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| Clinical data | |
|---|---|
| Trade names | Lorbrena, Lorviqua |
| Other names | PF-6463922 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a619005 |
| License data | |
| Pregnancy category | |
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 81% |
| Protein binding | 66% |
| Metabolism | MainlyCYP3A4 andUGT1A4 |
| Eliminationhalf-life | 24 hrs (single dose) |
| Excretion | 48% urine (<1% unchanged), 41% faeces (9% unchanged) |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.245.079 |
| Chemical and physical data | |
| Formula | C21H19FN6O2 |
| Molar mass | 406.421 g·mol−1 |
| 3D model (JSmol) | |
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Lorlatinib, sold under the brand nameLorbrena in the United States, Canada, and Japan, andLorviqua in the European Union, is ananti-cancer medication used for the treatment ofnon-small cell lung cancer.[4] It is an orally administered inhibitor ofanaplastic lymphoma kinase (ALK) andC-ros oncogene 1 (ROS1), two enzymes that play a role in the development of cancer.[6] It was developed byPfizer.[7]
The most common adverse reactions include edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough.[7]
Lorlatinib was approved for medical use in the United States in November 2018,[8][9] and in the European Union in May 2019.[5]
Lorlatinib isindicated for the treatment of adults with metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase (ALK)-positive.[4][5][6][7]
Lorlatinib must not be combined with stronginducers (i.e. activators) of the liver enzymesCYP3A4/5 if it can be avoided, as serious cases ofliver toxicity have been observed under combination with the CYP3A4/5 inducerrifampicin.[4][10]
The most common side effects in studies werehigh blood cholesterol (84% of patients),high blood triglycerides (67%),edema (55%),peripheral neuropathy (48%),cognitive effects (29%),fatigue (28%), weight gain (26%), and mood effects (23%). Serious side effects led to dose reduction in 23% of patients and to termination of lorlatinib treatment in 3% of patients.[4][10]
Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such as rifampicin,carbamazepine orSt John's wort decrease its concentrations in theblood plasma and can reduce its effectiveness. Additionally, the combination of lorlatinib with rifampicin showed liver toxicity in studies. Inhibitors of these enzymes such asketoconazole orgrapefruit juice increase lorlatinib plasma concentrations, leading to higher toxicity. Lorlatinib is also a (moderate) CYP3A4/5 inducer, so that drugs that are metabolized by these enzymes are broken down more quickly when combined with lorlatinib. Examples includemidazolam andciclosporin.[4][10]
Interactions via other enzymes have only been studiedin vitro. According to these findings, lorlatinib may inhibitCYP2C9,UGT1A1 and severaltransport proteins, induceCYP2B6, and has probably no relevant effect onCYP1A2.[10]
Lorlatinib is asmall moleculekinase inhibitor ofALK andROS1 as well as a number of otherkinases. It is activein vitro against many mutated forms of ALK.[4]
Lorlatinib is taken by mouth and reaches highest blood plasma concentrations 1.2 hours after a single dose, or 2 hours after ingestion when taken regularly.[medical citation needed] Its absolutebioavailability is 80.8%.[medical citation needed] Intake with fatty food increases its availability by 5%, which is not considered clinically significant.[medical citation needed] When in the bloodstream, 66% of the substance are bound toplasma proteins.[4][10] Lorlatinib is able to cross theblood–brain barrier.[12]
Lorlatinib is inactivated byoxidation, mainly through CYP3A4, and byglucuronidation, mainly throughUGT1A4.[medical citation needed] OtherCYPs andUGTs play a minor role.[medical citation needed] Lorlatinib and itsmetabolites are excreted with a half-life of 23.6 hours after a single dose; 47.7% into the urine (of which less than 1% in unchanged form), and 40.9% into the faeces (9.1% unchanged).[10]
Lorlatinib is a white to off-white powder. It has high solubility in 0.1Mhydrochloric acid and very low solubility at apH over 4.5.[11]
In November 2018, the USFood and Drug Administration (FDA) granted accelerated approval to lorlatinib for people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.[8] Approval was based on a subgroup of 215 participants with ALK-positive metastatic NSCLC, previously treated with one or more ALK kinase inhibitors, enrolled in a non‑randomized, dose-ranging and activity-estimating, multi‑cohort, multicenter study (Study B7461001; NCT01970865).[8] The major efficacy measures were overall response rate (ORR) and intracranial ORR, according to RECIST 1.1, as assessed by an independent central review committee.[8]
In March 2021, the FDA granted regular approval to lorlatinib based on data from study B7461006 (NCT03052608), a randomized, multicenter, open-label, active-controlled trial conducted in 296 participants with ALK-positive metastatic non-small cell lung cancer who had not received prior systemic therapy for metastatic disease. Participants were required to have ALK-positive tumors detected by the VENTANA ALK (D5F3) CDx assay. Participants were randomized 1:1 to receive lorlatinib 100 mg orally once daily (n=149) or crizotinib 250 mg orally twice daily (n=147).
In 2015, the FDA granted lorlatiniborphan drug status for the treatment of anaplastic lymphoma kinase (ALK)-positive or ROS1-positive non-small cell lung cancer.[13]
Lorlatinib was approved for medical use in the United States in November 2018,[8] and in the European Union in May 2019.[5][14][15]
In June 2024, Pfizer announced positive longer-term follow-up results from the phase III CROWN study of lorlatinib in advancednon-small cell lung cancer showing that 60% of participants treated with lorlatinib were alive without disease progression after five years.[16][17][18]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.