lorlatinib

Actions and Spectrum:

Actions:

The primary action of lorlatinib is the inhibition of the activity of these tyrosine kinase receptors, which are often overactive or mutated in cancer cells, leading to uncontrolled cell growth and proliferation. By inhibiting the activity of these receptors, lorlatinib can help to slow or stop the growth of cancer cells, leading to tumor shrinkage and improved survival rates in patients with NSCLC.

lorlatinib has demonstrated effectiveness in the treatment of NSCLC with ALK or ROS1 rearrangements that have progressed despite previous treatment with other TKIs, such as crizotinib or alectinib. It has also shown some activity against NSCLC with mutations in other tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR).

Spectrum:

The spectrum of activity of lorlatinib is primarily limited to the treatment of NSCLC with specific genetic mutations, and it is not currently used for the treatment of other types of cancer or conditions. It is generally administered orally in tablet form, and the dose and schedule of administration will depend on the individual patient’s condition and response to treatment. As with all medications, lorlatinib can cause side effects, and patients receiving this drug should be closely monitored for any potential adverse effects.

 

 

DRUG INTERACTION

Contraindicated  

Serious Use Alternative  

Monitor Closely  

Minor  

Adverse drug reactions:  

Frequency defined:  

>10% 

Upper respiratory tract infection (12%)

Pyrexia (12%)

Speech effects (12%)

Vomiting (12%)

Pain in extremity (13%)

Back pain (13%)

Rash (14%)

Constipation (15%)

Vision disorder (15%)

Dizziness (16%)

Myalgia (17%)

Nausea (18%)

Cough (18%)

Headache (18%)

Hypomagnesemia (21%)

Hyperkalemia (21%)

Lymphopenia (22%)

Increased amylase (22%)

Diarrhea (22%)

Mood effects (23%)

Arthralgia (23%)

Thrombocytopenia (23%)

Increased alkaline phosphatase (24%)

Increased lipase (24%)

Weight gain (24%)

Fatigue (26%)

Dyspnea (27%)

Cognitive effects (27%)

Increased ALT (28%)

Hypoalbuminemia (33%)

Increased AST (37%)

Peripheral neuropathy (47%)

Anemia (52%)

Hyperglycemia (52%)

Edema (57%)

Hypertriglyceridemia (90%)

Hypercholesterolemia (96%) 

1-10%

Respiratory failure (1.4%)

Mental status changes (1.4%)

Pyrexia (2%)

Dyspnea (2.7%)

Pneumonia (3.4%)

Hallucinations (7%)

Sleep effects (10%)

<1%:

Vision disorder

Headache

Dizziness

Speech effects

Nausea

Diarrhea

Pain in extremity

Fatigue

Pyrexia

Rash

Back pain

Thrombocytopenia

Arthralgia

Myalgia

 

 

 

 

Contraindication/Caution:

Contraindications:

• Hypersensitivity: lorlatinib is contraindicated in patients who have a known hypersensitivity to the drug or any of its components.
• Pregnancy and breastfeeding: lorlatinib is contraindicated in pregnancy, as it can cause fetal harm. It is also not recommended for use in breastfeeding mothers.

Caution:

• Hepatic impairment: lorlatinib is metabolized by the liver, and patients with hepatic impairment may require dose adjustments or more frequent monitoring to prevent potential liver damage.
• Interstitial lung disease: lorlatinib can cause or worsen interstitial lung disease (ILD) in some patients. Patients with a history of ILD or those with pre-existing pulmonary symptoms should be closely monitored for any signs of ILD.
• Bradycardia: lorlatinib can cause bradycardia in some patients, particularly those with pre-existing cardiac conditions or those taking medications that can lower heart rate. Close monitoring of heart rate and blood pressure is recommended in patients receiving lorlatinib.
• Central nervous system effects: lorlatinib can cause central nervous system (CNS) effects, including cognitive impairment, mood changes, and dizziness. Patients should be advised to avoid driving or operating heavy machinery if they experience these side effects.
• Drug interactions: lorlatinib can interact with other medications, particularly those that are metabolized by the liver or that affect heart rate. Patients should inform their healthcare providers of all medications they are taking before starting treatment with lorlatinib.

