Crizocent is a kinase inhibitor indicated for the treatment of patients with- Metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive. Metastatic NSCLC whose tumors are ROS1-positive.
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. Absorption : 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 (C.min 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%. 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. 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-glycoprotcin (P-gp). The blood-to-plasma concentration ratio is approximately 1. Metabolism : 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-dcalkylatcd metabolites. Elimination : 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 auto inhibition of CYP3A by crizotinib after multiple dosing.
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Recommended Dose : 250 mg orally, twice daily Geriatric Use : No differences in safety or efficacy were observed between older and younger patients. Clinical studies of Crizotinib in patients with ROS1-positive metastatic NSCLC did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients Pediatric Dose : The safety and effectiveness of Crizotinib in pediatric patients have not been established. Renal impairment : 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild (ClCr 60-89 mL/min) or moderate (ClCr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis. Hepatic Impairment : Caution should be used in patients with hepatic impairment
The most common adverse reactions (≥25%) are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.
CYP3A Inhibitors : Concurrent use of Crizocent should be avoided with strong CYP3A inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole CYP3A Inducers : Concurrent use of Crizocent should be avoided with strong CYP3A inducers including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort CYP3A Substrates : Concurrent use of Crizocent should be avoided with CYP3A substrates with narrow therapeutic indices including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus
Hepatotoxicity : Patients should undergo periodic liver testing. Crizocent should be temporarily suspended, dose reduced or permanently suspended Interstitial lung disease (ILD)/ Pneumonitis : Drug should be permanently discontinued in patients with ILD/ Pneumonitis QT interval prolongation : Electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT should be monitored. Crizocent should be temporarily suspended, dose reduced or permanently suspended Bradycardia : Crizocent can cause bradycardia. Heart rate and blood pressure should be regularly monitored. Crizocent should be temporarily suspended, dose reduced or permanently suspended Severe visual loss : Ophthalmological evaluation should be performed. Crizocent should be discontinued in severe visual loss Embryo-fetal toxicity : Crizocent can cause fetal harm. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception