Lorlatinib

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Lorlatinib
Clinical data
Trade namesLorbrena, Lorviqua
Other namesPF-6463922
AHFS/Drugs.comMonograph
MedlinePlusa619005
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability81%
Protein binding66%
MetabolismMainly CYP3A4 and UGT1A4
Elimination half-life24 hrs (single dose)
Excretion48% urine (<1% unchanged), 41% faeces (9% unchanged)
Identifiers
  • (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
JSmol)
  • C[C@H]1Oc2cc(cnc2N)c3c(CN(C)C(=O)c4ccc(F)cc14)nn(C)c3C#N
  • InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1
  • Key:IIXWYSCJSQVBQM-LLVKDONJSA-N

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.[4]

Medical uses

Lorlatinib 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).[5][6][4] It is the only ALK inhibitor with meaningful activity against ALK G1202R mutation in lung cancer.[clarification needed][medical citation needed]

Contraindications

Lorlatinib must not be combined with strong

liver toxicity have been observed under combination with the CYP3A4/5 inducer rifampicin.[7][8]

Side effects

The most common side effects in studies were

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.[7][8]

Interactions

Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such as rifampicin,

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.[7][8]

Interactions via other enzymes have only been studied

UGT1A1 and several transport proteins, induce CYP2B6, and has probably no relevant effect on CYP1A2.[8]

Pharmacology

Mechanism of action

Further information: ALK inhibitor

Lorlatinib is a

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.[7]

Pharmacokinetics

phase I metabolites are given in the bottom row. Most of these metabolites, as well as the original substance, undergo glucuronidation.[9]

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

plasma proteins.[7][8] Lorlatinib is able to cross the blood–brain barrier.[10]

Lorlatinib is inactivated by

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).[8]

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.[9]

History

Clinical studies

Several clinical trials were orchestrated. Lorlatinib was analyzed in a clinical trial[11] 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.[12]

Approval

In 2015, FDA granted Pfizer

orphan drug status for lorlatinib for the treatment of NSCLC.[13] In 2018, the FDA approved lortalinib for second- or third-line treatment of ALK-positive metastatic NSCLC.[5] In February 2019, the European CHMP of EMA recommended the granting of a conditional marketing authorisation.[14] In May 2019 the European Commission approved lorlatinib for the 28 countries of the EU, also as a second- or third-line treatment.[6][15]

References

  1. ^ a b "Lorviqua APMDS". Therapeutic Goods Administration (TGA). 26 May 2022. Retrieved 10 March 2024.
  2. ^ "Lorbrena Product information". Health Canada. Retrieved 29 May 2022.
  3. ^ "Summary Basis of Decision (SBD) for Lorbrena". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ^
    PMID 32416346
    .
  5. ^ a b "FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC". FDA. 2019-12-20.
  6. ^ a b "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.
  7. ^ a b c d e FDA Professional Drug Information on Lorbrena.
  8. ^ a b c d e f "Lorviqua: EPAR – Product Information" (PDF). European Medicines Agency. 2019-06-17.
  9. ^ a b "Lorviqua: EPAR – Public assessment report" (PDF). European Medicines Agency. 2019-06-17.
  10. ^ "Lorlatinib". NCI Drug Dictionary. National Cancer Institute. 2011-02-02.
  11. ^ "Clinical Trial Results". lorbrena.com. Pfizer. Retrieved 31 May 2022.
  12. ^ "IASLC 2017: Lorlatinib in ALK-Positive and ROS1-Positive Advanced Non–Small Cell Lung Cancer". The ASCO Post. 17 October 2017.
  13. ^ "Lorlatinib". drugspider.com.
  14. ^ "EMA Positive Opinion - Lorviqua, February 28, 2019". ema.europa.eu. Retrieved 15 May 2019.
  15. S2CID 57426966
    .
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