key ROS1 fusions identified in human tumors. The antitumor efficacy of crizotinib was dose dependent and demonstrated a correlation with inhibition of ROS1 phosphorylation in vivo.


Absorption: In patients, following a single oral administration in the fasted state, crizotinib was absorbed with a median time to achieve peak concentrations (Tmax) of 4 hours (range: 2 to 9.33 hours) in patients (see Clinical Pharmacokinetics section under DETAILED PHARMACOLOGY). The systemic exposure (Cmax, Ctrough and AUCtau) appears to be greater than dose-proportional within the dose range of 200-300 mg twice daily. With twice daily dosing, steady state was achieved within 15 days with a median accumulation ratio of 4.8 (range: 3 to 13), and remained stable. The mean absolute bioavailability of crizotinib was determined to be 43% (range: 32%-66%) following the administration of a single 250 mg oral dose. Following oral administration of a single dose of a 250 mg XALKORI capsule to healthy volunteers in the fasted state, the median Tmax was 5 hours, and the geometric mean Cmax and AUC of crizotinib were 135 ng/mL and 2887 ng.hr/mL, respectively.
A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14% when a 250 mg single dose was given to healthy volunteers. XALKORI can be administered with or without food (see DOSAGE AND ADMINISTRATION section).

Distribution: The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma. In non-clinical studies, tissues with the highest crizotinib and related metabolite concentrations were liver, uveal tract, adrenal gland, small intestine, and pituitary gland.

Binding of crizotinib to human plasma proteins in vitro is 91% and appears to be independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P‑gp).

Metabolism: In vitro studies demonstrated that CYP3A4/5 were the major enzymes involved in the metabolic clearance of crizotinib. 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.

Crizotinib lactam (M10, PF-06260182) is approximately 2.5- and 7.7-fold less potent than crizotinib in inhibiting ALK and c-Met tyrosine kinases, respectively, in vitro. The O-desalkyl crizotinib (M4, PF-03255243) and O-desalkyl crizotinib lactam (M2, PF-06268935) are inactive against ALK and c-Met.

In vitro studies in human microsomes demonstrated that crizotinib is a time-dependent inhibitor of CYP3A and CYP2B6.

Elimination: Following a single 250 mg oral dose, the terminal half-life (t1/2) of crizotinib was 42 hours (% coefficient of variation [CV]: 21) in patients; the mean apparent clearance (CL/F) was 100 L/hr (%CV: 50). At steady state after 250 mg twice daily (Cycle 1 Day 15), the CL/F appeared to be lower (65 L/hr with % CV of 56). The reduced clearance at steady state may be due to autoinhibition of CYP3A by crizotinib following repeated dosing.

In a non-clinical study, delayed clearance of crizotinib was observed; tissues with the longest t1/2 values (range: 576 to 118 hours) were eye, epididymis, testis, pigmented skin, kidney cortex, and brown fat.

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.

Special Populations and Conditions

Hepatic Impairment: Crizotinib is extensively metabolized in the liver. Patients with mild (either AST >ULN and total bilirubin ≤ULN or any AST and total bilirubin >ULN but ≤1.5×ULN), moderate (any AST and total bilirubin >1.5×ULN and ≤3×ULN), or severe (any AST and total bilirubin >3×ULN) hepatic impairment or normal (AST and total bilirubin ≤ULN) hepatic function (who were matched controls for mild or moderate hepatic impairment) were enrolled in an open-label, non-randomized clinical study (Study 1012), based on NCI classification.

Following XALKORI 250 mg twice daily dosing, patients with mild hepatic impairment (N=10) showed similar systemic crizotinib exposure at steady state compared to patients with normal hepatic function (N=8), with geometric mean ratios for area under the plasma concentration-time curve as daily exposure at steady state (AUCdaily) and Cmax of 91.1% and 91.2%, respectively. No starting dose adjustment is recommended for patients with mild hepatic impairment.

Following XALKORI 200 mg twice daily dosing, patients with moderate hepatic impairment (N=8) showed higher systemic crizotinib exposure compared to patients with normal hepatic function (N=9) at the same dose level, with geometric mean ratios for AUCdaily and Cmax of 150% and 144%, respectively. However, the systemic crizotinib exposure in patients with moderate hepatic impairment at the dose of 200 mg twice daily was comparable to that observed from patients with normal hepatic function at a dose of 250 mg twice daily, with geometric mean ratios for AUCdaily and Cmax of 114% and 109%, respectively.

The systemic crizotinib exposure parameters AUCdaily and Cmax in patients with severe hepatic impairment (N=6) receiving a XALKORI dose of 250 mg once daily were approximately 64.7% and 72.6%, respectively, of those from patients with normal hepatic function receiving a dose of 250 mg twice daily.

