TUKYSA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TUKYSA (TUKYSA).
Tucatinib is a tyrosine kinase inhibitor that selectively inhibits HER2 phosphorylation, thereby inhibiting downstream signaling pathways (MAPK and PI3K/Akt) and cell proliferation.
| Metabolism | Primarily metabolized by CYP2C8, with minor contributions from CYP3A4. |
| Excretion | Primarily fecal (86%) as unchanged drug; renal excretion accounts for <10% of the dose. |
| Half-life | Mean terminal elimination half-life is 30.3 hours (range 21-48 hours), supporting once-daily dosing with steady state achieved by 3 weeks. |
| Protein binding | 98% bound to human plasma proteins (mainly albumin and alpha-1 acid glycoprotein). |
| Volume of Distribution | Mean apparent volume of distribution (Vd/F) is 464 L (approximately 6.6 L/kg for 70 kg patient), indicating extensive extravascular distribution. |
| Bioavailability | Absolute oral bioavailability is approximately 48% (range 30-70%) under fasted conditions; food increases absorption (AUC increased by 1.5-fold with high-fat meal). |
| Onset of Action | Clinical effect on tumor growth inhibition occurs within 2 weeks of starting oral dosing based on early tumor response assessments. |
| Duration of Action | Sustained HER2 inhibition throughout the 24-hour dosing interval; continuous daily dosing required for maintained effect. |
| Molecular Weight | 585.68 |
300 mg orally twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl 30-89 mL/min). Insufficient data for severe renal impairment (CrCl <30 mL/min) or dialysis; use with caution. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce to 200 mg orally twice daily. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No overall differences in safety or efficacy observed, but greater sensitivity in elderly patients cannot be ruled out; monitor for adverse effects. |
| 1st trimester | Avoid. Pregnancy must be excluded before starting. Use effective contraception. Based on animal studies, it can cause fetal harm. |
| 2nd trimester | Avoid. No human data, but potential for teratogenicity and embryotoxicity. |
| 3rd trimester | Avoid. Potential harm to fetus; consider risk-benefit. |
Clinical note
Comprehensive clinical and safety monograph for TUKYSA (TUKYSA).
| Placental transfer | Based on molecular weight (average 585.68 Da) and animal studies, tucatinib is likely to cross the placenta. Human placental transfer data are not available. |
| Breastfeeding | It is not known whether tucatinib is excreted in human milk. Due to the potential for serious adverse reactions, advise women not to breastfeed during treatment and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to tucatinib or any excipientsPregnancy
| Precautions | Diarrhea: Severe diarrhea including dehydration and acute kidney injury may occur; monitor and manage aggressively., Hepatotoxicity: Elevated liver enzymes and bilirubin; monitor liver function before and during treatment., Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential and males with female partners of effective contraception. |
| Food/Dietary | Take with food (high-fat meal increases AUC by 58%). Avoid grapefruit juice due to CYP3A4 modulation. |
| Clinical Pearls |
Loading safety data…
| Lactation Rating |
| L5 (Contraindicated) |
| Teratogenic Risk | Tucatinib (TUKYSA) is a tyrosine kinase inhibitor. Based on its mechanism of action and animal studies, there is potential for fetal harm. In rat and rabbit studies, maternal toxicity and fetal abnormalities (including skeletal and visceral malformations) were observed at exposures within clinical range. No human data exist. First trimester exposure carries highest risk for major malformations; second and third trimester exposure may affect fetal growth and organ maturation due to inhibition of HER2 signaling involved in development. |
| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) monthly and as clinically indicated due to hepatotoxicity risk. Monitor for diarrhea and electrolyte imbalances. Perform pregnancy testing before initiating therapy and advise effective non-hormonal contraception during treatment and for 1 week after last dose. If accidental exposure during pregnancy, consider ultrasound to assess fetal anatomy and growth. |
| Fertility Effects | In animal studies, tucatinib caused testicular toxicity (degeneration of seminiferous tubules) in male rats and ovarian follicular atrophy in female rats at clinically relevant doses, potentially impairing fertility. No human data; based on mechanism, may impair both male and female fertility. Advise patients about potential reproductive risks. |
| Administer with food to enhance bioavailability and reduce gastrointestinal adverse effects. Monitor for hepatotoxicity with baseline and periodic LFTs; hold for ALT/AST >3x ULN with bilirubin >2x ULN. Avoid strong CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampin) due to significant drug interaction risk. Assess LVEF before and during therapy due to potential cardiac toxicity. |
| Patient Advice | Take with food to increase absorption and reduce nausea and diarrhea. · Report signs of liver problems: yellow skin/eyes, dark urine, right upper quadrant pain. · Avoid grapefruit and grapefruit juice while taking this medication. · Use effective contraception during treatment and for at least 1 week after the last dose. · Inform your doctor of all other medications, including over-the-counter and herbal supplements. |