GAVRETO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GAVRETO (GAVRETO).
Gavreto (pralsetinib) is a potent and selective RET kinase inhibitor. It inhibits wild-type RET and oncogenic RET fusions and mutations (including RET V804L, V804M, and M918T), leading to inhibition of RET-mediated signaling and tumor cell growth.
| Metabolism | Primarily metabolized by CYP3A4 and CYP3A5; major metabolite is M1 (desmethyl pralsetinib). |
| Excretion | Primarily hepatic metabolism; 60% excreted in feces as metabolites, 25% in urine as metabolites; <1% unchanged in urine. |
| Half-life | Terminal half-life approximately 53 hours; supports once-daily dosing with steady state reached within 2-3 weeks. |
| Protein binding | 99.8% bound to plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Vd/F approximately 178 L (2.5 L/kg for 70 kg); large distribution indicates extensive tissue penetration. |
| Bioavailability | Oral bioavailability approximately 70%; high-fat meal reduces Cmax and AUC by 30-50% (administer on empty stomach). |
| Onset of Action | Oral: Clinical antineoplastic effect observed within 2 weeks of initiation based on tumor response assessments. |
| Duration of Action | Continuous suppression of RET-driven signaling; duration limited by disease progression or unacceptable toxicity. |
| Molecular Weight | 533.56 |
400 mg orally once daily with or without food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. For GFR <30 mL/min or ESRD, no specific recommendation available; use caution. |
| Liver impairment | Child-Pugh A: No dose adjustment. Child-Pugh B: Reduce dose to 300 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established; no specific dosing recommendations available. |
| Geriatric use | No specific dose adjustment required based on age alone; monitor for renal function and potential drug interactions. |
| 1st trimester | Contraindicated. Based on mechanism of action (RET kinase inhibitor), there is potential for embryofetal toxicity; animal studies show teratogenicity and fetal loss. |
| 2nd trimester | Contraindicated. Similarly high risk; no human data but animal reproductive studies indicate adverse effects. |
| 3rd trimester | Contraindicated. Potential for fetal harm; risk outweighs any potential benefit. |
Clinical note
Comprehensive clinical and safety monograph for GAVRETO (GAVRETO).
| Placental transfer | Pralsetinib is expected to cross the placenta due to its molecular weight and lipophilicity; animal studies confirm placental transfer. |
| Breastfeeding | It is unknown if pralsetinib is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 1 week after the last dose. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
Hypersensitivity to pralsetinib or any excipients
| Precautions | Interstitial lung disease (ILD)/pneumonitis, Hypertension, Hepatotoxicity, Hemorrhage, Tumor lysis syndrome, Risk of impaired wound healing, Hypothyroidism, Embryo-fetal toxicity |
| Food/Dietary | Avoid grapefruit, grapefruit juice, and Seville oranges as they inhibit CYP3A4 and may increase pralsetinib exposure. No other dietary restrictions are required. |
| Clinical Pearls | Gavreto (pralsetinib) is a selective RET inhibitor indicated for RET fusion-positive non-small cell lung cancer (NSCLC) and RET-mutant medullary thyroid cancer (MTC). Monitor for serious adverse reactions including interstitial lung disease (ILD), pneumonitis, hypertension, hepatotoxicity, hemorrhage, and tumor lysis syndrome. Dose reduction may be required for strong CYP3A4 inhibitors or moderate CYP3A4 inducers. Avoid coadministration with strong CYP3A4 inducers. Assess AST, ALT, and bilirubin prior to initiation, then monthly for 3 months, and as clinically indicated. Monitor blood pressure at baseline and regularly thereafter. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Based on its mechanism of action (RET inhibitor) and animal studies, GAVRETO (pralsetinib) is expected to cause fetal harm. There are no human data. In animal reproduction studies, pralsetinib caused embryofetal toxicity and malformations at maternal exposures lower than the human exposure at the recommended dose. Advise pregnant women of the potential risk to a fetus. First trimester: Highest risk for major congenital malformations. Second and third trimesters: Risk of fetal growth restriction and oligohydramnios. |
| Fetal Monitoring | Monitor pregnant women with serial ultrasounds to assess fetal growth and amniotic fluid volume. Monitor for maternal hypertension and proteinuria. Avoid use during pregnancy unless no safer alternative and potential benefit justifies potential fetal risk. |
| Fertility Effects | Based on animal studies, pralsetinib may impair male and female fertility. In male rats, testicular degeneration and reduced sperm counts were observed. In female rats, ovarian effects including decreased corpora lutea and fertility index were noted. Human fertility effects are unknown but potentially reversible. |
| Patient Advice | Take Gavreto exactly as prescribed, usually twice daily with or without food. · Avoid grapefruit, grapefruit juice, and Seville oranges during treatment as they may interact with the medication. · Report any new or worsening respiratory symptoms such as cough, shortness of breath, or fever immediately. · Notify your healthcare provider if you experience signs of liver problems like yellowing of skin or eyes, dark urine, or right upper quadrant pain. · Gavreto can cause high blood pressure; monitor blood pressure regularly and report elevations. · Use effective contraception during treatment and for 2 weeks after the last dose if you are of childbearing potential. · Do not breastfeed while taking Gavreto and for 1 week after the last dose. · Inform your doctor of all medications you are taking, including over-the-counter drugs and supplements. · Avoid driving or operating machinery if you experience dizziness or fatigue. |