Crizotinib

Introduction Overview

Generic Name

crizotinib

Brand Name

Xalkori

Dosage Form

oral capsules, oral pellets

Drug Class

Multikinase inhibitors

Pharmacokinetics

Absorption:
Crizotinib is orally administered and demonstrates effective absorption in the gastrointestinal tract. Pharmacokinetic studies have shown that peak plasma concentrations are typically reached approximately 4 to 6 hours post-dose. The bioavailability of the drug can be influenced by food intake; however, crizotinib may be taken with or without food without clinically significant effects on systemic exposure. The presence of grapefruit juice is contraindicated due to its interaction with metabolic pathways, notably CYP3A, potentially altering absorption and systemic drug levels. The oral pellets provide an alternative administration route for pediatric patients or those unable to swallow capsules, designed to maintain appropriate absorption profiles.

Distribution:
Crizotinib exhibits extensive distribution throughout body tissues with a large volume of distribution, indicative of substantial tissue penetration. It binds moderately to plasma proteins, approximately 92%, primarily albumin, which influences its pharmacokinetic behavior and tissue bioavailability. Notably, crizotinib preferentially accumulates in tumor tissues expressing ALK or ROS1 mutations, facilitating its targeted therapeutic effect. The distribution pattern is critical for reaching therapeutic concentrations within difficult-to-access tumor sites, including metastatic sites in lung cancer and lymphomas.

Metabolism:
Crizotinib is predominantly metabolized in the liver via the cytochrome P450 3A4 (CYP3A4) isoenzyme pathway. The metabolic process leads to several metabolites, with the major metabolite being less pharmacologically active but contributing to the overall effect. Metabolic clearance is impacted by concomitant administration of CYP3A inhibitors or inducers, which can respectively increase toxicity risk or reduce therapeutic efficacy. Hepatic function impairment may result in altered metabolism and necessitate dose adjustments or more intensive monitoring.

Elimination:
Crizotinib and its metabolites are primarily eliminated via fecal excretion, with approximately 63% of the administered dose recovered in feces and around 22% in urine, mostly as metabolites. The elimination half-life ranges approximately from 42 to 51 hours, supporting twice-daily dosing frequency. Renal impairment has limited direct effect on clearance, but severe hepatic impairment demands caution due to hepatic metabolism predominance. Steady-state concentrations are usually achieved within 15 days of regular dosing. Clinical implications of elimination pathways necessitate careful management in patients with hepatic dysfunction, and awareness of prolonged drug retention influencing side-effect profiles.

Dosage Forms

Available Dosage Forms:
Xalkori is available in two primary oral formulations designed to accommodate various patient requirements:
- Oral capsules: 200 mg and 250 mg strengths.
- Oral pellets: 20 mg, 50 mg, and 150 mg doses, intended for pediatric use or patients unable to swallow capsules.

Dosages for Adults and Adolescents:
- The standard adult dosage for metastatic non-small cell lung cancer (NSCLC) and unresectable inflammatory myofibroblastic tumors (IMT) is 250 mg taken orally twice daily.
- Dosage for adolescents and children aged 1 year and older with ALK-positive anaplastic large cell lymphoma (ALCL) or unresectable IMT is calculated based on body surface area (BSA) at 280 mg/m² orally twice daily.

Specific Patient Populations:
- Pediatric patients require oral pellets, which facilitate appropriate dosing and ease of administration, specifically supervised to ensure full ingestion.
- Dosing adjustments may be necessary based on treatment tolerance, hepatic impairment, or emergent adverse effects.
- Capsules must be swallowed whole and not crushed or chewed, while pellets must be administered as instructed, either directly into the mouth or via a dry spoon followed by water to ensure complete delivery.
- Monitoring during therapy is essential, especially in children or young adults prone to severe gastrointestinal side effects.

Clinical guidelines recommend twice-daily administration with or without food, avoiding grapefruit products due to the risk of pharmacokinetic interactions.

Mechanism Of Action

Crizotinib, marketed as Xalkori, exerts its therapeutic effects primarily through selective inhibition of receptor tyrosine kinases that are aberrantly activated in certain cancers. It targets Anaplastic Lymphoma Kinase (ALK), ROS1 receptor tyrosine kinase, hepatocyte growth factor receptor (HGFR, c-Met), and the Recepteur d’Origine Nantais (RON). These RTKs are critical mediators of intracellular signaling pathways that regulate cell growth, differentiation, and survival.

