Lorlatinib

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.

Lorlatinib
Clinical data
Trade namesLorbrena, Lorviqua
Other namesPF-6463922
AHFS/Drugs.comlorbrena
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability81%
Protein binding66%
MetabolismMainly CYP3A4 and UGT1A4
Elimination half-life24 hrs (single dose)
Excretion48% urine (<1% unchanged), 41% faeces (9% unchanged)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ECHA InfoCard100.245.079
Chemical and physical data
FormulaC21H19FN6O2
Molar mass406.421 g·mol−1
3D model (JSmol)

Medical uses

Lortalinib is approved in the US and in Europe for the second- or third-line treatment of ALK-positive metastatic non-small-cell lung cancer (NSCLC).[1][2]

Contraindications

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.[3][4]

Side effects

The most common side effects in studies were high 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 in termination of lorlatinib treatment in 3% of patients.[3][4]

Interactions

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.[3][4]

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.[4]

Pharmacology

Mechanism of action
Further information: ALK inhibitor

Lorlatinib is a small molecule kinase inhibitor of ALK and ROS1 as well as a number of other kinases. It is active in vitro against many mutated forms of ALK.[3]

Pharmacokinetics
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.[5]

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.[3][4] Lorlatinib is able to cross the blood-brain barrier.[6]

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).[4]

Chemistry

Lorlatinib is a white to off-white powder. It has high solubility in 0.1 M hydrochloric acid and very low solubility at a pH over 4.5.[5]

History

Clinical studies

Several clinical trials are ongoing. A phase II trial comparing avelumab alone and in combination with lorlatinib or crizotinib for non-small-cell lung cancer is expected to be complete in late 2017. A phase II trial comparing lorlatinib with crizotinib is expected to be complete in mid-2018.[7] A phase II trial for treatment of ALK-positive or ROS1-positive non-small-cell lung cancer with central nervous system metastases is not expected to be complete until 2023.[8] 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.[9]

Approval

In 2015, FDA granted Pfizer orphan drug status for lorlatinib for the treatment of NSCLC.[10] In 2018, the FDA approved lortalinib for second- or third-line treatment of ALK-positive metastatic NSCLC.[1] In February 2019, the European CHMP of EMA recommended the granting of a conditional marketing authorisation.[11] In May 2019 the European Commission approved lorlatinib for the 28 countries of the EU, also as a second- or third-line treatment.[2]

References
  1. "FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC".
  2. "European Commission Approves LORVIQUA (lorlatinib) for Certain Adult Patients with Previously-Treated ALK-Positive Advanced Non-Small Cell Lung Cancer, PM Pfizer, May 7, 2019". pfizer.com. Retrieved 15 May 2019.
  3. FDA Professional Drug Information on Lorbrena.
  4. "Lorviqua: EPAR – Product Information" (PDF). European Medicines Agency. 2019-06-17.
  5. "Lorviqua: EPAR – Public assessment report" (PDF). European Medicines Agency. 2019-06-17.
  6. "NCI Drug Dictionary". National Cancer Institute.
  7. "A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations - Full Text View - ClinicalTrials.gov".
  8. "A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions - Full Text View - ClinicalTrials.gov".
  9. http://www.ascopost.com/News/58148
  10. http://drugspider.com/drug/lorlatinib
  11. "EMA Positive Opinion - Lorviqua, February 28, 2019". ema.europa.eu. Retrieved 15 May 2019.
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