Usage
Lorlatinib is prescribed for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on:
- crizotinib and at least one other ALK inhibitor for metastatic disease; or
- alectinib as the first ALK inhibitor therapy for metastatic disease; or
- ceritinib as the first ALK inhibitor therapy for metastatic disease.
Pharmacological Classification: Kinase inhibitor, specifically an ALK and ROS1 tyrosine kinase inhibitor.
Mechanism of Action: Lorlatinib works by selectively and reversibly inhibiting ALK and ROS1 tyrosine kinases, thereby blocking downstream signaling pathways crucial for tumor growth and survival. It is effective against multiple mutant forms of the ALK enzyme, including those resistant to other ALK inhibitors.
Alternate Names
International Nonproprietary Name (INN): lorlatinib
Brand Name: Lorbrena, Lorviqua
How It Works
Pharmacodynamics: Lorlatinib inhibits tumor growth by targeting ALK and ROS1 tyrosine kinases. This leads to a reduction in tumor size and improved survival in patients with ALK-positive NSCLC.
Pharmacokinetics:
- Absorption: Lorlatinib is well-absorbed orally, with or without food. A high-fat meal slightly increases absorption but decreases peak concentration.
- Metabolism: Primarily metabolized by CYP3A4, a liver enzyme. Lorlatinib is also a moderate inducer of CYP3A4 and a weak inducer of CYP2B6.
- Elimination: Primarily eliminated through hepatic metabolism and biliary excretion. The terminal half-life is approximately 24 hours.
Mode of Action: Lorlatinib binds to the ATP-binding site of ALK and ROS1 tyrosine kinases, preventing phosphorylation and activation of downstream signaling pathways involved in cell growth and proliferation.
Receptor Binding/Enzyme Inhibition: Lorlatinib selectively inhibits ALK and ROS1 tyrosine kinases. It also inhibits P-glycoprotein (P-gp), organic cation transporter 1 (OCT1), organic anion transporter 3 (OAT3), multidrug and toxin extrusion protein 1 (MATE1), and breast cancer resistance protein (BCRP), which may contribute to its ability to overcome resistance mechanisms.
Elimination Pathways: Hepatic metabolism (primarily via CYP3A4) followed by biliary excretion.
Dosage
Standard Dosage
Adults:
100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Swallow tablets whole; do not crush, chew, or split.
Children:
The safety and efficacy of lorlatinib in pediatric patients have not been established.
Special Cases:
- Elderly Patients: No dose adjustment is generally required, but monitor for increased risk of certain side effects like cognitive effects, dyspnea, fatigue, arthralgia, diarrhea, anemia, myalgia, vomiting, back pain, and rash.
- Patients with Renal Impairment: No dose adjustment is needed for mild or moderate renal impairment. For severe renal impairment (CLcr 15 to <30 mL/min), reduce dose to 75 mg orally once daily.
- Patients with Hepatic Dysfunction: No dose adjustment is recommended for mild hepatic impairment. The recommended dose has not been established for moderate or severe hepatic impairment.
- Patients with Comorbid Conditions: Use with caution in patients with cardiovascular disease, diabetes, or other conditions that may be exacerbated by lorlatinib’s side effects.
Clinical Use Cases
Lorlatinib is specifically indicated for ALK-positive metastatic NSCLC that has progressed on other ALK inhibitor therapies. It is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions (to 75 mg or 50 mg once daily) may be necessary to manage adverse effects. Permanently discontinue if 50 mg is not tolerated. For severe renal impairment, reduce the dose to 75 mg daily. If strong CYP3A4 inhibitors are unavoidable, reduce lorlatinib to 75 mg daily. After discontinuation of the inhibitor, resume the prior dose following a washout period of 3 to 5 half-lives of the inhibitor.
Side Effects
Common Side Effects
Edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood changes, cough, hypercholesterolemia, hypertriglyceridemia.
Rare but Serious Side Effects
Hepatotoxicity (especially with strong CYP3A inducers), interstitial lung disease/pneumonitis, atrioventricular block, severe hypertension, severe hyperglycemia, CNS effects (cognitive impairment, mood changes, sleep disturbances), pancreatitis.
Long-Term Effects
Potential long-term effects are not fully characterized but may include chronic peripheral neuropathy, cognitive impairment, and cardiovascular complications.
Adverse Drug Reactions (ADR)
Severe hepatotoxicity, ILD/pneumonitis, AV block, pancreatitis, severe hyperlipidemia requiring immediate intervention.
Contraindications
- Hypersensitivity to lorlatinib.