Molecularly, crizotinib binds competitively to the ATP-binding site of these kinases, blocking their phosphorylation activity. This inhibition prevents downstream signaling cascades such as the PI3K/AKT and RAS/MAPK pathways, which are crucial for the proliferation and survival of tumor cells harboring ALK or ROS1 gene rearrangements. The blockade of these pathways leads to cell cycle arrest and apoptosis in cancer cells dependent on these aberrant kinases.

At the cellular level, crizotinib induces tumor regression by promoting programmed cell death and inhibiting malignant cell proliferation in ALK-positive non-small cell lung cancer, ALK-positive anaplastic large cell lymphoma, and ALK-positive inflammatory myofibroblastic tumors. Laboratory studies demonstrate crizotinib-induced cell death in ALCL-derived cell lines expressing nucleophosmin-ALK or c-Met fusion proteins.

Comparatively, crizotinib differs from other targeted therapies by its multitarget kinase inhibitory profile, inhibiting multiple RTKs implicated in oncogenesis, thus broadening its clinical application spectrum. Clinical trials have validated its efficacy in patients with ALK or ROS1 mutations, showcasing its ability to delay disease progression and achieve partial or complete tumor responses. Ongoing research continues to explore resistance mechanisms, such as secondary mutations in target kinases, and combination therapies to enhance clinical outcomes.

Pharmacological Actions

Selective inhibition of anaplastic lymphoma kinase (ALK) receptor tyrosine kinase.
Inhibition of ROS1 receptor tyrosine kinase activity.
Blockade of hepatocyte growth factor receptor (c-Met) signaling pathways.
Suppression of receptor tyrosine kinase-mediated cell proliferation and survival.
Induction of apoptosis in tumor cells harboring ALK or ROS1 gene rearrangements.
Interruption of downstream signaling pathways such as PI3K/AKT and RAS/MAPK.
Anti-proliferative effects on ALK-positive non-small cell lung cancer cells.
Anti-tumor activity in ALK-positive anaplastic large cell lymphoma and inflammatory myofibroblastic tumors.
Reduction of tumor progression by inhibiting cellular growth signals.
Multikinase inhibitory profile targeting multiple oncogenic receptors.
Modulation of tumor microenvironment through kinase blockade.
Prevention of cancer cell migration and metastasis signaling.
Facilitation of programmed cell death in malignant cells.
Selectivity minimizes off-target toxicity, improving tolerability.
Potential interaction with cellular DNA repair and stress response mechanisms.

Therapeutic Or Clinical Uses

Treatment of metastatic non-small cell lung cancer (NSCLC) expressing ALK gene rearrangements in adults.
Management of NSCLC caused by ROS1 gene defects in adult patients.
Therapy for ALK-positive anaplastic large cell lymphoma (ALCL) in children aged 1 year and older and young adults, particularly for relapsed or refractory disease.
Treatment of ALK-positive inflammatory myofibroblastic tumors (IMT) in adults and children aged 1 year and older, specifically for unresectable, recurrent, or treatment-resistant cases.
Use in patients with tumors harboring ALK or ROS1 mutations where surgical options are limited.
An option for patients who have failed or are intolerant to conventional chemotherapy.
Part of targeted therapy regimens aiming to improve progression-free survival in ALK- or ROS1-positive cancers.
Indicated in pediatric oncology for specific ALK-driven malignancies requiring systemic treatment.
Utilized in clinical settings requiring oral kinase inhibitor therapy with manageable side effect profiles.
Employed in personalized medicine approaches for tumor genotyping-driven treatment selection.
Adjunctive treatment to reduce tumor burden and improve quality of life in affected patients.
Effective in delaying tumor progression in patients with ALK or ROS1 fusion gene-driven cancers.
Considered for use in patients with advanced disease where other targeted therapies are contraindicated.
Treats malignancies with limited treatment options due to molecular target specificity.
Potential off-label consideration in investigational protocols for other RTK-driven malignancies.

