What Are the Uses of Lorlatinib?

What Is Lorlatinib?

Lorlatinib is a type of targeted cancer drug. It is a therapy for non-small cell lung cancer, or ALK-positive non-small cell lung cancer, which has a mutation in the anaplastic lymphoma kinase (ALK) gene. If a patient's non-small cell lung cancer has advanced after receiving prior treatment with an ALK-targeted medication, they may be prescribed Lorlatinib. The United States Food and Drug Administration (US FDA) approved Lorlatinib on March 3, 2021.

Drug Group:

Lorlatinib belongs to a class of drugs known as kinase inhibitors.

Indications:

Lorlatinib is a medication used to treat non-small cell lung cancer (NSCLC), a particular kind of lung cancer. It was developed for patients whose cancer has progressed and whose tumors exhibit anaplastic lymphoma kinase (ALK)-positive, a specific genetic abnormality.

For patients whose cancer has worsened despite receiving treatment with Crizotinib and one or more additional ALK inhibitors, Alectinib or Ceritinib is the initial ALK inhibitor treatment.

Contraindications:

Patients taking strong CYP3A (Cytochrome P450, family 3, subfamily A) inducers should avoid taking Lorlatinib since it may cause significant liver damage.

Dosage Forms and Available Strengths: Lorlatinib is available in tablet form.

• 25 mg (Milligrams):

A small, round, tan pill. It is a film-coated, immediate-release tablet.

• 100 mg:

An oval-shaped, somewhat bigger pill with a lavender tint. It is a film-coated, immediate-release tablet as well.

For Patients

What Is Anaplastic Lymphoma Kinase-Positive Metastatic Non-small Cell Lung Cancer?

Anaplastic Lymphoma Kinase Positive, or ALK+, is a unique genetic alteration that is present in people who are ALK-positive. Just under one in every 25 patients with non-small-cell lung cancer (NSCLC) experiences this alteration. Patients who are younger and have never smoked, typically 55 years of age or younger, are more likely to have an ALK-positive diagnosis.

What Are the Clinical Uses of Lorlatinib?

Adults with a certain type of lung cancer (known as non-small cell lung cancer, or NSCLC) that has metastasized to other areas of the body can take the medication Lorlatinib. Lorlatinib is a member of the kinase inhibitor drug class. It works by preventing the action of a peculiar protein that promotes the growth and division of cancer cells. This interferes with or eliminates the cancer's capacity to spread.

How Should Lorlatinib Be Used?

Lorlatinib is available as an oral tablet. It is often taken once a day, with or without food. Lorlatinib needs to be taken daily at approximately the same time. It is important to carefully follow the instructions on the prescription label and ask the pharmacist or doctor to clarify any parts one is unsure about.

Take Lorlatinib precisely as prescribed. It is not recommended to take it more, less, or more frequently than the doctor has advised. Do not take another dose of the drug if vomiting happens after taking it. It is recommended to stick to the usual dosing regimen. It is recommended that the pills be consumed whole without splitting, chewing, or crushing them. It is not advisable to ingest tablets that are already cracked or broken.

Depending on whether any side effects are noticed, the doctor may lower the dosage or halt the treatment either temporarily or permanently. Throughout the Lorlatinib treatment, the patient's feelings should be communicated to the doctor.

What Are the Side Effects of Lorlatinib?

Lorlatinib may cause adverse reactions. Report any of the following to the doctor:

• Chest pain or difficulty breathing.

• Fever and cough.

• Gaining weight.

• Vision changes.

• Rashes or itching.

• Arm, leg, hand, or foot swelling.

• Back, muscle, or joint pain.

• Vomiting or nausea.

• Mood swings or delusions.

• Dizziness or convulsions.

• Issues with sleep or strange nightmares.

• Severe weakness.

• Disorientation.

• Fruity breath odor.

• Excessive appetite, thirst, or urination.

• Headache or fatigue.

• Difficulty speaking or thinking.

• Constipation or diarrhea.

• Numbness or tingling in limbs or joints.

What Are the Things to Inform the Doctor Before Taking Lorlatinib?

• Patients should let their doctor and pharmacist know if they have any allergies to Lorlatinib, other drugs, or any substances in the tablets before starting to take Lorlatinib. They can get an ingredient list from their pharmacist.

• Inform the physician about any medications they are taking, as Lorlatinib may interfere with pharmaceuticals such as Carbamazepine, Efavirenz, Nevirapine, Phenobarbital, Phenytoin, Pioglitazone, Rifabutin, or Rifampin.

