Lorlatinib

Lorlatinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

The FDA approved Lorlatinib for treating Metastatic Non-Small Cell Lung Cancer (NSCLC).

Lorlatinib is rapidly absorbed with 81% bioavailability, crossing the blood-brain barrier. It is extensively metabolized by enzymes such as CYP3A4; it undergoes excretion via urine (48%) and faeces (41%), with a 24-hour elimination half-life.

The most common side effects of Lorlatinib include oedema (swelling in arms, legs, hands, and feet), peripheral neuropathy (numbness and tingling feeling in joints, arms, and legs), and cognitive disorders (confusion, forgetfulness, and lack of concentration or attention).

Lorlatinib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Lorlatinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

Kinase inhibitor lorlatinib exhibits in vitro activity against TYK1, FER, FPS, TRKA, FAK, FAK2, ACK,TRKB, TRKC, and ALK and ROS1. Against various mutant forms of the ALK enzyme, including some mutations found in tumours during the disease while on crizotinib and other ALK inhibitors, erlotinib showed efficacy in vitro.

Lorlatinib was administered subcutaneously to mice that had tumours with EML4 fusions and either ALK variant 1 or ALK mutations (including the G1202R and I1171T mutations found in tumours during disease progression on ALK inhibitors). This treatment produced antitumor activity. In mice with intracranial tumour cell lines driven by EML4-ALK, lorlatinib also showed anti-tumour activity and extended survival. In in vivo models, lorlatinib's overall antitumor activity was dose-dependent and associated with inhibition of ALK phosphorylation.

The peak plasma concentration of Lorlatinib is 577 ng/mL.

The peak plasma time for a single 100-mg dose of lorlatinib is 1.2 hours, and at steady-state with a daily 100 mg dose, it occurs at 2 hours.

The lorlatinib Area Under the Curve (AUC) is 5650 ng·hr/mL.

Lorlatinib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without food.

In non-small cell lung cancer (NSCLC), specifically ALK-positive cancers with anaplastic lymphoma kinase (ALK) or c-ros Oncogene 1(ROS1) gene mutations that have spread to the brain, Lorlatinib effectively shrinks tumours and limits the spread of cancer. Lorlatinib, crossing the blood-brain barrier, inhibits tyrosine kinase enzymes, triggering cancer cell death and preventing disease progression. This medication is instrumental in reducing recurrence risks and ensuring long-term disease control for patients with altered ALK genes.

Lorlatinib is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK) and whose disease has progressed on one of the following regimens:

Orally: Patients take Lorlatinib orally, using tablets swallowed with water once daily. The tablets should be ingested whole on an empty stomach, with or without meals, following the prescribed dosage and timing to ensure effectiveness in treating conditions like non-small cell lung cancer. Patients should refrain from crushing, chewing, or breaking the tablets unless instructed by their healthcare provider. Adherence to these instructions is crucial for the medication to work optimally in managing the specified conditions, emphasizing the importance of following the healthcare professional's guidance for proper administration.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Lorlatinib is available as an oral tablet.

100 mg PO per day, either with or without meals

Continue until the disease worsens or the toxicity becomes intolerable.

Depending on each person's safety or tolerability, a dose reduction, dose interruption, or dose discontinuation may be necessary. If the patient cannot take 50 mg once daily, stop the medication permanently.

While using Lorlatinib, refrain from consuming grapefruit or its juice to prevent potential drug metabolism issues. There are no specific dietary restrictions; maintain regular meals and emphasize adequate hydration. Quit smoking and alcohol consumption. Include green leafy vegetables, sweet potatoes, broccoli, tomatoes, carrots, mangoes, citrus fruits, berries, and cocoa. Consume lean proteins such as fish, meat, and poultry. Prioritize hydration by drinking plenty of water, herbal tea, and vegetable and fruit juices. Avoid processed and refined foods.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Lorlatinib can be categorized as:

Common Adverse Effects: Edema, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhoea.

Less Common Adverse Effects: Liver enzyme elevations, muscle pain, and peripheral neuropathy.

Rare Adverse Effects: Pneumonia, myocardial infarction, acute pulmonary oedema, embolism, peripheral artery occlusion, and respiratory distress.

