In this article, we will discuss Tucatinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
Exposure Response Relationship
Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with Tucatinib at the recommended dose of 300 mg taken orally twice daily.
Tucatinib AUC0-INF and Cmax increases proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Tucatinib exhibited 1.7-fold accumulation for AUC and 1.5-fold accumulation for Cmax following administration of Tucatinib 300 mg twice daily for 14 days. Time to steady state was approximately 4 days.
The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).
Effects of Food
Following administration of a single oral dose of Tucatinib in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not
The geometric mean (CV%) apparent volume of distribution of tucatinib was approximately 1670 L (66%). The
plasma protein binding was 97.1% at clinically relevant concentrations.
The geometric mean (CV%) half-life of tucatinib was approximately 8.5 (21%) hours and apparent clearance was 148 L/h (55%).
Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.
Following 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 with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.