Lorlatinib

Uses

Lorlatinib is an anaplastic lymphoma kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung cancer.

Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on a) the prior use of crizotinib and at least one other ALK inhibitor for metastatic disease, or b) the prior use of alectinib as the first ALK inhibitor therapy for metastatic disease, or c) the prior use of certinib as the first ALK inhibitor therapy for metastatic disease .

Lorlatinib is also used to associated treatment for these conditions: Progressive, metastatic Anaplastic lymphoma kinase-positive Metastatic Non-Small Cell Lung Cancer

How Lorlatinib works

Non-small cell lung cancer (NSCLC) accounts for up to 85% of lung cancer cases worldwide and remains a particularly difficult to treat condition . The gene rearrangement of anaplastic lymphoma kinase (ALK) is a genetic alteration that drives the development of NSCLC in a number of patients . Ordinarily, ALK is a natural endogenous tyrosine kinase receptor that plays an important role in the development of the brain and elicits activity on various specific neurons in the nervous system .

Subsequnetly, lorlatinib is a kinase inhibitor with in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK . Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors . Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well . The overall antitumor activity of lorlatinib in in-vivo models appears to be dose-dependent and correlated with the inhibition of ALK phosphorylation .

Although many ALK-positive metastatic NSCLC patients respond to initial tyrosine kinase therapies, such patients also often experience tumor progression . Various clinical trials performed with lorlatinib, however, have demonstrated its utility to effect tumor regression in ALK-positive metastatic NSCLC patients who experience tumor progression despite current use or having already used various first and second-generation tyrosine kinase inhibitors like crizotinib, alectinib, or ceritinib .

Toxicity

Although there is no formal data available on the use of lorlatinib in pregnant women, based on findings from animal studies and its mechanism of action, it is believed that lorlatinib can cause embryo-fetal harm when administered to a pregnant woman .

There are no data on the presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production . Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with lorlatinib and for 7 days after the final dose .

Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with lorlatinib and for at least 6 months after the final dose . Advise females of reproductive potential to use a non-hormonal method of contraception, because lorlatinib can render hormonal contraceptives ineffective .

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with lorlatinib and for at least 3 months after the final dose .

Based on findings from animal studies, use of lorlatinib may transiently impair male fertility .

The safety and effectiveness of lorlatinib in pediatric patients have not been established .

Of the 295 patients in Study B7461001 who received 100 mg lorlatinib orally once daily, 18% of patients were aged 65 years or older . Although data are limited, no clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients .

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST) . The recommended dose of lorlatinib has not been established for patients with moderate or severe hepatic impairment .

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault) . The recommended dose of lorlatinib has not been established for patients with severe renal impairment .

Carcinogenicity studies have not been conducted with lorlatinib . Lorlatinib was aneugenic in an in vitro assay in human lymphoblastoid TK6 cells and positive for micronuclei formation in vivo in the bone marrow of rats. Lorlatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay .

Dedicated fertility studies were not conducted with lorlatinib . Findings in male reproductive organs occurred in repeat-dose toxicity studies and included lower testicular, epididymal, and prostate weights; testicular tubular degeneration/atrophy; prostatic atrophy; and/or epididymal inflammation at 15 mg/kg/day and 7 mg/kg/day in rats and dogs, respectively (approximately 8 and 2 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC) . The effects on male reproductive organs were reversible .

Distended abdomen, skin rash, and increased cholesterol and triglycerides occurred in animals . These findings were accompanied by hyperplasia and dilation of the bile ducts in the liver and acinar atrophy of the pancreas in rats at 15 mg/kg/day and in dogs at 2 mg/kg/day (approximately 8 and 0.5 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC) . All effects were reversible within the recovery period .

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of lorlatinib.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of lorlatinib and may reduce its serum concentration. Co-administration of lorlatinib with St. John's Wort is contraindicated.
• Take at the same time every day.
• Take with or without food.

[Major] GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of lorlatinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients treated with lorlatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

If coadministration is unavoidable, some authorities recommend reducing the initial dosage of lorlatinib from 100 mg orally once daily to 75 mg orally once daily.

In patients who have had a dosage reduction to 75 mg orally once daily due to adverse reactions, the lorlatinib dosage should be further reduced to 50 mg orally once daily upon initiation of a potent CYP450 3A4 inhibitor.

After 3 plasma half-lives following discontinuation of the potent CYP450 3A4 inhibitor, the lorlatinib dosage may be increased to that used prior to initiation of the inhibitor.

Lorlatinib Cholesterol interaction

[Moderate] Increases in serum cholesterol and triglycerides have been reported in patients receiving lorlatinib.

Grade 3 or 4 elevations in total cholesterol occurred in 17% and Grade 3 or 4 elevations in triglycerides occurred in 17% of the patients enrolled in a clinical trial with up to 80% percent of patients requiring initiation of lipid-lowering medications.

Caution is advised in patients with hyperlipidemias.

Monitor serum cholesterol and triglycerides before initiating treatment and 1 and 2 months after initiating, and periodically thereafter.

Initiation or increase of the dose of lipid-lowering agents might be required on these patients.

Lorlatinib Hypertension interaction

[Moderate] The use of lorlatinib might cause hypertension.

It is recommended to assess and control blood pressure prior to treatment initiation.

Caution should be exercised when treating patients with prior history of hypertension, uncontrolled hypertension, and those at risk.

Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment.

Withhold and resume lorlatinib at a reduced dose or permanently discontinue treatment based on severity.

Lorlatinib Drug Interaction

Major: fosphenytoin, dexamethasone / lidocaine, phenytoinModerate: naproxen, warfarin, crizotinibUnknown: mannitol, bevacizumab, methohexital, clobetasol topical, ubiquinone, secukinumab, dehydroepiandrosterone, difluprednate ophthalmic, omega-3 polyunsaturated fatty acids, floxuridine, ferumoxsil, sermorelin, sitagliptin, cholecalciferol

Lorlatinib Disease Interaction

Moderate: atrioventricular block, CNS effects, hepatotoxicity/hepatic impairment, hyperglycemia, hyperlipidemia, hypertension, interstitial lung disease, severe renal impairment

Volume of Distribution

The mean (CV%) steady-state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose .

Elimination Route

The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady state .

The mean absolute bioavailability is 81% (90% CI 75.7%, 86.2%) after oral administration compared to intravenous administration .

Administration of lorlatinib with a high fat, high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) had no clinically meaningful effect on lorlatinib pharmacokinetics .

Half Life

The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib .

Clearance

The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady state, suggesting autoinduction .

Elimination Route

Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (Label.

Innovators Monograph

You find simplified version here Lorlatinib