Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer drug developed by Pfizer. It is an orally administered inhibitor of ALK and ROS1, two enzymes that play a role in the development of cancer.[3]
Lorlatinib must not be combined with strong inducers (i.e. activators) of the liver enzymes CYP3A4/5 if it can be avoided, as serious cases of liver toxicity have been observed under combination with the CYP3A4/5 inducer rifampicin.[6][7]
Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such as rifampicin, carbamazepine or St John's wort decrease its concentrations in the blood plasma and can reduce its effectiveness. Additionally, the combination of lorlatinib with rifampicin showed liver toxicity in studies. Inhibitors of these enzymes such as ketoconazole or grapefruit 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 include midazolam and ciclosporin.[6][7]
Interactions via other enzymes have only been studied in vitro. According to these findings, lorlatinib may inhibit CYP2C9, UGT1A1 and several transport proteins, induce CYP2B6, and has probably no relevant effect on CYP1A2.[7]
Lorlatinib is cleaved to the metabolite M8 (top left), which makes up 21% of the circulating substance, and an undetected metabolite (given in brackets). Other phase I metabolites are given in the bottom row. Most of these metabolites, as well as the original substance, undergo glucuronidation.[8]
The drug is swallowed in the form of tablets. It reaches highest blood plasma concentrations 1.2 hours after a single dose, or 2 hours after ingestion when taken regularly. Its absolute bioavailability is 80.8%. Intake with fatty food increases its availability by 5%, which is not considered clinically significant. When in the bloodstream, 66% of the substance are bound to plasma proteins.[6][7] Lorlatinib is able to cross the blood–brain barrier.[9]
Lorlatinib is inactivated by oxidation, mainly through CYP3A4, and by glucuronidation, mainly through UGT1A4. Other CYPs and UGTs play a minor role. Lorlatinib and its metabolites 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).[7]
Chemistry
Lorlatinib is a white to off-white powder. It has high solubility in 0.1 Mhydrochloric acid and very low solubility at a pH over 4.5.[8]
History
Clinical studies
This section needs to be updated. Please help update this article to reflect recent events or newly available information. (September 2019)
Several clinical trials were orchestrated. Lorlatinib was analyzed in a clinical trial[10] of 296 patients with ALK+ NSCLC whose cancer had migrated to multiple parts of the body including the brain. A trial comparing lorlatinib with crizotinib was conducted, with a primary endpoint of "progression-free survival", which is the period of time a patient is in remission (the tumor ceases growth). Preclinical studies are investigating lorlatinib for treatment of neuroblastoma.
In 2017, Pfizer announced that lorlatinib was shown to have activity against lung and brain tumors in people with ALK or ROS1 positive advanced non-small-cell lung cancer.[11]
Approval
In 2015, FDA granted Pfizer orphan drug status for lorlatinib for the treatment of NSCLC.[12] In 2018, the FDA approved lortalinib for second- or third-line treatment of ALK-positive metastatic NSCLC.[4] In February 2019, the European CHMP of EMA recommended the granting of a conditional marketing authorisation.[13] In May 2019 the European Commission approved lorlatinib for the 28 countries of the EU, also as a second- or third-line treatment.[5][14]