Pregnancy  

Animal studies reveal data about mechanism of action, where in lenvatinib can cause harm to ingrowing fetus. 

Breastfeeding warnings:    

It is advised to discontinue lactation during and after the treatment up to 1 week later the last dose. Distribution of drug in breast milk is unknown, but due to potential adverse reactions, precautions should be taken. 

Pregnancy Categories: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus.  
• Category B: No evidence shown of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women      
• Category C: No adequate evidence for a result in humans must take care of potential risks in pregnant women. It is advised to use the drug with caution as the benefits outweigh the risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases of life threat for potential benefits      
• Category X: Drugs listed in this category outweigh risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. Apart from this medication, pregnant women can prefer better alternatives. 
• Category N: There is no data available for the drug under this category 

 

 

Pharmacology:

lorlatinib is a tyrosine kinase inhibitor (TKI) that targets several different tyrosine kinase receptors, including anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R). It is used for the treatment of certain types of non-small cell lung cancer (NSCLC) that have specific genetic mutations, such as ALK or ROS1 rearrangements. Pharmacodynamics:

The pharmacodynamics of lorlatinib involve its interaction with tyrosine kinase receptors, which are important signaling molecules that regulate cellular growth, survival, and differentiation. lorlatinib inhibits the activity of several tyrosine kinase receptors, including anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R).

Pharmacokinetics:

Absorption:

Peak plasma concentration is 577 ng/mL

Peak plasma is achieved in 1.2 hours (for a single 100-mg dose); 2 hours (for 100 mg per day at steady-state)

AUC is 5650 ng·hr/mL

Bioavailability is 81%

Distribution:

Volume of distribution achieved during (steady state) is 305 L

Protein bound is 66%

Metabolism:

The drug is metabolized primarily by CYP3A4 and UGT1A4; and some minor contributions are given by CYP2C8, CYP3A5, CYP2C19 and UGT1A3

Excretion/Excretion:

Half-life of (single 100-mg dose) is 24 hours

Oral clearance rate is 11 L/hr (for single100-mg dose); and 18 L/hr (at steady-state)

Excretion (of single 100-mg dose) in urine (is 48%); and in feces (is 41%)

 

 

Administration:

lorlatinib is an oral medication that is typically administered in the form of tablets, and it is usually taken once daily. The tablets should be taken at approximately the same time each day, with or without food, as directed by the prescribing physician.

Do not skip or alter doses without first consulting with the healthcare team. If a dose of lorlatinib is missed, the patient should take the missed dose as soon as possible, unless it is within 4 hours of the next scheduled dose. In this case, the missed dose should be skipped, and the patient should resume the regular dosing schedule.

lorlatinib should be stored at room temperature, in a dry place and away from direct sunlight. The tablets should be kept in their original container until they are ready to be used and should not be stored in a pillbox or any other type of container.

 

 

Patient information leaflet

Generic Name: lorlatinib

Pronounced: lor-LAT-i-nib

Why do we use lorlatinib?

lorlatinib is an anti-cancer agent that belongs to the tyrosinase class of inhibitors and treats the tumor by retarding or cessing the growth of cancerous cells. It treats metastatic lung cancer patients with the ALK gene (abnormal anaplastic lymphoma kinase). The side effects occurring after taking medicine include nausea, headache, dizziness, itchiness, runny or stuffy nose, fevers, cough, chills, throat tightness, or trouble breathing. If any of the side effects worsen, immediately contact your physician.

Tell your health care provider if you are allergic to lorlatinib or any other ingredients/excipients mentioned on the product label. Mention any other general allergies if you have any. There are no studies corresponding to the secretion of a drug in breastmilk, but one should outweigh the potential benefits against any potential risks. The drug interacts with tobacco and alcohol, so it is better to refrain from them during the medication.

If you miss a dose, take it no sooner you remember it, but do not take the missed one nearby to the next one. Avoid doubling the amount. The fertile males should use protection during a sexual activity during the treatment with doxorubicin. Pregnant females should not take this medication, and if, in the course, a female gets pregnant, she should consult the doctor. If you miss a dose, tell your healthcare professional to reschedule it. Store the medication in a cool and moisture-free place.