VONJO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VONJO (VONJO).
Pacritinib is a Janus kinase 2 (JAK2) and interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitor. It inhibits JAK2 and mutant JAK2V617F, reducing cytokine signaling and proliferation of malignant cells.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2C8; minor contributions from CYP1A2, CYP2C9, CYP2D6, and CYP3A5. |
| Excretion | Primarily metabolized by the liver via CYP3A4 and CYP2C8; ~90% eliminated in feces as metabolites, ~10% in urine as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life approximately 40–60 hours; allows once-daily dosing. Steady-state achieved in 8–14 days. |
| Protein binding | >99% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution (Vd/F) approximately 400–600 L, indicating extensive extravascular distribution and tissue binding. |
| Bioavailability | Oral bioavailability is approximately 5–10% due to extensive first-pass metabolism; absorption is increased with a high-fat meal. |
| Onset of Action | Clinical effect (reduction in palpable spleen size and symptom improvement) observed within 4–8 weeks of oral administration. |
| Duration of Action | Duration of therapeutic effect persists with continued dosing; rebound of symptoms may occur within weeks of discontinuation. Continuous daily dosing is required for sustained response. |
400 mg orally once daily with food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), reduce dose to 200 mg orally once daily. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 200 mg orally once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no recommended dose. |
| Geriatric use | No specific dose adjustment required based on age; monitor renal function and for increased risk of adverse effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VONJO (VONJO).
| Breastfeeding | It is unknown whether pacritinib is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose. No M/P ratio data available. |
| Teratogenic Risk | VONJO (pacritinib) is contraindicated in pregnancy. Based on its mechanism of action (JAK2/IRAK1 inhibition) and animal studies, there is a potential for fetal harm. First trimester: High risk of teratogenicity; embryofetal toxicity observed in rats and rabbits. Second and third trimesters: Continued risk of fetal growth restriction and developmental abnormalities. Adequate contraception is required for females of reproductive potential during treatment and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
Concurrent use of strong CYP3A4 inhibitors or inducers.
| Precautions | ["Hemorrhage","Thrombocytopenia","QTc interval prolongation","Infections","Hepatotoxicity","Gastrointestinal toxicity","Fetal harm"] |
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| Fetal Monitoring | Monitor complete blood count (CBC) with differential, liver function tests, and serum creatinine at baseline and periodically during therapy. Assess pregnancy status in females of reproductive potential prior to initiation. Monitor for signs of infection, bleeding, and thrombosis. Fetal monitoring via ultrasound if pregnancy is suspected or confirmed. |
| Fertility Effects | Based on animal studies, pacritinib may impair fertility in females and males. In rats, decreased fertility and embryonic viability were observed at clinically relevant doses. Effects on human fertility are unknown; advise reproductive potential patients of potential risks. |