LORBRENA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LORBRENA (LORBRENA).
LORBRENA (lorlatinib) is a potent, selective, brain-penetrant inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinases. It inhibits ALK phosphorylation and downstream signaling pathways (STAT3, PI3K/AKT, MAPK/ERK), and shows activity against most known ALK resistance mutations.
| Metabolism | Primarily metabolized by CYP3A4 and UGT1A4; minor contributions from CYP2C8, CYP2C19, CYP3A5, and CYP2D6. |
| Excretion | Primarily fecal (95%), with unchanged drug accounting for approximately 7% of the dose. Renal excretion is minimal (<1%). |
| Half-life | Terminal elimination half-life is approximately 24 hours (range 20-30 hours), supporting once-daily dosing. |
| Protein binding | 99.8% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 305 L (3.9 L/kg for a 78 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 81% (range 60-100%). |
| Onset of Action | Time to peak concentration (Tmax) is approximately 2 hours after oral administration. Clinical response (tumor regression) typically observed within 6-8 weeks. |
| Duration of Action | Duration of clinical effect is continuous with daily dosing. Steady-state achieved in approximately 5 days. |
| Molecular Weight | 471.5 |
100 mg orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl >= 30 mL/min). For severe renal impairment (CrCl < 30 mL/min), reduce dose to 75 mg once daily. |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh A). For moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, reduce dose to 75 mg once daily. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended based on age; monitor renal function and potential increased risk of adverse events. |
| 1st trimester | No data on use in pregnant women; based on mechanism of action, may cause fetal harm. Avoid use during first trimester unless benefit outweighs risk. |
| 2nd trimester | No data; potential for fetal harm. Use only if clearly needed and benefit justifies potential risk. |
| 3rd trimester | No data; may cause fetal harm. Consider maternal benefit vs fetal risk. |
Clinical note
Comprehensive clinical and safety monograph for LORBRENA (LORBRENA).
| Placental transfer | Likely crosses placenta due to low molecular weight (471.5 Da) and high lipid solubility, but no human data. |
| Breastfeeding | No data on presence in human milk; due to high protein binding, transfer likely low but unknown. Consider developmental and health benefits of breastfeeding with mother's clinical need. |
■ FDA Black Box Warning
None
| Serious Effects |
None known based on drug labeling
| Precautions | Hepatotoxicity: Elevations of AST, ALT, and bilirubin; monitor liver function tests., Interstitial lung disease (ILD)/pneumonitis: Monitor for pulmonary symptoms; discontinue if ILD is suspected., Hyperlipidemia: Monitor serum cholesterol and triglycerides; manage with lipid-lowering agents., Central nervous system effects: Seizures, hallucinations, changes in cognitive function, mood disorders; monitor and manage., Hypertension: Monitor blood pressure; manage with antihypertensive therapy., AV block: PR interval prolongation; monitor ECG in patients with predisposing conditions., Fetal harm: Can cause fetal harm; advise effective contraception., Risk of hepatotoxicity with concomitant use of strong CYP3A inducers/ inhibitors. |
| Food/Dietary | Avoid grapefruit and grapefruit juice due to potential CYP3A4 inhibition increasing lorlatinib exposure. No other specific food restrictions; take with or without food. |
Loading safety data…
| Lactation Rating |
| L3 (Moderately Safe) |
| Teratogenic Risk | LORBRENA (lorlatinib) is an ALK inhibitor. Based on its mechanism of action and animal studies, it is expected to cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women. Animal studies demonstrated embryofetal toxicity including increased post-implantation loss, reduced fetal body weights, and external and visceral malformations at exposures below the clinical dose. Therefore, LORBRENA is contraindicated in pregnancy. If used during pregnancy or if patient becomes pregnant while taking this drug, apprise of potential hazard to fetus. |
| Fetal Monitoring | Monitor complete blood counts for anemia, neutropenia, and thrombocytopenia. Monitor hepatic function (ALT, AST, bilirubin) monthly and as clinically indicated. Monitor serum uric acid levels for hyperuricemia. Monitor for hyperlipidemia (fasting serum cholesterol and triglycerides). Monitor for hypertension. Monitor for peripheral neuropathy and neurotoxicity (including CNS effects). Monitor for pneumonitis. In pregnant women, perform fetal ultrasound to assess for growth abnormalities and oligohydramnios if drug must be used (though contraindicated). |
| Fertility Effects | Fertility studies have not been conducted with lorlatinib. However, based on animal studies, LORBRENA may impair female fertility. In female rats, decreased corpora lutea and increased post-implantation loss were observed at doses ≥ 10 mg/kg (approximately 4.5 times the clinical AUC at the recommended human dose). Effects on male fertility have not been evaluated in animals. |
| Clinical Pearls | LORBRENA (lorlatinib) is a third-generation ALK/ROS1 tyrosine kinase inhibitor with high CNS penetration. Monitor for hypertriglyceridemia, hypercholesterolemia, edema, peripheral neuropathy, and CNS effects (seizures, hallucinations, mood changes). Baseline and periodic lipid panel, ECG, and blood pressure monitoring are essential. Dose reduction may be needed for toxicities; avoid in severe hepatic impairment. P-glycoprotein and CYP3A4 substrate; caution with strong CYP3A4 inducers/inhibitors. |
| Patient Advice | Take LORBRENA exactly as prescribed, with or without food. Do not crush or chew tablets. · Report new or worsening symptoms: confusion, mood changes, hallucinations, seizures, difficulty breathing, severe fatigue, or swelling in legs/feet. · You will need regular blood tests to monitor cholesterol, triglycerides, and liver function. · Avoid grapefruit or grapefruit juice during treatment as it may increase drug levels. · Use effective contraception during treatment and for at least XXX days [per prescribing info] after last dose; do not breastfeed. · Notify your doctor of all medications you take, including over-the-counter and herbal supplements, to avoid interactions. |