Introduction
Zydelig (idelalisib) is an oral phosphatidylinositol 3-kinase (PI3K) delta inhibitor approved by the FDA in 2014 for the treatment of specific hematologic malignancies. It represents a targeted therapy approach for patients with relapsed or refractory B-cell malignancies who have limited treatment options.
Mechanism of Action
Idelalisib selectively inhibits the delta isoform of phosphoinositide 3-kinase (PI3Kδ), which is predominantly expressed in hematopoietic cells. PI3Kδ signaling is crucial for B-cell activation, proliferation, and survival. By inhibiting this pathway, idelalisib induces apoptosis in malignant B-cells and disrupts their microenvironment interactions. The drug also affects multiple signaling pathways downstream of B-cell receptor activation.
Indications
FDA-approved indications:
- Relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab for patients for whom rituximab alone would be considered appropriate therapy
- Relapsed follicular B-cell non-Hodgkin lymphoma (FL) after at least two prior systemic therapies
- Relapsed small lymphocytic lymphoma (SLL) after at least two prior systemic therapies
Dosage and Administration
Standard dosing: 150 mg orally twice daily with or without food Dose modifications:- Hepatic impairment: Avoid use in patients with ALT or AST >5× ULN or bilirubin >3× ULN
- Renal impairment: No dosage adjustment required for mild to moderate impairment; use with caution in severe impairment
- Treatment interruption: Required for severe or life-threatening adverse reactions
- Swallow tablets whole with water
- Do not crush, break, or chew tablets
- If a dose is missed, take as soon as remembered unless next dose is due within 6 hours
Pharmacokinetics
Absorption: Median Tmax approximately 1.5 hours; bioavailability ~39% Distribution: Volume of distribution ~19 L; 84% protein-bound Metabolism: Primarily via aldehyde oxidase and CYP3A; UGT1A4 also contributes Elimination: Half-life ~8.2 hours; primarily fecal excretion (78%) with minor renal excretion (14%)Contraindications
- History of serious hypersensitivity reactions to idelalisib or any component of the formulation
- Concurrent administration with strong CYP3A inducers (rifampin, phenytoin, carbamazepine, St. John's wort)
- Severe hepatic impairment (Child-Pugh Class C)
Warnings and Precautions
Boxed Warnings:1. Fatal and serious hepatotoxicity: ALT/AST elevations occur in >50% of patients 2. Fatal and serious diarrhea/colitis: Can occur at any time during treatment 3. Fatal and serious pneumonitis: May present with pulmonary symptoms 4. Fatal and serious intestinal perforation: Monitor for abdominal pain, chills, fever
Additional warnings:- Severe cutaneous reactions including Stevens-Johnson syndrome
- Neutropenia and increased infection risk
- Anaphylaxis and infusion reactions
Drug Interactions
Strong CYP3A inducers: Contraindicated (decreased idelalisib exposure) Strong CYP3A inhibitors: Avoid concomitant use (increased idelalisib exposure) CYP3A substrates: Idelalisib is a strong CYP3A inhibitor - adjust doses of sensitive substrates P-gp substrates: May increase concentrations of digoxin, dabigatran, and other P-gp substrates BCRP substrates: May increase concentrations of rosuvastatin, sulfasalazineAdverse Effects
Very common (≥10%):- Diarrhea (47%)
- Pyrexia (29%)
- Nausea (29%)
- Chills (19%)
- Cough (18%)
- Fatigue (17%)
- Rash (17%)
- Pneumonia (16%)
- Elevated transaminases (14%)
- Hepatotoxicity (14% severe)
- Severe diarrhea/colitis (14%)
- Pneumonitis (4%)
- Intestinal perforation (<1%)
- Severe neutropenia (28%)
Monitoring Parameters
Baseline:- Complete blood count with differential
- Liver function tests (ALT, AST, bilirubin)
- Renal function
- Infection screening
- CBC with differential every 2 weeks for first 3 months, then monthly
- Liver function tests every 2 weeks for first 3 months, then monthly
- Monitor for signs/symptoms of colitis, pneumonitis, infection
- Regular assessment of diarrhea severity
- Continue monitoring for several months after discontinuation due to prolonged immunosuppressive effects
Patient Education
- Take exactly as prescribed; do not adjust dose without medical supervision
- Report any new or worsening symptoms immediately, especially:
- Yellowing of skin/eyes, dark urine - Severe diarrhea or abdominal pain - Shortness of breath or cough - Fever, chills, or signs of infection - Unusual bleeding or bruising
- Use effective contraception during treatment and for at least 1 month after discontinuation
- Avoid grapefruit and grapefruit juice during treatment
- Inform all healthcare providers about Zydelig use before starting new medications
- Keep all scheduled follow-up appointments for laboratory monitoring
References
1. FDA Prescribing Information: Zydelig (idelalisib) tablets 2. Gilead Sciences, Inc. (2022). Zydelig Package Insert 3. Furman RR, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007 4. Coutré SE, et al. Management of adverse events associated with idelalisib treatment. Expert Rev Hematol. 2015;8(6):799-806 5. Brown JR, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397 6. NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 3.2023) 7. Flinn IW, et al. Idelalisib in combination with rituximab or bendamustine or both in patients with relapsed/refractory CLL. Blood. 2014;124:Abstract 325