Idelalisib

Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers.

Idelalisib
Idelalisib structure
Clinical data
Pronunciation/aɪˈdɛləlɪsɪb/
eye-DEL-ə-li-sib
Trade namesZydelig
Other namesGS-1101, CAL-101
AHFS/Drugs.comzydelig
License data
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    administration    		Oral (tablets)
    ATC code
    Legal status
    Legal status
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Protein binding>84%[1]
    MetabolismAldehyde oxidase (~70%), CYP3A4 (~30%);[2] UGT1A4 (minor)
    MetabolitesGS-563117 (inactive in vitro)
    Onset of actionTmax = 1.5 hours
    Elimination half-life8.2 hours
    ExcretionFeces (78%), urine (14%)
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.235.089
    Chemical and physical data
    FormulaC22H18FN7O
    Molar mass415.432 g·mol−1
    3D model (JSmol)

    The substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase.[3][4] It was developed by Gilead Sciences. Idelalisib had annual sales of $168 million (USD) during the year of 2016, up from $132 million (USD) in 2015.[5]

    Medical uses

    Idelalisib is a second-line drug for patients whose chronic lymphocytic leukemia (CLL) has relapsed. Used in combination with rituximab,[6] idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions.[6] It appears to be effective and leads to improvement of lymphadenopathy and splenomegaly. However, the lymphocyte counts take longer to decrease to normal levels with idelalisib. It is not recommended as a first-line treatment.[1]

    It is also approved for the treatment of follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL), both in patients who have received at least two prior systemic therapies.[1]

    Adverse effects

    Clinical symptoms include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash. Laboratory abnormalities may include: neutropenia, hypertriglyceridemia, hyperglycemia and elevated levels of liver enzymes. Idelalisib's safety and effectiveness to treat relapsed FL and relapsed SLL were established in a clinical trial with 123 participants with slow-growing (indolent) non-Hodgkin lymphomas. All participants were treated with idelalisib and were evaluated for complete or partial disappearance of their cancer after treatment (objective response rate, or ORR). Results showed 54% of participants with relapsed FL and 58% of participants with SLL experienced ORR.[7]

    The U.S. label for idelalisib has a boxed warning describing toxicities that can be serious and fatal, including liver toxicity, severe diarrhea, colon inflammation, lung tissue inflammation (pneumonitis) and intestinal perforation, and the manufacturer was required to put in place a Risk Evaluation and Mitigation Strategy (REMS) under which the risk of toxicities would be managed.[8]

    In March 2016, as reports were made from three ongoing clinical trials of serious adverse events and deaths, mostly due to infections, the European Medicines Agency opened a review of the drug and its risks.[9] On March 21, 2016 Gilead Sciences (the manufacturer of idelalisib) alerted healthcare providers about decreased overall survival and increased risk of serious infections in patients with CLL and indolent non-Hodgkin lymphoma (iNHL) treated with idelalisib.[10] The company also disclosed that it stopped six clinical trials in patients with CLL, SLL and iNHL due to an increased rate of adverse events, including deaths.[11] In 2016, the EMA recommended that people on idelalisib should be given medication against the lung infection Pneumocystis jirovecii pneumonia and this should be continued for up to 6 months after idelalisib has stopped. In addition, people should be monitored for signs of infection.[12]

    Pharmacology

    Mechanism of action

    PI3Kδ kinase is expressed in normal and malignant B-cells. By inhibiting it, idelalisib induces apoptosis and prevents proliferation in cell lines derived from malignant B-cells and in primary tumor cells. It also inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow.[1]

    Binding profile

    Idelalisib is a competitive inhibitor of the ATP binding site of the PI3Kδ catalytic domain. Its in vitro potency and selectivity relative to the other Class I PI3K isoforms is the following:[13]

    PI3K isoformIC50, nMIC50-based PI3Kδ-fold selectivity
    PI3Kα8,600453
    PI3Kβ4,000211
    PI3Kγ2,100110
    PI3Kδ191

    History

    Regulatory

    In July 2014, the FDA and EMA granted idelalisib approval to treat different types of leukemia.[7][14] The FDA is also granted approval for idelalisib to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. Idelalisib is intended to be used in patients who have received at least two prior systemic therapies.

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    gollark: No. God stops you.

    References
    1. "ZYDELIG (idelalisib) Tablets, for Oral Use. U.S. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Retrieved 15 April 2016.
    2. "Clinical Pharmacology and Biopharmaceutics Review: Zydelig (idelalisib)" (PDF). U.S. Food and Drug Administration. p. 6. Retrieved 15 April 2016.
    3. Spreitzer H (13 May 2013). "Neue Wirkstoffe – Ibrutinib und Idelalisib". Österreichische Apothekerzeitung (in German) (10/2013): 34.
    4. Wu M, Akinleye A, Zhu X (May 2013). "Novel agents for chronic lymphocytic leukemia". Journal of Hematology & Oncology. 6: 36. doi:10.1186/1756-8722-6-36. PMC 3659027. PMID 23680477.
    5. "Annual Sales of Idelalisib reported using PharmaCompass' compilation of Annual Reports of Global Pharmaceutical Companies". Pharmacompass. Retrieved January 21, 2019.
    6. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. (March 2014). "Idelalisib and rituximab in relapsed chronic lymphocytic leukemia". The New England Journal of Medicine. 370 (11): 997–1007. doi:10.1056/NEJMoa1315226. PMC 4161365. PMID 24450857.
    7. "FDA approves Zydelig for three types of blood cancers". Food and Drug Administration. July 23, 2014.
    8. "Press Announcements — FDA approves Zydelig for three types of blood cancers". www.fda.gov. Retrieved 2016-03-14.
    9. "European Medicines Agency — News and Events — EMA reviews cancer medicine Zydelig". www.ema.europa.eu. Retrieved 2016-03-14.
    10. "Important Drug Warning: Decreased Overall Survival and Increased Risk of Serious Infections in Patients Receiving ZYDELIG (idelalisib)" (PDF). Gilead Sciences, Inc. March 21, 2016. Retrieved 19 April 2016.
    11. "Drug Safety and Availability — FDA Alerts Healthcare Professionals About Clinical Trials with Zydelig (idelalisib) in Combination with Other Cancer Medicines". FDA Center for Drug Evaluation and Research. Retrieved 19 April 2016.
    12. "CHMP confirms recommendations for use of Zydelig". European Medicines Agency. 15 September 2016.
    13. "Committee for Medicinal Products for Human Use Assessment Report: Zydelig (idelalisib)" (PDF). European Medicines Agency. p. 17. Retrieved 19 April 2016.
    14. "European Medicines Agency recommends approval of two new treatment options for rare cancers". European Medicines Agency. July 25, 2014.
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