Introduction
Vonjo (pacritinib) is an oral kinase inhibitor approved for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis with platelet counts below 50 × 10⁹/L. This novel therapeutic agent represents a significant advancement for patients with cytopenic myelofibrosis who have limited treatment options due to thrombocytopenia.
Mechanism of Action
Pacritinib is a multikinase inhibitor with activity against Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Unlike other JAK inhibitors, pacritinib demonstrates greater specificity for JAK2 over JAK1, which may contribute to its improved hematologic tolerability profile. The drug also inhibits additional kinases including IRAK1 and CSF1R, which may contribute to its clinical effects in reducing inflammatory cytokines and improving disease-related symptoms.
Indications
Vonjo is indicated for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis with platelet counts below 50 × 10⁹/L. This includes patients with:
- Primary myelofibrosis
- Post-polycythemia vera myelofibrosis
- Post-essential thrombocythemia myelofibrosis
Dosage and Administration
Recommended dosage: 200 mg orally twice daily with or without food Dose modifications:- Hepatic impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh C)
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment; use caution in severe impairment
- Management of adverse reactions: Dose interruption or reduction to 100 mg twice daily may be necessary
- Swallow tablets whole with water
- Do not crush, chew, or split tablets
- If a dose is missed, take as soon as possible unless the next dose is due within 6 hours
Pharmacokinetics
Absorption: Median Tmax is approximately 4 hours post-dose. Food does not significantly affect exposure. Distribution: Apparent volume of distribution is approximately 1,760 L. Protein binding is >99%. Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9, CYP2D6, and CYP2E1. Elimination: Mean elimination half-life is approximately 28 hours. Excretion is primarily fecal (80%) with minor renal elimination (10%).Contraindications
- Hypersensitivity to pacritinib or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors
- Concomitant use with strong CYP3A4 inducers
Warnings and Precautions
Hemorrhage: Serious and fatal hemorrhages have occurred. Monitor patients for bleeding and manage promptly. QTc Prolongation: May prolong QTc interval. Avoid use in patients with baseline QTc >480 ms or certain arrhythmias. Monitor electrolytes and ECGs. Gastrointestinal Toxicity: Diarrhea, nausea, and vomiting may occur. Provide anti-diarrheal and anti-emetic prophylaxis. Infections: Serious infections, including opportunistic infections, may occur. Monitor for signs and symptoms of infection. Thrombocytopenia: May cause worsening thrombocytopenia. Monitor platelet counts regularly. Hepatotoxicity: Liver enzyme elevations may occur. Monitor liver function tests regularly.Drug Interactions
Strong CYP3A4 Inhibitors: Concomitant use increases pacritinib exposure approximately 2-fold. Avoid concomitant use. Strong CYP3A4 Inducers: Concomitant use decreases pacritinib exposure approximately 70%. Avoid concomitant use. QTc-Prolonging Drugs: May have additive effects on QTc prolongation. Avoid concomitant use with other drugs known to prolong QTc. Acid-Reducing Agents: Proton pump inhibitors may decrease pacritinib exposure. Separate administration by at least 2 hours.Adverse Effects
Most common adverse reactions (≥20%):- Diarrhea (52%)
- Thrombocytopenia (39%)
- Nausea (35%)
- Anemia (32%)
- Vomiting (21%)
- Hemorrhage (9%)
- Infections (8%)
- Cardiac arrhythmias (2%)
- Hepatotoxicity (2%)
Monitoring Parameters
Baseline:- Complete blood count with differential
- Comprehensive metabolic panel including liver function tests
- ECG with QTc measurement
- Electrolytes (potassium, magnesium, calcium)
- Assessment of bleeding risk
- CBC weekly for first 12 weeks, then periodically
- Liver function tests every 2 weeks for first 3 months, then monthly
- ECG at weeks 2, 4, and 8, then periodically
- Electrolytes as clinically indicated
- Signs and symptoms of bleeding, infection, and gastrointestinal toxicity
Patient Education
- Take Vonjo exactly as prescribed at approximately the same times each day
- Report any signs of bleeding (unusual bruising, blood in urine or stool)
- Monitor for diarrhea and report severe or persistent cases
- Inform all healthcare providers about Vonjo use before starting new medications
- Avoid grapefruit and grapefruit juice during treatment
- Report symptoms of infection (fever, chills, cough)
- Regular monitoring of blood tests and ECGs is essential
- Use effective contraception during treatment and for at least 2 weeks after final dose
- Do not stop treatment without discussing with healthcare provider
References
1. FDA Prescribing Information: Vonjo (pacritinib) capsules. 2022. 2. Mascarenhas J, et al. Pacritinib vs Best Available Therapy for Myelofibrosis. JAMA Oncol. 2022;8(5):1-10. 3. Gerds AT, et al. Phase 3 trial of pacritinib in patients with myelofibrosis and thrombocytopenia. Leukemia. 2022;36(5):1371-1376. 4. National Comprehensive Cancer Network. Myeloproliferative Neoplasms Guidelines. Version 3.2023. 5. ClinicalTrials.gov: PERSIST-1 and PERSIST-2 trials (NCT01773187, NCT02055781).