Side Or Adverse Effects

Hepatotoxicity including life-threatening liver injury manifested by jaundice, elevated liver enzymes, dark urine, and right upper quadrant pain.
Serious pulmonary adverse events such as pneumonitis and interstitial lung disease leading to respiratory distress.
Cardiac arrhythmias including very slow, very fast, or abnormal heart rhythms potentially causing dizziness or syncope.
Visual disturbances ranging from mild blurred vision to severe visual loss, double vision, light sensitivity, flashes, and increased floaters.
Gastrointestinal effects: severe nausea, vomiting, diarrhea, constipation, and mouth ulcers.
Peripheral neuropathy presenting as numbness, tingling, or nerve pain in hands or feet.
Edema or swelling of extremities, face, or periorbital area.
Headache and dizziness, possibly affecting patient safety with activities requiring alertness.
Fatigue and muscle weakness impairing daily function and mobility.
Increased susceptibility to infections due to immunosuppression.
Cold-like symptoms including nasal congestion, sneezing, and sore throat.
Bleeding tendencies or easy bruising indicating hematologic effects.
Elevations in liver function tests without clinical symptoms.
Potential QT prolongation requiring monitoring in patients with cardiac risk factors.
Photosensitivity leading to increased risk of sunburn and skin damage.

Precautions

Perform baseline and regular liver function tests due to risk of hepatotoxicity.
Monitor for respiratory symptoms indicative of interstitial lung disease or pneumonitis.
Assess cardiac function and electrocardiogram for QT prolongation or arrhythmias before and during therapy.
Advise patients to report any vision changes immediately for ophthalmologic evaluation.
Use caution in patients with pre-existing liver or kidney impairment; dose adjustments may be necessary.
Avoid concomitant use of strong CYP3A inhibitors or inducers to prevent altered drug levels.
Educate patients on avoiding grapefruit and grapefruit-containing products due to interaction risks.
Counsel patients on the importance of adherence to dosing schedule and not to double doses if a dose is missed.
Use effective contraception for both men and women during treatment and for an extended period after completion.
Monitor blood counts regularly as treatment may impact hematologic parameters.
Supervise administration in pediatric patients, especially with oral pellets, to ensure proper ingestion.
Advise avoidance of prolonged sun exposure and use of sun protection measures.
Be vigilant for symptoms of allergic reactions or severe gastrointestinal side effects requiring prompt intervention.
Pregnancy must be ruled out prior to initiation; avoid breastfeeding during and after treatment as recommended.
Use caution in elderly patients due to limited data on safety and efficacy.

Warnings

Can cause severe and potentially fatal liver injury; monitor liver enzymes frequently and discontinue if significant abnormalities develop.
Risk of life-threatening lung problems such as pneumonitis; discontinue therapy if severe pulmonary symptoms occur.
May induce serious cardiac adverse effects including arrhythmias; careful monitoring of ECG and electrolytes is necessary.
Potential for severe visual impairment including blindness; immediate evaluation required upon vision loss or disturbances.
Severe gastrointestinal toxicity including nausea, vomiting, diarrhea, and mouth ulcers particularly in children and young adults.
May cause fetal harm; contraindicated in pregnancy with mandatory effective contraception for both sexes.
Photosensitivity reaction risk necessitates protective measures from sunlight exposure.
Impaired fertility has been reported; implications for reproductive planning must be discussed.
Avoid use if known hypersensitivity to crizotinib or formulation components.
Use caution with concomitant medications that prolong QT interval or interact via CYP3A metabolic pathway.
Increased risk of bleeding and bruising; monitor patients with bleeding diatheses closely.
Not established as safe or effective in children under 1 year of age or in older adults with ALCL.
Potential serious hypersensitivity or allergic reactions requiring immediate medical attention.
Patients must avoid grapefruit products due to risk of toxic plasma levels.
Risk of severe dehydration secondary to gastrointestinal symptoms necessitates hydration monitoring.