• All other medications, both over-the-counter and prescription, vitamins, supplements, and herbal products that a person is taking or intends to take should be disclosed to their physician.

• Any medical disorders one may have, such as high blood pressure, irregular heartbeat, diabetes, depression, seizures, high cholesterol, kidney disease, or lung illness, should be disclosed to the doctor.

• The person should talk to their doctor if they are planning to father a child, are pregnant, or intend to become pregnant. During therapy, use non-hormonal birth control methods, as Lorlatinib may interfere with hormonal contraceptives.

• During therapy and for a while after the last dosage, both men and women should take birth control.

• If a person becomes pregnant while using Lorlatinib, they should call their doctor right away.

• Breastfeeding should be discontinued while taking Lorlatinib and for a short while after the last dosage.

• Talk to the doctor about the possibility of a brief drop in male fertility brought on by Lorlatinib.

Dietary Considerations:

When taking Lorlatinib, talk to the physician about consuming grapefruits and grapefruit juice.

Missed Dose:

If a dose is missed, it should be taken as missing unless the following dose is scheduled to be taken in four hours. It is not recommended to take two doses at once to catch up on missed doses.

Storage:

To preserve this medication's efficacy and avoid accidents, storage must be done correctly. To prevent exposure to air and moisture, keep it in the original container and make sure that it is well closed. Keep the container in a safe place, out of children's reach. Lorlatinib should be kept at room temperature; do not store it in bathrooms or other locations that absorb a lot of heat or moisture.

Disposal:

It is crucial to dispose of medications safely to prevent accidental consumption by children, pets, and other people. Because many medicine containers are not child-resistant, always keep medication out of children's sight and reach. Put safety caps on and keep medicine in a location that kids cannot reach.

Overdose:

Always call the poison control hotline if someone takes too much of this medication. Make an immediate call to emergency services if they pass out, experience a seizure, have difficulty breathing, or are unable to awaken.

For Doctors

Pharmacodynamics

Relations Between Exposure and Response:

Data from Study B7461001 demonstrated a correlation between the amount of Lorlatinib in patients' bodies and the risk of developing Grade 3 or 4 hypercholesterolemia (high cholesterol) and other serious adverse reactions when patients were exposed to Lorlatinib at the recommended dosage. The likelihood of developing these side effects increases with Lorlatinib exposure.

The Heart’s Electrophysiology:

The maximum mean change in the PR interval (a measure of heart rhythm) from the initial ECG reading for 295 participants in Study B7461001 who took Lorlatinib at the indicated dosage was 16.4 milliseconds. After initiating Lorlatinib, the PR interval lengthened to more than 200 milliseconds in about 14 percent of patients who had a normal PR interval at baseline. Higher Lorlatinib concentrations in the body were associated with a greater frequency of this PR interval prolongation. One cardiac rhythm issue, called atrioventricular block, happens in one percent of patients. No significant increases in the QTcF interval, another measure of cardiac rhythm, were observed in another section of the trial encompassing 275 individuals when compared to their initial data.

Mechanism of Action:

Lorlatinib inhibits the activity of specific kinases in the body. It has been discovered to be effective against multiple enzymes, including TYK1 (tyrosine kinase 1), FER (feline sarcoma oncogene protein), TRK (tropomyosin receptor kinase), and ALK (anaplastic lymphoma kinase), in addition to ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase). Lorlatinib demonstrated efficacy in vitro against several ALK enzyme forms, including those that have developed resistance to Crizotinib and other ALK inhibitors.

Pharmacokinetics

Absorption:

When taken orally, Lorlatinib achieves its maximum blood concentration (Cmax) in approximately 1.2 hours for single doses and two hours for daily doses. Around 81 percent of the dose of Lorlatinib that is absorbed by the body enters the bloodstream.

Impact of Food:

The body's ability to absorb Lorlatinib is not considerably altered by eating a high-fat, high-calorie meal with it.

Distribution:

Lorlatinib is not firmly attached to proteins and is primarily retained in the blood. With an average volume of roughly 305 liters, it is distributed throughout the body very widely.

Elimination:

Lorlatinib remains in the body for approximately 24 hours following a single dosage, and as time passes, its clearance (the rate at which it exits the body) increases, suggesting a process known as autoinduction.

