Tucatinib tablets are used in combination with trastuzumab and capecitabine for the treatment of adult patients with advanced, unresectable, or metastatic HER2-positive breast cancer. This includes patients with brain metastases who have previously received one or more anti-HER2 therapies in the metastatic setting.

Tucatinib is a tyrosine kinase inhibitor that targets HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, leading to suppression of downstream MAPK and AKT signaling pathways and inhibition of cell proliferation. It has demonstrated antitumor activity in HER2-expressing tumor cells. In vivo studies have shown that tucatinib suppresses the growth of HER2-expressing tumors. The combination of tucatinib with trastuzumab has demonstrated enhanced antitumor effects both in vitro and in vivo compared with either agent alone.

Exposure-Response Relationship: The relationship between tucatinib exposure and response, as well as the time course of pharmacodynamic effects, has not been fully established.

Cardiac Electrophysiology: No clinically significant increase in QTc interval (i.e., >20 ms) has been observed following administration of tucatinib at the recommended oral dose of 300 mg twice daily.

Pharmacokinetics: Tucatinib AUC₀–INF and Cmax increase proportionally over a dose range of 50 mg to 300 mg (0.17 to 1 times the approved recommended dose). Following administration of tucatinib 300 mg twice daily for 14 days, accumulation was approximately 1.7-fold for AUC and 1.5-fold for Cmax. Steady-state concentrations are achieved in approximately 4 days.

Absorption: The median time to reach peak plasma concentration (Tmax) of tucatinib is approximately 2 hours (range: 1 to 4 hours).

Distribution: The geometric mean apparent volume of distribution of tucatinib is approximately 1670 L (66%). Plasma protein binding is about 97.1% at clinically relevant concentrations.

Elimination: The geometric mean half-life of tucatinib is approximately 8.5 hours (21%), and the apparent clearance is 148 L/h (55%).

Metabolism: Tucatinib is primarily metabolized by CYP2C8 and to a lesser extent by CYP3A.

Excretion: After a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the dose is recovered in feces (including 16% as unchanged drug) and 4.1% in urine, with a total recovery of about 90% within 13 days. In plasma, approximately 76% of the radioactivity corresponds to unchanged tucatinib, 19% to identified metabolites, and about 5% remains uncharacterized.

Recommended Dosage: The recommended dosage of Tucatinib is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity. Patients are advised to swallow Tucatinib tablets whole and not to chew, crush, or split prior to swallowing. Patients are advised not to ingest tablet if it is broken, cracked, or not otherwise intact. Patients are advised to take Tucatinib approximately 12 hours apart and at the same time each day with or without a meal. If the patient vomits or misses a dose of Tucatinib, Patients are advised to take the next dose at its usual scheduled time. When given in combination with Tucatinib, the recommended dosage of capecitabine is 1000 mg/m² orally twice daily taken within 30 minutes after a meal. Tucatinib and capecitabine can be taken at the same time.

Dosage Modifications for Severe Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 200 mg orally twice daily.

Dosage Modifications for Concomitant Use with Strong CYP2C8 Inhibitors: Avoid concomitant use of strong CYP2C8 inhibitors with Tucatinib. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the Tucatinib dose that was taken prior to initiating the inhibitor.

Clinically important side effects of Tucatinib include diarrhea and liver toxicity.
Common side effects (reported in more than 20% of patients) include diarrhea, hand-foot syndrome (palmar-plantar erythrodysesthesia), nausea, fatigue, liver toxicity, vomiting, mouth sores, decreased appetite, abdominal pain, headache, anemia, and skin rash.

Pregnancy: Tucatinib is used in combination with trastuzumab and capecitabine. Based on findings in animals and its mechanism of action, Tucatinib can cause fetal harm when administered to a pregnant woman. There are no available human data on Tucatinib use in pregnant women to inform a drug-associated risk. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Lactation: Tucatinib is used in combination with trastuzumab and capecitabine. There are no data on the presence of Tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Tucatinib and for at least 1 week after the last dose.

Diarrhea: Tucatinib may cause severe diarrhea, which can lead to dehydration, low blood pressure, kidney injury, and even death. If diarrhea occurs, appropriate antidiarrheal treatment should be given, and dose adjustment or discontinuation may be required depending on severity.

Hepatotoxicity: Tucatinib may cause serious liver injury. Liver function tests (ALT, AST, bilirubin) should be monitored before and during treatment. Dose modification or discontinuation may be required in severe cases.

Embryo-Fetal Toxicity: Tucatinib may cause harm to an unborn baby. Women of reproductive age should use effective contraception during treatment and for at least 1 week after the last dose. Male patients should also take precautions.

Pediatric Use: The safety and effectiveness of Tucatinib in pediatric patients have not been established.

Renal Impairment: The use of Tucatinib in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (ClCr < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment (ClCr 30 to 89 mL/min).

Hepatic Impairment: Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of Tucatinib for patients with severe (Child-Pugh C) hepatic impairment. No dose adjustment for Tucatinib is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

There is no specific antidote for Tucatinib overdose. In such cases, treatment should be stopped and supportive care should be provided.

Cytotoxic chemotherapy

Store below 25°C in a cool, dry place. Protect from light and keep out of reach of children.