Lorlatinib

Lorlatinib
Names
Trade namesLorbrena, Lorviqua
Other namesPF-6463922
IUPAC name
  • (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
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesNon-small cell lung cancer (NSCLC)[1]
Side effectsHigh cholesterol, high triglycerides, swelling, peripheral neuropathy, problems with memory, tiredness, weight gain, joint pain[2]
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		By mouth
    Typical dose100 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    US NLMLorlatinib
    MedlinePlusa619005
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability81%
    Protein binding66%
    MetabolismMainly CYP3A4 and UGT1A4
    Elimination half-life24 hrs (single dose)
    Excretion48% urine (<1% unchanged), 41% faeces (9% unchanged)
    Chemical and physical data
    FormulaC21H19FN6O2
    Molar mass406.421 g·mol−1
    3D model (JSmol)
    SMILES
    • C[C@H]1Oc2cc(cnc2N)c3c(CN(C)C(=O)c4ccc(F)cc14)nn(C)c3C#N
    InChI
    • 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 and Lorviqua, is a medication used to treat non-small cell lung cancer (NSCLC).[1] Specifically it is used in anaplastic lymphoma kinase (ALK) positive cases that have failed other treatments.[1] It is taken by mouth.[1]

    Common side effects are high cholesterol, high triglycerides, swelling, peripheral neuropathy, problems with memory, tiredness, weight gain, and joint pain.[2] Other side effects may include liver problems, seizures, hallucinations, pneumonitis, and AV block.[1] Use in pregnancy may harm the baby.[1] It is a tyrosine kinase inhibitor of ALK and ROS1.[1]

    Lorlatinib was approved for medical use in the United States in 2018 and Europe in 2019.[1][2] In the United Kingdom it costs the NHS about £5,300 a month as of 2021.[3] This amount in the United States is about 18,500 USD.[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][7]

    Dosage

    It is taken at a dose of 100 mg per day.[1]

    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.[8][9]

    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.[8][9]

    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.[8][9]

    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.[9]

    Pharmacology

    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.[10]

    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.[8]

    Pharmacokinetics

    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.[8][9] Lorlatinib is able to cross the blood-brain barrier.[11]

    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).[9]

    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.[10]

    History

    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.[5] 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.[6][14]

    Research

    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.[15] 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.[16] 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.[17]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 "Lorlatinib Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2021. Retrieved 24 November 2021.
    2. 1 2 3 "Lorviqua". Archived from the original on 14 November 2021. Retrieved 24 November 2021.
    3. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1033. ISBN 978-0857114105.
    4. ↑ "Lorbrena Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 26 January 2021. Retrieved 24 November 2021.
    5. 1 2 "FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC". FDA. 2019-12-20. Archived from the original on 2019-04-23. Retrieved 2021-06-30.
    6. 1 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. Archived from the original on 15 May 2019. Retrieved 15 May 2019.
    7. ↑ Nagasaka M, Ge Y, Sukari A, Kukreja G, Ou SI (July 2020). "A user's guide to lorlatinib". Critical Reviews in Oncology/Hematology. 151: 102969. doi:10.1016/j.critrevonc.2020.102969. PMID 32416346.
    8. 1 2 3 4 5 FDA Professional Drug Information on Lorbrena.
    9. 1 2 3 4 5 6 "Lorviqua: EPAR – Product Information" (PDF). European Medicines Agency. 2019-06-17. Archived (PDF) from the original on 2021-11-02. Retrieved 2021-06-30.
    10. 1 2 "Lorviqua: EPAR – Public assessment report" (PDF). European Medicines Agency. 2019-06-17. Archived (PDF) from the original on 2021-11-02. Retrieved 2021-06-30.
    11. ↑ "Lorlatinib". NCI Drug Dictionary. National Cancer Institute. 2011-02-02. Archived from the original on 2020-10-15. Retrieved 2021-06-30.
    12. ↑ "Lorlatinib". drugspider.com. Archived from the original on 2017-07-04. Retrieved 2021-06-30.
    13. ↑ "EMA Positive Opinion - Lorviqua, February 28, 2019". ema.europa.eu. Archived from the original on 15 May 2019. Retrieved 15 May 2019.
    14. ↑ Syed YY (January 2019). "Lorlatinib: First Global Approval". Drugs. 79 (1): 93–98. doi:10.1007/s40265-018-1041-0. PMID 30604291. S2CID 57426966.
    15. ↑ Clinical trial number NCT01970865 for "A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations" at ClinicalTrials.gov
    16. ↑ Clinical trial number NCT02927340 for "A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions" at ClinicalTrials.gov
    17. ↑ "IASLC 2017: Lorlatinib in ALK-Positive and ROS1-Positive Advanced Non–Small Cell Lung Cancer". The ASCO Post. 17 October 2017. Archived from the original on 26 February 2021. Retrieved 30 June 2021.
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