Lorlatinib

Absorption

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 .

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 .

Description

(R)-Lorlatinib1 is an oral medication for treating anaplastic lymphoma kinase (ALK)–positive non–small-cell lung carcinomas resistant to crizotinib2, an earlier drug used to combat the cancer. It was first disclosed by Pfizer (New York City) in a 2013 world patent application.
In 2014, Ted W. Johnson, Paul F. Richardson, and colleagues at Pfizer Worldwide Research and Development (San Diego) described the discovery of what was then called PF-06463922. They used structure-based drug design, lipophilic efficiency considerations, and physical-property–based optimization procedures to synthesize potent macrocyclic ALK inhibitors with the desired characteristics for effective carcinoma control. The inhibitors were potent against wild-type ALK and clinically reported ALK domain mutations. PF-06463922 emerged as the optimum drug candidate.
The US Food and Drug Administration granted orphan status to lorlatinib in 2014 and full approval in 2018 for second- or third-line treatment of ALK-positive metastatic non-small-cell-lung-cancer. The European Medicines Agency followed suit in 2019. The following year, NPS MedicineWise, an Australian medical information provider, issued a fact sheet for lorlatinib.
1. SciFinder: 2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10R)-. 2. CAS Reg. No. 877399-52-5.

The Uses of Lorlatinib

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that promotes cell proliferation and blocks apoptosis. PF-06463922 is an ATP-competitive, selective inhibitor of ALK (Ki = < 0.07 nM) and c-Ros oncogene 1 (ROS1, Ki = 0.7 nM). It has strong activity against all known ALK and ROS1 mutants identified in patients, including the EML4-L1196M mutant of ALK (Ki = < 0.02 nM). PF-06463922 is orally available, displaying inhibition of ALK phosphorylation and antitumor efficacy in a xenograft model expressing EML4-L1196M ALK. It demonstrates efficient blood-brain barrier penetration, produces brain tumor regression in mice harboring EML4-ALK tumors, and increases overall survival.[Cayman Chemical]

The Uses of Lorlatinib

PF- 06463922 is a potent and selective ROS1/ALK inhibitor capable to block crizotinib-resistant ROS1 mutations. Used in the treatment of human cancers.

Background

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

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 alectinib or ceritinib, or crizotinib and at least one other ALK inhibitor.

Definition

ChEBI: Lorlatinib is a cyclic ether that is 16,17-dihydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecin-15(10H)-one substituted by methyl groups at positions 2 and 10R, and by cyano, amino and fluoro groups at positions 3, 7 and 12 respectively. It is a small molecule inhibitor of ALK and ROS1 kinase developed by Pfizer for the treatment of ALK-positive non-small cell lung cancer. It has a role as an antineoplastic agent and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is a member of pyrazoles, a member of monofluorobenzenes, an aromatic ether, a nitrile, a member of benzamides, an azamacrocycle, an aminopyridine, a cyclic ether and an organic heterotetracyclic compound.

brand name

Lorbrena?

General Description

Class: receptor tyrosine kinase; Treatment: NSCLC; Oral bioavailability = 81%; Elimination half-life = 24 h; Protein binding = 66%

Biological Activity

pf-06463922 is a potent and selective alk/ros1 inhibitor with ic50 values ranging from 0.19-0.53 nm for the kinase activity of ros1 fusion enzymes [1].the receptor tyrosine kinase c-ros oncogene1 (ros1) is a receptor with a kinase domain that is related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (alk/ltk) and insulin receptor (insr) rtk families [1].via cellular ros1 autophosphorylation in the recombinant enzyme assay, pf-06463922 showed a 30-fold improved potency against ros1, compared with crizotinib, ceritinib, alectinib and foretinib (xl-880). engineered nih 3t3 cells were expressing oncogenic human ros1 fusions. in these cells, pf-06463922 was more potent than foretinib and crizotinib by >10 folds, more potent than alectinib and ceritinib by >100 folds against cellular ros1 autophosphorylation [1].oncogenic gene fusions involving the 3' region of ros1 kinase had been found in various human cancers [2]. mice bearing cd74-ros1, cd74-ros1g2032r and fig-ros1(s) s.c. tumors (250 mm3) were used. treatments with pf-06463992 at various doses were applied consecutively for 7 or 9 d. at dosages of 0.2 to 1 mg/kg/d, pf-06463922 significantly inhibited the growth of both established figros1(s) and cd74-ros1 tumors compared with vehicle control. at 2-6 mg/kg/d, pf-06463922 significantly made tumor volumes regress (58–85%, p < 0.0001). in animals bearing nih 3t3-cd74-ros1g2032r tumors, treatment with pf-06463922 at 1.0, 3.0, and 10 mg/kg/d significantly inhibited tumor growth by 28%, 44% and 90%, respectively. at 30 mg/kg/d, pf-06463922 made tumor regress by 12%, compared with vehicle [1].

Pharmacokinetics

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 [CI] 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 .

Enzyme inhibitor

This potent, dual ALK/ROS1 inhibitor (FW = 406.41 g/mol; CAS 1454846- 35-5), also named (10R)-7-amino-12-fluoro-10,15,16,17-tetrahydro- 2,10,16-trimethyl-15-oxo-2H-4,8-methenopyrazolo[4,3- h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, targets the protooncogene tyrosine-protein kinase ROS1 (Ki < 0.02 nM) as well as wild-type anaplastic lymphoma kinase ALKWT (Ki < 0.07 nM) and its Leu-to-Met mutant ALKL1196M (Ki of = 0.7 nM). PF-06463922 significantly inhibits cell proliferation and induces cell apoptosis in the HCC78 human NSCLC cells harboring SLC34A2-ROS1 fusions and the BaF3-CD74-ROS1 cells expressing human CD74-ROS1

Metabolism

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 [14C] mass balance study . The oxidative cleavage metabolite, M8, is pharmacologically inactive .

References

[1]. zou hy, li q, engstrom ld, et al. pf-06463922 is a potent and selective next-generation ros1/alk inhibitor capable of blocking crizotinib-resistant ros1 mutations. proceedings of the national academy of sciences, 2015, 112(11): 3493-3498.
[2]. davies kd, le at, theodoro mf, et al. identifying and targeting ros1 gene fusions in non–small cell lung cancer. clinical cancer research, 2012, 18(17): 4570-4579.