Metabolism:

The primary enzymes in the body that break down Lorlatinib are CYP3A4 (cytochrome P450 3A4) and UGT1A4 (UDP-glucuronosyltransferase 1A4). A minor portion of it is broken down by other enzymes such as CYP2C8 (cytochrome P450 2C8), CYP2C19 (cytochrome P450 2C19), CYP3A5 (cytochrome P450 3A5), and UGT1A3 (UDP-glucuronosyltransferase 1A3).

Excretion:

Following a dose of Lorlatinib, approximately half is removed in urine, leaving very little unaffected, and around 41 percent is eliminated in feces, leaving very little unaltered.

What Is the Prescribed Dosage and Method of Administration For Lorlatinib?

Recommended Dosage:

• Until the disease progresses or the toxicity is intolerable, 100 mg of Lorlatinib taken orally once daily, with or without meals, is the recommended dosage.

• It is best to consume tablets whole. It is not recommended to chew, crush, or split tablets. Tablets that are cracked, fractured, or in any other way not intact should not be consumed.

• Lorlatinib needs to be taken daily at the same time.

• If vomiting happens after taking Lorlatinib, the patient should take the next prescribed dose instead of taking another one.

Adverse Reaction Dosage Modifications:

The following dosage decreases are advised:

• First Dosage Reduction:

Once-daily oral Lorlatinib 75 mg.

• Second Dosage Reduction:

Take 50 mg of Lorlatinib orally once a day.

For anyone who cannot take 50 mg once a day orally, Lorlatinib should be permanently stopped.

Concurrent Use of Strong or Moderate CYP3A Inducers:

People who take strong CYP3A inducers should not take Lorlatinib. Before starting Lorlatinib, powerful CYP3A inducers should be stopped for three plasma half-lives of the inducer. It is not recommended to take Lorlatinib and mild CYP3A inducers together.

Dosage Adjustment for Severe CYP3A Inhibitors:

It is not advisable to take Lorlatinib with powerful CYP3A inhibitors at the same time. If it is not possible to avoid concurrent usage with a potent CYP3A inhibitor, Lorlatinib’s beginning dosage should be lowered from 100 mg to 75 mg once a day.

The Lorlatinib dose should be decreased to 50 mg orally once daily in patients who have had their dose reduced to 75 mg orally once daily as a result of adverse reactions and who have started taking a potent CYP3A inhibitor.

The Lorlatinib dose should be increased to the dose that was used before starting the strong inhibitor after three plasma half-lives of the strong CYP3A inhibitor if concurrent usage of the strong inhibitor is discontinued.

Clinical Studies:

Patients with metastatic non-small cell lung cancer (NSCLC) who were positive for ALK and had previously taken one or more ALK kinase inhibitors showed improvement with Lorlatinib. Patients with brain metastases, steady or declining steroid use, quantifiable target lesions, satisfactory performance status, and confirmed ALK rearrangement were included in the study. This group's overall response rate (ORR) was 48 percent, and responses took an average of 12.5 months to complete. The intracranial response rate was 60 percent among brain metastasis patients, and the response lasted for 19.5 months. Promising response rates with Lorlatinib were found in further analysis across a range of previous treatment regimens: 39 percent ORR in patients treated with Crizotinib plus at least one other ALK inhibitor, 31 percent ORR in patients treated with Alectinib alone, and 46 percent ORR in patients treated with Ceritinib alone.

Drug Interactions:

Impact of other drugs on Lorlatinib:

Impact of CYP3A Inducers:

A potent CYP3A inducer combined with Lorlatinib lowers the quantity of Lorlatinib in the blood. Lorlatinib may become less effective as a result. In several cases, taking Lorlatinib together with Rifampin, a potent CYP3A inducer, resulted in serious liver issues. Strong CYP3A inducers should not be administered with Lorlatinib due to this risk. Strong CYP3A inducers should be discontinued for a specific amount of time prior to beginning Lorlatinib. Steer clear of Lorlatinib when taking mild CYP3A inducers. Physicians should keep a close eye on specific liver enzymes if they cannot be prevented.

Strong CYP3A Inhibitors' Effects:

The blood level of Lorlatinib rises when taken with a potent CYP3A inhibitor. More severe adverse consequences may result from this. Taking Lorlatinib together with a potent CYP3A inhibitor is best avoided. The doctor may lower the Lorlatinib dosage if it is unavoidable.

