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General Description:

Lorlatinib, identified by CAS number 1454846-35-5, is a notable compound with significant therapeutic applications. Lorlatinib is a third-generation ALK tyrosine kinase inhibitor (TKI) for patients with ALK-positive metastatic non-small cell lung cancer which was first approved by the US FDA in November of 2018. It was subsequently approved by the EMA in 2019 for the treatment of select patients with previously treated advanced ALK-positive non-small cell lung cancer, followed by an expanded approval in 2022 to include lorlatinib as a first-line treatment option in advanced ALK-positive NSCLC.

Indications:

This drug is primarily indicated for: Lorlatinib is indicated for the treatment of adult patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). In the EU, it is indicated for the treatment of adult patients with ALK-positive advanced NSCLC not previously treated with an ALK inhibitor, or whose disease has progressed after using either or , or and at least one other ALK inhibitor. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lorlatinib undergoes metabolic processing primarily in: In vitro, lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3 . In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity in a human mass balance study . The oxidative cleavage metabolite, M8, is pharmacologically inactive . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lorlatinib are crucial for its therapeutic efficacy: 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lorlatinib is an important consideration for its dosing schedule: The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lorlatinib exhibits a strong affinity for binding with plasma proteins: In vitro, lorlatinib was 66% bound to plasma proteins at a concentration of 2.4 µM . The blood-to-plasma ratio was 0.99 . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lorlatinib from the body primarily occurs through: Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged) . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lorlatinib is distributed throughout the body with a volume of distribution of: The mean (CV%) steady-state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lorlatinib is a critical factor in determining its safe and effective dosage: 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lorlatinib exerts its therapeutic effects through: Based on data from Study B7461001, exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure . In 295 patients who received lorlatinib at the recommended dosage of 100 mg once daily and had an ECG measurement in the same Study B7461001, the maximum mean change from baseline for their PR interval was 16.4 ms (2-sided 90% upper confidence interval 19.4 ms) . Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation ≥200 ms after starting use with lorlatinib . The prolongation of PR interval occurred in a concentration-dependent manner and atrioventricular block occurred in 1% of patients . Finally, in 275 patients who received lorlatinib at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e, >20 ms) were detected . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lorlatinib functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lorlatinib belongs to the class of organic compounds known as macrolactams. These are cyclic amides of amino carboxylic acids, having a 1-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. They are nitrogen analogues (the a nitrogen atom replacing the o atom of the cyclic carboxylic acid group ) of the naturally occurring macrolides, classified under the direct parent group Macrolactams. This compound is a part of the Organic compounds, falling under the Phenylpropanoids and polyketides superclass, and categorized within the Macrolactams class, specifically within the None subclass.

Categories:

Lorlatinib is categorized under the following therapeutic classes: Amides, Amines, Anaplastic lymphoma kinase (ALK) inhibitors, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Kinase Inhibitor, Lactams, MATE 1 Inhibitors, MATE inhibitors, OAT3/SLC22A8 Inhibitors, Organic Cation Transporter 1 Inhibitors, P-glycoprotein inducers, Protein Kinase Inhibitors, Pyridines, UGT1A3 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.