- Concomitant use of strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John’s wort).
Drug Interactions
- Strong CYP3A Inducers: Contraindicated due to decreased lorlatinib concentrations and risk of hepatotoxicity.
- Strong CYP3A Inhibitors: Avoid or reduce lorlatinib dose if unavoidable.
- Moderate CYP3A Inducers: Avoid if possible due to decreased lorlatinib concentrations.
- CYP3A Substrates: Lorlatinib may decrease the concentrations of other CYP3A substrates.
- P-gp Substrates: Lorlatinib may increase the concentrations of P-gp substrates.
- Fluconazole: Avoid concomitant use.
- Other Medications: Numerous other drug interactions exist; consult a comprehensive drug interaction resource before co-prescribing.
- Food: A high-fat meal can slightly increase lorlatinib absorption.
- Lifestyle factors: Not specifically identified, but general healthy lifestyle recommendations should be encouraged.
Pregnancy and Breastfeeding
Pregnancy Safety Category: Contraindicated in pregnancy. Can cause fetal harm. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose.
Breastfeeding: Contraindicated. Lorlatinib may be present in breast milk and can harm a nursing infant. Do not breastfeed during treatment and for 7 days after the last dose.
Drug Profile Summary
- Mechanism of Action: Selective, reversible inhibitor of ALK and ROS1 tyrosine kinases.
- Side Effects: Edema, peripheral neuropathy, weight gain, cognitive effects, hyperlipidemia, hepatotoxicity, ILD/pneumonitis, AV block.
- Contraindications: Hypersensitivity, concomitant strong CYP3A inducers.
- Drug Interactions: Numerous; consult a drug interaction resource. Avoid strong CYP3A inducers/inhibitors and monitor CYP3A substrates.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 100 mg orally once daily; adjust for adverse effects and renal impairment.
- Monitoring Parameters: Liver function tests, lipid panel, ECG, blood pressure, blood glucose, signs and symptoms of ILD/pneumonitis and peripheral neuropathy.
Popular Combinations
Lorlatinib is generally used as a single agent. Combining with other ALK inhibitors is not recommended due to potential overlapping toxicities and lack of demonstrated benefit.
Precautions
- General Precautions: Monitor for hepatotoxicity, ILD/pneumonitis, cardiovascular effects, hyperglycemia, and neurological effects. Baseline and periodic monitoring of liver function, lipid levels, ECG, blood pressure, and blood glucose are recommended.
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Not established for children; monitor elderly for increased risk of certain side effects.
- Menstruating Individuals: Non-hormonal contraception recommended due to potential for rendering hormonal contraceptives ineffective.
- Lifestyle Considerations: No specific restrictions, but encourage a healthy lifestyle.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Lorlatinib?
A: 100 mg orally once daily for adults. Adjust for side effects and renal impairment. Not established for pediatric patients.
Q2: What are the most common side effects of Lorlatinib?
A: Edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood changes, and cough.
Q3: What are the serious side effects of Lorlatinib?
A: Hepatotoxicity, ILD/pneumonitis, AV block, hyperlipidemia, hyperglycemia, and severe CNS effects.
Q4: Can Lorlatinib be used during pregnancy or breastfeeding?
A: No, lorlatinib is contraindicated in pregnancy and breastfeeding due to potential harm to the fetus or infant.
Q5: What are the major drug interactions with Lorlatinib?
A: Strong CYP3A inducers are contraindicated. Avoid concomitant use of strong CYP3A inhibitors, moderate CYP3A inducers, and certain CYP3A and P-gp substrates. Numerous other interactions exist; consult a drug interaction resource.
Q6: How should Lorlatinib be administered?
A: Orally, once daily, with or without food. Swallow tablets whole; do not crush, chew, or split.
Q7: How does Lorlatinib work?
A: Lorlatinib is a kinase inhibitor that selectively and reversibly targets ALK and ROS1 tyrosine kinases, blocking signaling pathways crucial for cancer cell growth and survival.
A: Primarily metabolized by CYP3A4 in the liver.
Q9: What should be monitored in patients taking Lorlatinib?
A: Liver function, lipid panel, ECG, blood pressure, blood glucose, signs and symptoms of ILD/pneumonitis and peripheral neuropathy.
Q10: What should patients be counseled on regarding contraception while taking Lorlatinib?
A: Females of reproductive potential should use effective non-hormonal contraception during treatment and for at least 6 months after the last dose. Males with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose. Hormonal contraceptives may be rendered ineffective by lorlatinib.
