Introduction
Jaypirca (pirtobrutinib) is a novel, highly selective, non-covalent (reversible) Bruton's tyrosine kinase (BTK) inhibitor developed for the treatment of certain B-cell malignancies. It represents a significant advancement in the treatment landscape for patients who have developed resistance to prior covalent BTK inhibitor therapy.
Mechanism of Action
Jaypirca works through non-covalent, reversible inhibition of Bruton's tyrosine kinase (BTK), a crucial enzyme in the B-cell receptor signaling pathway. Unlike earlier covalent BTK inhibitors (e.g., ibrutinib, acalabrutinib) that form irreversible covalent bonds with cysteine-481 in the BTK active site, pirtobrutinib binds reversibly to both wild-type and C481-mutated BTK. This mechanism allows it to overcome resistance mutations that develop following prior covalent BTK inhibitor therapy, particularly the common C481S mutation that reduces drug binding affinity.
Indications
Jaypirca is FDA-approved for:
- Adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor
- Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor
Dosage and Administration
Standard dosing: 200 mg orally once daily until disease progression or unacceptable toxicity Administration:- Take with or without food
- Swallow tablets whole with water; do not crush, split, or chew
- If a dose is missed by more than 12 hours, skip the missed dose and take the next dose at the regular time
- For Grade 3 or 4 adverse reactions: interrupt treatment until resolution to Grade ≤1, then resume at same dose or reduced dose (100 mg or 50 mg daily)
- Severe hepatic impairment (Child-Pugh C): reduce dose to 100 mg once daily
- No dosage adjustment recommended for mild to moderate hepatic impairment or renal impairment
Pharmacokinetics
Absorption: Median Tmax is approximately 1-2 hours post-dose; bioavailability is approximately 85% Distribution: Mean volume of distribution is 45 L; protein binding is 96% (primarily to albumin) Metabolism: Primarily metabolized by CYP3A4; forms inactive metabolites Elimination: Mean half-life is approximately 17-19 hours; primarily excreted in feces (82%) with minor renal excretion (12%) Special populations: Age, sex, race, and body weight do not clinically affect pharmacokineticsContraindications
- Hypersensitivity to pirtobrutinib or any component of the formulation
- Concurrent use with strong CYP3A inhibitors when alternative therapies are available
Warnings and Precautions
Infections: Serious infections (including bacterial, viral, and fungal infections) have occurred. Monitor for signs and symptoms of infection and treat promptly. Hemorrhage: Serious hemorrhagic events have been reported. Consider risks and benefits in patients with predisposing factors for hemorrhage. Cytopenias: Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, anemia) may occur. Monitor blood counts regularly. Cardiac arrhythmias: Atrial fibrillation and flutter have been reported. Monitor for signs of arrhythmia. Second Primary Malignancies: Other malignancies have occurred, including skin cancers. Perform regular skin examinations. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk and use effective contraception.Drug Interactions
Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Increase pirtobrutinib exposure; avoid concomitant use or reduce Jaypirca dose to 50 mg daily Strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John's Wort): Decrease pirtobrutinib exposure; avoid concomitant use Moderate CYP3A inhibitors (e.g., fluconazole, diltiazem, verapamil): May increase pirtobrutinib exposure; monitor for adverse reactions Sensitive CYP3A, CYP2B6, CYP2C19, CYP2C9, P-gp, BCRP substrates: Jaypirca may increase concentrations of these substrates; monitor for increased toxicityAdverse Effects
Most common (≥20%):- Fatigue (32%)
- Musculoskeletal pain (26%)
- Diarrhea (22%)
- Dyspnea (21%)
- Pyrexia (20%)
- Constipation (20%)
- Infections (including opportunistic infections)
- Hemorrhage
- Cytopenias
- Atrial fibrillation/flutter
- Second primary malignancies
Monitoring Parameters
- Complete blood counts (baseline and periodically during treatment)
- Signs and symptoms of infection
- Signs and symptoms of bleeding
- Cardiac monitoring (especially in patients with cardiac risk factors)
- Skin examinations for new malignancies
- Liver function tests
Patient Education
- Take Jaypirca exactly as prescribed at the same time each day
- Report signs of infection (fever, chills), unusual bleeding or bruising, dizziness, palpitations, or shortness of breath
- Use effective contraception during treatment and for at least one week after final dose
- Inform all healthcare providers about all medications being taken, including over-the-counter drugs and supplements
- Do not grapefruit or Seville oranges during treatment
- Keep all follow-up appointments for monitoring
References
1. FDA Approval Package: Jaypirca (pirtobrutinib). U.S. Food and Drug Administration. 2023. 2. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. 3. Woyach JA, Blachly JS, Rogers KA, et al. Acalabrutinib plus obinutuzumab in treatment-naïve chronic lymphocytic leukemia: five-year follow-up of the ELEVATE-TN study. J Clin Oncol. 2023;41(6):1224-1235. 4. Jaypirca [package insert]. Indianapolis, IN: Lilly USA, LLC; 2023. 5. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 3.2023.