 Idelalisib structure | |
| Clinical data | |
|---|---|
| Pronunciation | /aɪˈdɛləlɪsɪb/ eye-DEL-ə-li-sib |
| Trade names | Zydelig |
| Other names | GS-1101, CAL-101 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a614040 |
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| Routes of administration | Oral |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | >84%[4] |
| Metabolism | Aldehyde oxidase (~70%),CYP3A4 (~30%);[5]UGT1A4 (minor) |
| Metabolites | GS-563117 (inactivein vitro) |
| Onset of action | Tmax = 1.5 hours |
| Eliminationhalf-life | 8.2 hours |
| Excretion | Feces (78%), urine (14%) |
| Identifiers | |
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| CAS Number | |
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| DrugBank | |
| ChemSpider | |
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| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.235.089 |
| Chemical and physical data | |
| Formula | C22H18FN7O |
| Molar mass | 415.432 g·mol−1 |
| 3D model (JSmol) | |
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Idelalisib, sold under the brand nameZydelig, is a medication used to treat certainblood cancers.[4][3] Idelalisib acts as aphosphoinositide 3-kinase inhibitor; more specifically, it blocksP110δ, the delta isoform of the enzymephosphoinositide 3-kinase.[6][7] It was developed byGilead Sciences. It is takenorally (swallowed by mouth).
Idelalisib is a second-line medication for people whosechronic lymphocytic leukemia (CLL) has relapsed. Used in combination withrituximab,[8] idelalisib is to be used in people for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions.[8] It appears to be effective and leads to improvement oflymphadenopathy andsplenomegaly. However, the lymphocyte counts take longer to decrease to normal levels with idelalisib. It is not recommended as a first-line treatment.[4]
Clinical symptoms includediarrhea, fever,fatigue,nausea,cough,pneumonia,abdominal pain,chills andrash. 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.[9]
The US label for idelalisib has aboxed warning describing toxicities that can be serious and fatal, includingliver toxicity, severediarrhea,colon inflammation, lung tissue inflammation (pneumonitis) andintestinal perforation, and the manufacturer was required to put in place aRisk Evaluation and Mitigation Strategy (REMS) under which the risk of toxicities would be managed.[10]
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.[11] On March 21, 2016Gilead 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.[12] 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.[13] In 2016, the EMA recommended that people on idelalisib should be given medication against the lung infectionPneumocystis 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.[14]
PI3Kδ is expressed in normal and malignantB-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 cellsignaling pathways, includingB-cell receptor (BCR) signaling and theCXCR4 andCXCR5 signaling, which are involved in the trafficking and homing of B-cells to thelymph nodes andbone marrow.[4]
Idelalisib is acompetitive inhibitor of theATP binding site of the PI3Kδcatalytic domain. Itsin vitro potency and selectivity relative to the otherClass I PI3K isoforms is the following:[15]
| PI3K isoform | IC50 (nM) | IC50-based PI3Kδ-fold selectivity |
|---|---|---|
| PI3Kα | 8,600 | 453 |
| PI3Kβ | 4,000 | 211 |
| PI3Kγ | 2,100 | 110 |
| PI3Kδ | 19 | 1 |
In July 2014, the FDA and EMA granted idelalisib approval to treatchronic lymphocytic leukemia.[9][16]
It was also approved by the FDA for the treatment of relapsedfollicular lymphoma (FL) andsmall lymphocytic lymphoma (SLL), both in patients who had received at least two prior systemic therapies.[4] This approval was voluntarily withdrawn by the manufacturer in May 2022 after they failed to complete post-marketing confirmatory studies required by the FDA.[17] This has coincided with the withdrawal of every other PI3K inhibitor for follicular lymphoma:duvelisib in December 2021,umbralisib in January 2022, andcopanlisib in November 2023.[18][19][20] These withdrawals are attributed to a possibly detrimental effect on survival seen in multiple studies of this drug class, likely due to toxic side effects.[21]
Idelalisib had annual sales of $168 million (USD) during the year of 2016, up from $132 million (USD) in 2015.[22]
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