Umbralisib
Introduction to Umbralisib
Umbralisib (brand name Ukoniq) is a novel, dual inhibitor of PI3K-δ and CK1-ε. It was approved by the FDA in 2021 for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) and follicular lymphoma (FL). While not currently approved for pediatric use, it represents an important advancement in targeted therapy for certain hematologic malignancies and may have future applications in pediatric oncology.
Mechanism of Action
Umbralisib has a dual mechanism of action:
- PI3K-δ inhibition:
- Blocks phosphatidylinositol 3-kinase delta (PI3K-δ)
- PI3K-δ is expressed in normal and malignant B-cells
- Inhibition leads to reduced proliferation and survival of malignant B-cells
- CK1-ε inhibition:
- Blocks casein kinase 1 epsilon (CK1-ε)
- CK1-ε is involved in the regulation of cell division and apoptosis
- Inhibition may enhance the anti-tumor effects and potentially reduce PI3K-δ-associated toxicities
Indications
FDA-approved indications (adults only):
- Relapsed or refractory marginal zone lymphoma (MZL) in patients who have received at least one prior anti-CD20-based regimen
- Relapsed or refractory follicular lymphoma (FL) in patients who have received at least three prior lines of systemic therapy
Potential future applications in pediatrics (research ongoing):
- Pediatric B-cell lymphomas
- Refractory autoimmune conditions
Pharmacokinetics
- Absorption:
- Time to peak concentration (Tmax): 4 hours
- Bioavailability is increased with high-fat meals
- Distribution:
- Protein binding: 99.7%
- Volume of distribution: 1873 L
- Metabolism:
- Primarily metabolized by CYP3A4
- Also metabolized by CYP2C9, CYP1A2, and UGT1A4
- Elimination:
- Half-life: 11.6 hours
- Primarily eliminated in feces (81%) and urine (4%)
Dosage and Administration
Note: Currently not approved for pediatric use. Adult dosing provided for reference:
- Recommended dose: 800 mg (4 x 200 mg tablets) taken orally once daily
- Take with food
- Continue treatment until disease progression or unacceptable toxicity
Dose modifications:
- May require dose reduction or interruption for adverse reactions
- Recommended dose reductions: 600 mg daily, then 400 mg daily
Side Effects
Common side effects (≥15%):
- Diarrhea
- Nausea
- Fatigue
- Musculoskeletal pain
- Vomiting
- Abdominal pain
- Decreased appetite
- Rash
Serious side effects:
- Infections
- Neutropenia
- Diarrhea or colitis
- Hepatotoxicity
- Severe cutaneous reactions
- Pneumonitis
Monitoring
- Before treatment:
- Complete blood count
- Liver function tests
- Screen for hepatitis B virus infection
- During treatment:
- Monitor complete blood count at least monthly
- Monitor liver function tests at least monthly
- Monitor for signs and symptoms of infection
- Assess for new or worsening respiratory symptoms (potential pneumonitis)
- Monitor for severe diarrhea or colitis
- Assess for severe cutaneous reactions
Drug Interactions
- Strong CYP3A inhibitors: May increase umbralisib concentrations; avoid concomitant use
- Strong CYP3A inducers: May decrease umbralisib concentrations; avoid concomitant use
- CYP3A substrates: Umbralisib may increase concentrations of CYP3A substrates
- P-gp substrates: Umbralisib may increase concentrations of P-gp substrates
Special Populations
- Pregnancy:
- No human data available
- May cause fetal harm based on mechanism of action
- Advise females of reproductive potential to use effective contraception
- Lactation:
- No data on presence in human milk or effects on breastfed child
- Advise not to breastfeed during treatment and for 1 month after last dose
- Pediatric use:
- Safety and effectiveness not established in pediatric patients
- Geriatric use:
- No overall differences in effectiveness observed
- Higher incidence of adverse reactions in patients ≥65 years
- Renal impairment:
- No dose adjustment for mild or moderate renal impairment
- Not studied in severe renal impairment
- Hepatic impairment:
- No dose adjustment for mild hepatic impairment
- Not recommended in moderate or severe hepatic impairment