The clinically relevant drug interactions of Lorlatinib are briefly summarized here.

Reduced plasma concentrations when CYP3A inducers are moderate. Strong CYP3A inhibitors (such as itraconazole, boceprevir, ritonavir, cobicistat, and itraconazole) have been associated with increased plasma concentrations. Decreased levels of CYP3A substrates with limited therapeutic indexes (e.g., ergotamine, fentanyl, ciclosporin, pimozide, quinidine, sirolimus) and P-glycoprotein substrates (e.g., dabigatran, digoxin).

Elevated AST/ALT, when using potent CYP3A inducers concurrently, such as phenytoin, carbamazepine, mitotane, rifampicin, or enzalutamide, can cause severe hepatotoxicity.

Avoid using St. John's wort and reduce plasma concentrations simultaneously. Raised plasma concentrations when using products containing grapefruit.

The common side effects of Lorlatinib include:

Edema (fluid retention)

Peripheral neuropathy

Cognitive effects

Fatigue

Respiratory issues

Increased cholesterol levels

Weight gain

Muscle pain

Increased blood pressure

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Pregnant women who take it may experience embryo-fetal harm due to the mechanism of action and results from animal studies.

There is no information currently available on usage in expectant mothers.

Inform expectant mothers about the possible risk to the fetus.

Before starting treatment, find out if any females can become pregnant.

During organogenesis, lorlatinib was given orally to pregnant rats and rabbits via gavage. This caused malformations, increased post-implantation loss, and abortion at maternal exposures that were on par with or lower than the human exposure at 100 mg qDay.

Use effective non-hormonal contraception during treatment and for a minimum of six months following the last dose if you are a female patient of reproductive potential. This is because lorlatinib can render hormonal contraceptives ineffective.

Males: Male partners who are capable of having children should be advised to use effective contraception during treatment and for at least three months following the last dose in light of the genotoxicity findings.

Male fertility may be temporarily hampered, according to research on animals.

No information is available about the presence of erlotinib or its metabolites in human or animal milk, their effects on nursing infants, or how much milk is produced.

Advise women not to breastfeed during treatment and for seven days following the last dose due to its possibility of severe adverse reactions in breastfed infants.

As per the FDA, the safety and efficacy of Lorlatinib have not been specifically studied in pediatric patients.

Moderate to mild (CrCl 30-89 mL/min): No dosage modification is required.

Severe (CrCl 15 to <30 mL/min): Decrease dose to 75 mg PO qDay.

End-stage renal disease (ERD) requiring hemodialysis: not investigated.

Mild (any AST and total bilirubin [TB] <1.5x ULN): No dosage modification is required.

Severe or moderate (TB ≥1.5x ULN with any AST): The pharmacokinetics are unclear.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Lorlatinib.

Overconsumption of Lorlatinib could lead to CNS effects (seizures, hallucinations), cardiovascular issues, gastrointestinal distress, respiratory complications, and generalized weakness.

In the event of a Lorlatinib overdose, promptly discontinue the medication and initiate supportive care. Consider immediate gastric lavage or induced vomiting for toxin removal. Monitor vital signs and neurological and cardiovascular functions closely and administer symptomatic treatment for observed complications. Maintain hydration and apply appropriate medical interventions for managing symptoms. Severe cases may necessitate hospitalization for comprehensive monitoring and intervention.

Based on one clinical data, exposure-response relationships were found at steady-state exposures reached at the recommended dosage for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction. The likelihood of adverse reactions occurring increased with increased erlotinib exposure.

In 295 patients who took Lorlatinib at the prescribed dosage of 100 mg once daily and had an ECG measurement during the trial, the maximum mean difference from baseline for PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms).. Of the 284 patients with a PR interval of less than 200 ms at baseline, 14% experienced a prolonged PR interval of more than 200 ms after beginning Lorlatinib. There was a concentration-dependent extension of the PR interval. One per cent of patients experienced an atrioventricular block.

In the activity-estimating part of Study, 275 patients received Lorlatinib at the recommended dosage; no significant mean increases from baseline in the QTcF interval (i.e., >20 ms) were found.