Lorlatinib’s Impact on Other Drugs:

Effect on Substrates of CYP3A:

When CYP3A enzyme-dependent medications are taken with Lorlatinib, the concentration of these medications in the blood is reduced. This may lessen such medications' efficacy. It is advised to stay away from taking Lorlatinib along with medications that are substrates of CYP3A. In accordance with the directions on the medication, the doctor might have to increase the CYP3A substrate's dosage if it cannot be prevented.

Warnings and Precautions

• Dangers of Severe Liver Issues Associated with Potent CYP3A Inducers:

When Rifampin, a potent CYP3A inducer, was combined with Lorlatinib in healthy individuals, significant liver issues developed in 10 out of 12 cases. High concentrations of specific liver enzymes were among them. Usually occurring within three days, these liver problems return to normalcy after approximately 15 days of treatment. Lorlatinib should not be used with potent CYP3A inducers due to this danger. Stop taking strong CYP3A inducers for a predetermined amount of time before starting Lorlatinib. Additionally, try to avoid using Lorlatinib together with mild CYP3A inducers. For the first week of Lorlatinib medication, clinicians should closely monitor certain liver enzymes if they cannot be avoided. Depending on which is more critical for the patient, stop either Lorlatinib or the inducer if liver problems continue.

• Impact on the Central Nervous System:

Lorlatinib can have a variety of negative effects on the brain and nerves, including mood swings, altered thinking, seizures, and hallucinations. In one study, more than half of the people using Lorlatinib reported having a side effect related to their brains. Generally, a month or so after beginning the medicine, these side effects begin. Should these adverse reactions materialize, the physician may decide to temporarily or permanently discontinue Lorlatinib or lower the dosage.

• Elevated Triglycerides and Cholesterol:

Lorlatinib may increase blood levels of triglycerides and cholesterol. Around 17 percent of the individuals in one research had elevated triglycerides or cholesterol. In such an event, the physician may decide to temporarily stop Lorlatinib, adjust the dosage, or recommend drugs to lower triglycerides and cholesterol.

• Issues with Heart Rhythm:

Certain patients who were taking Lorlatinib showed signs of irregular cardiac rhythm on their electrocardiograms (ECGs). ECG monitoring can assist in identifying these problems both before and during treatment. The doctor may temporarily cease Lorlatinib or change the dosage if cardiac rhythms develop.

• Lung Issues:

Rarely, Lorlatinib may result in life-threatening lung conditions such as pneumonitis or interstitial lung disease (ILD), which can impede breathing. In cases where a patient presents with symptoms such as coughing, shortness of breath, or fever, the doctor may decide to permanently halt Lorlatinib treatment.

• Risk to Pregnancy:

If used while pregnant, Lorlatinib may have negative effects on the fetus. Studies on animals revealed birth abnormalities and other problems. Effective birth control should be used by women who are fertile both during and after Lorlatinib treatment. Similarly, to avoid getting their partners pregnant while on Lorlatinib, men should use reliable birth control during treatment and for a while following.

Use in Specific Populations:

• Pregnancy:

If used while pregnant, Lorlatinib may be harmful to the fetus. According to studies conducted on animals, giving Lorlatinib to pregnant animals resulted in birth abnormalities and miscarriages. Although there is no information on Lorlatinib use in pregnancy, it is important to warn expectant mothers about the possible risks to their unborn children. Birth malformations and miscarriage rates in the general population are between two and four percent and 15 to 20 percent, respectively.

• Breastfeeding:

The presence of Lorlatinib or its byproducts in breast milk and the impact they have on newborns are unknown. Women taking Lorlatinib should refrain from breastfeeding for a week after quitting the medication due to the risk of severe responses in breastfed newborns.

• Males and Females of Reproductive Potential:

Pregnancy testing is required for women who are capable of becoming pregnant prior to beginning Lorlatinib. Because Lorlatinib may render hormonal contraceptives ineffective, women should take effective non-hormonal birth control during Lorlatinib treatment and for at least six months after stopping it. Effective contraception should be used by males who have female partners who are capable of having children, both during the Lorlatinib treatment and for a minimum of three months after it is stopped.

• Use in Pediatrics:

There is no proof of Lorlatinib’s safety or efficacy in kids.

• Geriatric Use:

The available data do not indicate any appreciable variations in safety or efficacy between patients 65 years of age or older and younger patients.

• Hepatic Impairment:

The dosage should not be adjusted for people with mild liver problems; the recommended dosage is unclear for those with moderate or severe liver problems.

• Renal Impairment:

Patients with mild or moderate renal impairment do not require a dose adjustment; however, patients with severe kidney impairment do not yet have a recommended dose.