An adjustment of the dose of XALKORI is recommended when administering XALKORI to patients with moderate or severe hepatic impairment (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Impairment: The exposure to crizotinib was evaluated in patients with mild (CLcr 60-89 mL/min, N=226) and moderate (CLcr 30-59 mL/min, N=73) renal impairment enrolled in Studies A8081001 and A8081005. An evaluation on the baseline renal function status measured by CLcr on observed crizotinib steady state trough concentrations (Ctrough,ss) demonstrated that in Study A8081001, the adjusted geometric mean of plasma Ctrough,ss in mild (Ctrough,ss= 319 ng/mL, N=35) and moderate (Ctrough,ss = 338 ng/mL, N=8) renal impairment patients were 105.10% (90% CI: 92.90%, 118.91%) and 111.41% (90% CI: 90.17%, 137.66%), respectively, of those in patients with normal renal function (Ctrough,ss = 304 ng/mL, N=44). In Study A8081005, the adjusted geometric mean Ctrough,ss of crizotinib in mild (Ctrough,ss = 311 ng/mL, N=191) and moderate (Ctrough,ss = 328 ng/mL, N=65) renal impairment groups were 109.14% (90% CI: 102.08%, 116.68%) and 115.07% (90% CI: 104.08%, 127.23%), respectively, of those in patients with normal renal function (Ctrough,ss = 285 ng/mL, N=331). The population pharmacokinetic analysis from Studies A8081001, A8081005 and A8081007 indicated that baseline CLcr did not have a clinically relevant effect on crizotinib pharmacokinetics.

An open-label, single dose parallel-group study (A8081020) evaluated the effect of severe renal impairment on exposure to crizotinib. Eight subjects with normal renal function (CLcr ≥90 mL/min) were matched 1-to-1 to 8 subjects with severe renal impairment not requiring dialysis (CLcr <30 mL/min) with respect to age (mean 61 vs. 63 years), weight (mean 84 vs. 86 kg) race (6 white and 2 black vs. 5 white and 3 black subjects), and sex (2 males and 6 females in each group). All subjects received a single oral crizotinib dose of 250 mg. The results of Study A8081020 are summarized in Table 8.

Table 8. Statistical Summary of Crizotinib Plasma Exposures by Normal Renal Function and Severe Renal Impairment
Abbreviation: CI=confidence interval.
One subject from severe renal impairment group was excluded in the analysis due to vomit episodes occurring at 1 hour post dose.
The ratios (and 90% CIs) are expressed as percentages.

Parameter (units)

Adjusted Geometric Means

Ratio (Test/Reference) of Geometric Meansb

90% CI for Ratio

Test (Severe Renal Impairment)a

Reference (Normal Renal Function)

AUCinf (ng·hr/mL)




(126.80, 254.03)

AUClast (ng·hr/mL)




(128.05, 259.19)

Cmax (ng/mL)




(99.34, 181.65)

In subjects with severe renal impairment, crizotinib AUC and Cmax increased by 79% and 34%, respectively, compared to those with normal renal function. Based on these results, a starting dose reduction by 50% (250 mg once daily) is recommended when administering crizotinib to patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Special Populations).

No dedicated renal impairment study has been conducted in patients with mild (CLcr 60-89mL/min) or moderate (CLcr 30-59mL/min) renal impairment. Based on the population pharmacokinetic analysis described above, no starting dose adjustment is recommended in patients with mild or moderate renal impairment (see WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION). No data are available for patients with end-stage renal disease.

Age: Based on the population pharmacokinetic analysis of pooled PK dataset from Studies A8081001, A8081005 and A8081007 containing 1214 patients with a mean (range) age of 51.8 years (19-83 years), age has no effect on crizotinib pharmacokinetics. Therefore, no starting dose adjustments of crizotinib are recommended based on age.

Pediatrics (range: 2-22 years): Limited data are available on the use of XALKORI in pediatric patients. XALKORI has been studied in a phase 1/2 trial, with 64 children who had solid tumors or anaplastic large cell lymphoma and had pharmacokinetic sampling after the first dose (n=15) of XALKORI or at steady state (n=49). Dose levels evaluated ranged from 100 to 365 mg/m2/dose administered twice daily. The effectiveness of XALKORI in this pediatric population has not been established.

Ethnicity: After 250 mg twice daily dosing, steady-state crizotinib Cmax and AUCt in Asian patients were 1.57- (90% CI: 1.16-2.13) and 1.50- (90% CI: 1.10-2.04) fold those seen in non-Asian patients, respectively. There was a higher incidence of Grade 3 or 4 adverse events in non-Asians (17%) than Asians (10%). (see Clinical Pharmacokinetics section under DETAILED PHARMACOLOGY).