Contraindication

Known hypersensitivity to crizotinib or any component of the formulation.
Pregnancy due to teratogenic and fetal toxicity potential.
Concurrent use with strong CYP3A inhibitors or inducers that cannot be discontinued.
Patients with significant or uncontrolled cardiac arrhythmias.
Patients with severe hepatic impairment not evaluated or recommended for therapy without dose adjustment.
Use contraindicated in individuals unable to take medication orally or swallow capsules without the pellet formulation option.
Known or suspected retinal disorders that may worsen with treatment.
Severe gastrointestinal disorders that may interfere with drug absorption or increase risk of adverse effects.
Co-administration with drugs that prolong QT interval without possibility of monitoring.
Patients with active infections that could be exacerbated by immunosuppression.
History of allergic reactions specifically to components such as gelatin in capsules or pellet excipients.
Children under one year of age with ALCL or IMT due to lack of safety and efficacy data.
Patients with significant electrolyte imbalances that cannot be corrected prior to treatment initiation.
Individuals with a family history of congenital long QT syndrome without appropriate cardiac evaluation.
Concurrent use with grapefruit or grapefruit-derived products.

Drug Interactions

Strong CYP3A inhibitors (e.g., clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, grapefruit) increase crizotinib plasma levels and risk toxicity; concomitant use should be avoided.
Strong CYP3A inducers (e.g., phenobarbital, phenytoin, rifampicin, St. John's Wort, glucocorticoids) reduce crizotinib efficacy via decreased plasma concentrations; concomitant use should be avoided.
Drugs metabolized by CYP3A where minimal concentration changes may cause serious adverse reactions should be co-administered cautiously with crizotinib.
Concomitant use with heart medications that prolong QT interval may enhance risk of cardiac arrhythmias.
Potential interaction with blood pressure medications requiring close monitoring of blood pressure and heart rate.
Interactions with medications used to treat infections (antibiotics, antivirals) may require dosage adjustments due to metabolic overlap.
Possible reduced effectiveness of hormonal contraceptives necessitates use of additional reliable contraception methods.
Combination with drugs causing electrolyte abnormalities (e.g., diuretics) may increase cardiac event risks.
Concomitant use with psychotropic medications may require monitoring for enhanced CNS adverse effects.
Potential additive immunosuppressive effects when used with other chemotherapeutic or immunomodulatory agents.
Potentially altered crizotinib clearance when used with glucocorticoids or other inducers of hepatic enzymes.
Avoidance of grapefruit and related products due to CYP3A4 inhibition.
Interactions may impact therapeutic levels requiring dose adjustments and close clinical monitoring.
Not all drug interactions are known; comprehensive medication review is essential before initiation.
Monitoring for heightened toxicity or therapeutic failure is critical during concomitant administration with relevant drugs.

Preparations Of The Drug

Xalkori Capsules: 200 mg and 250 mg strengths. Capsules contain crizotinib as the active ingredient, with inactive constituents including colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and gelatin capsule shells with colorants such as titanium dioxide and iron oxides.
Pink opaque capsule shell includes gelatin, titanium dioxide, and red iron oxide; white opaque capsules include gelatin and titanium dioxide; printing ink includes shellac, propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide.
Xalkori Oral Pellets: 20 mg, 50 mg, and 150 mg doses designed for pediatric use and patients with swallowing difficulties.
The uncoated pellets consist of poloxamer and stearyl alcohol; the film-coating contains hypromellose, glyceryl monostearate, medium-chain triglycerides, polyethylene glycol/macrogol, sucrose, and talc.
Oral pellets are administered under adult supervision, ensuring proper dosing and ingestion, with specific instructions regarding opening and delivering pellets directly or via a spoon followed by water.
Storage conditions require room temperature between 20° to 25°C (68° to 77°F), with allowed excursions from 15° to 30°C (59° to 86°F).
Packaging is designed to protect pellets and capsules from moisture and light to maintain stability and potency.
Both formulations have been formulated to optimize bioavailability and improve patient compliance across age groups.
Pellet formulation particularly addresses pediatric administration challenges where capsules are not appropriate.
Inactive ingredients are selected to ensure stability, palatability, and appropriate release profiles.
Manufactured by Pfizer, ensuring adherence to stringent regulatory standards for oncology therapeutics.
Detailed prescribing information and medication guides are provided with each preparation to facilitate safe administration.
Available through prescription with specific dosing and administration instructions tailored to patient condition and tumor genotype.
Packaging includes clear labeling for capsule strength and pellet dosage units to avoid dosing errors.
Preparation and handling recommendations include disposal of empty pellet shells and precautions for caregivers handling contaminated materials.