AYVAKIT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AYVAKIT (AYVAKIT).
Avapritinib is a tyrosine kinase inhibitor that selectively targets platelet-derived growth factor receptor alpha (PDGFRA) activation loop mutants, including D842V mutations, and KIT exon 17 mutants. It inhibits PDGFRA D842V and KIT D816V with IC50 values of 0.24 nM and 0.27 nM, respectively.
| Metabolism | Avapritinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP3A5. Minor contributions from CYP2C9 and CYP2C19. |
| Excretion | Primarily hepatobiliary excretion; 77% of dose recovered in feces (predominantly as metabolites) and 19% in urine (<1% unchanged). |
| Half-life | Terminal elimination half-life approximately 14.8 hours (range 11-20 hours) supporting once-daily dosing. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 162 L (2.2 L/kg for a 70 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 66% under fasting conditions; absorption is enhanced with a high-fat meal (2.1-fold increase in AUC). |
| Onset of Action | Clinical effects observed within 1-2 weeks of oral administration; symptomatic improvement may occur by 4 weeks. |
| Duration of Action | Duration covers the 24-hour dosing interval; continuous daily dosing required for sustained effect. |
300 mg orally once daily with or without food, swallowed whole; do not crush or chew tablets.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment recommended for mild to moderate renal impairment (CrCl ≥30 mL/min). Severe renal impairment (CrCl <30 mL/min) not studied; use with caution. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 200 mg once daily. Child-Pugh C: reduce dose to 100 mg once daily. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no dosing recommendations available. |
| Geriatric use | No specific dose adjustment recommended based on age alone; monitor for increased adverse effects due to age-related renal or hepatic decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AYVAKIT (AYVAKIT).
| Breastfeeding | No data are available on the presence of avapritinib or its metabolites in human milk, effects on the breastfed child, or effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with AYVAKIT and for at least 2 weeks after the last dose. The M/P ratio is unknown. |
| Teratogenic Risk | Based on its mechanism of action (inhibition of KIT and PDGFRA), AYVAKIT (avapritinib) is expected to cause fetal harm when administered to a pregnant woman. There are no available human data. In animal studies, avapritinib caused embryo-fetal mortality and structural abnormalities at maternal exposures below the clinical exposure at the recommended dose. First trimester exposure poses the highest risk for major congenital malformations; second and third trimester exposure risks include fetal growth restriction and oligohydramnios. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None listed in prescribing information.","Relative: Concomitant use with strong CYP3A4 inducers or inhibitors should be avoided or dose-adjusted."]
| Precautions | ["Intracranial hemorrhage: Fatal and serious intracranial hemorrhage can occur.","Cognitive effects: Can cause cognitive adverse reactions, including confusion, memory impairment, and encephalopathy.","Fluid retention: Can lead to severe edema and pleural effusions.","Cardiotoxicity: Prolongation of QT interval and left ventricular dysfunction.","Hepatotoxicity: Elevations in liver enzymes.","Embryo-fetal toxicity: Can cause fetal harm."] |
| Food/Dietary | Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit. Take on empty stomach. High-fat meals increase absorption and risk of toxicity. |
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| Fetal Monitoring | Monitor pregnancy status in women of reproductive potential prior to initiating treatment, monthly during treatment, and after treatment discontinuation. If pregnancy occurs, immediate consultation with an obstetrician and maternal-fetal medicine specialist is recommended. Serial ultrasounds should be considered to assess fetal growth and amniotic fluid volume if exposure occurs during the second or third trimester. |
| Fertility Effects | Based on animal studies, AYVAKIT may impair fertility in females and males. In female rats, reduced ovarian weights and altered estrous cycles were observed at exposures below the clinical exposure. In male rats, testicular degeneration and reduced sperm counts occurred at exposures similar to clinical exposure. Reversibility of these effects is unknown. |
| Clinical Pearls | AYVAKIT (avapritinib) is a potent KIT and PDGFRα inhibitor. Monitor for cognitive adverse effects, intracranial hemorrhage, and photosensitivity. Dose reduce for moderate hepatic impairment (Child-Pugh B). Avoid strong CYP3A4 inhibitors and inducers. |
| Patient Advice | Take on empty stomach, at least 1 hour before or 2 hours after a meal. · Avoid grapefruit, grapefruit juice, and Seville oranges. · Report any unusual bleeding, bruising, confusion, or memory problems immediately. · Use sun protection (SPF ≥ 30) and limit sun exposure. · Do not breastfeed while taking this medication. |