The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment

Abstract

Background and Objective Tucatinib, a highly selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved for HER2-positive metastatic breast cancer, is cleared by hepatic metabolism and subsequent biliary excretion. Liver disease can alter drug disposition and pharmacokinetics (PK). The objective of this study is to characterize PK and safety of tucatinib in volunteers with hepatic impairment. Methods This Phase 1 study compared the PK and safety of a single 300-mg oral dose of tucatinib in volunteers with mild, moderate, and severe hepatic impairment (Child-Pugh A/B/C) to healthy volunteers matched for sex, age, and body mass index. Pharmacokinetic parameters were determined for tucatinib and its predominant metabolite ONT-993. Results Compared with healthy volunteers, tucatinib exposure was similar in volunteers with mild impairment and increased in those with moderate or severe impairment without reaching statistical significance. Respective fold increases in geometric mean ratios for AUC 0-t and AUC 0-∞ were 1.13 and 1.15 in moderate impairment, and 1.43 and 1.61 in severe impairment compared with healthy volunteers. Three treatment-emergent adverse events (nausea, dermatitis, and increased transaminases) were reported in three volunteers and showed no obvious association with hepatic impairment status. Conclusion The 1.61-fold geometric mean ratio AUC 0-∞ increase in volunteers with severe hepatic impairment supports the recommendation in the tucatinib prescribing information to reduce the dose from 300 mg twice daily to 200 mg twice daily in patients with severe impairment; no dose adjustment is recommended for patients with mild or moderate hepatic impairment. This trial (NCT03722823) was registered on October 29, 2018. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01183-6 .

HER3 V104 mutations regulate cell signaling, growth, and drug sensitivity in cancer

“…Our data indicated that HCC1569HER3KO cells expressing HER3 WT/V104L had reduced cell proliferation and viability in response to increasing concentration of tucatinib (1.5 −5.0 µM) (Figure 2D,E and Figure ). Since tucatinib has a shorter half‐life (~8.67 h), 36 HCC1569HER3KO cells stably expressing HER3 WT or HER3 V104L were subjected to 1.5 µM tucatinib for 1–4 h and our immunoblotting data showed that 1.5 µM tucatinib suppressed HER2 activation in both HCC1569HER3KO expressing HER3 WT/V104L in time dependent manner (Figure 2F and Figure ). We used another pan‐HER inhibitor, afatinib on HCC1569HER3KO cells expressing HER3‐WT and HER3‐V104L.…”

“…Figure S3C). Since tucatinib has a shorter half-life (~8.67 h),36 HCC1569HER3KO cells stably expressing HER3 WT or HER3 V104L were subjected to 1.5 µM tucatinib for 1-4 h and our immunoblotting data showed that 1.5 µM tucatinib suppressed HER2 activation in both HCC1569HER3KO expressing HER3 WT/V104L in time dependent manner (Figure2Fand FigureS3D).We used another pan-HER inhibitor, afatinib on HCC1569HER3-KO cells expressing HER3-WT and HER3-V104L. Our data showed that afatinib in a dose dependent manner (0.25−1 µM) inhibited both HER3-WT and HER3-V104L cell proliferation (FigureS4A-C).…”

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib

“…2 Geometric mean oral clearance after a single 300 mg tablet dose was ~ 109 L/h. 3 Due to the moderate-high clearance and low-moderate distribution volume of tucatinib, the elimination half-life in human was ~ 9 hours, 3 requiring b.i.d. administration to maintain drug levels.…”

“…Tucatinib fraction absorbed was assumed to be 50% based on mass‐balance data 2 . Geometric mean oral clearance after a single 300 mg tablet dose was ~ 109 L/h 3 . Due to the moderate‐high clearance and low‐moderate distribution volume of tucatinib, the elimination half‐life in human was ~ 9 hours, 3 requiring b.i.d.…”