Tukanic

Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, it blocks phosphorylation of HER2 and HER3, which inhibits downstream MAPK and AKT signaling and cell proliferation, and it showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. Tucatinib and trastuzumab together showed increased anti-tumor activity in vitro and in vivo compared to either drug alone. Exposure response relationship: the exposure-response relationships of tucatinib and the time course of its pharmacodynamic response have not been fully characterized. Cardiac electrophysiology: no large mean increase in QTc (i.e., > 20 ms) was detected after treatment with tucatinib at the recommended dose of 300 mg taken orally twice daily. Pharmacokinetics: tucatinib AUC0-INF and Cmax increase proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). After 300 mg twice daily for 14 days, tucatinib showed 1.7-fold accumulation for AUC and 1.5-fold accumulation for Cmax. Time to steady state was approximately 4 days. Absorption: the median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours). Distribution: the geometric mean (CV%) apparent volume of distribution of tucatinib was approximately 1670 L (66%). Plasma protein binding was 97.1% at clinically relevant concentrations. Elimination: the geometric mean (CV%) half-life of tucatinib was approximately 8.5 (21%) hours, and apparent clearance was 148 L/h (55%). Metabolism: tucatinib is metabolized mainly by CYP2C8 and, to a lesser extent, by CYP3A. Excretion: after a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine, giving an overall total recovery of 90% within 13 days after the dose. In plasma, approximately 76% of the radioactivity was unchanged tucatinib, 19% was attributed to identified metabolites, and approximately 5% was unassigned.

Pregnancy: Tucatinib is given together with trastuzumab and capecitabine. Animal findings and the way the medicine works suggest that Tucatinib can harm the baby if a pregnant woman takes it. There are no human data on Tucatinib in pregnant women, so the actual risk is not known. Pregnant women and women who could become pregnant should be told about the possible risk to the baby. For the people this medicine is meant for, the background risk of major birth defects and miscarriage is unknown.

Lactation: Tucatinib is again used with trastuzumab and capecitabine. No data exist on whether Tucatinib or its metabolites pass into human or animal milk, or what they might do to a breastfed child or to milk production. Because a breastfed child could have serious adverse reactions, women should be advised not to breastfeed while on Tucatinib and for at least 1 week after the last dose.

Pediatric use: The safety and effectiveness of Tucatin in pediatric patients have not been established.

Renal impairment: Tucatin is not recommended together with capecitabine and trastuzumab in patients with severe renal impairment (ClCr < 30 mL/min, estimated by the Cockcroft-Gault Equation). The reason is that capecitabine is contraindicated in severe renal impairment. Patients with mild or moderate renal impairment (ClCr 30 to 89 mL/min) don't need a dose adjustment.

Hepatic impairment: Exposure to Tucatin is increased in patients with severe hepatic impairment (Child-Pugh C), so the dose of Tucatin should be reduced for them. For mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, no dose adjustment of Tucatin is required.

There's no specific antidote for a Tucatin overdose, and it isn't known whether haemodialysis helps. If an overdose happens, stop Tucatin and give general supportive care.

Keep Tucatinib below 25°C, in a cool and dry place. Keep it away from light, and keep it out of the reach of children.