The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment.

Autor: Topletz-Erickson AR; Clinical Pharmacology and Pharmacometrics, Seagen Inc., 21823 30th Drive SE, Bothell, WA, 98021, USA., Lee AJ; Translational ADME and PKPD, Seagen Inc., Bothell, WA, USA., Mayor JG; Clinical Development, Seagen Inc., Bothell, WA, USA., Sun H; Translational ADME and PKPD, Seagen Inc., Bothell, WA, USA., Abdulrasool LI; Clinical Development, Seagen Inc., Bothell, WA, USA., Rustia EL; Clinical Development, Seagen Inc., Bothell, WA, USA.; Gilead Sciences, Seattle, WA, USA., Walker LN; Clinical Development, Seagen Inc., Bothell, WA, USA.; Harpoon Therapeutics, South San Francisco, CA, USA., Endres CJ; Clinical Pharmacology and Pharmacometrics, Seagen Inc., 21823 30th Drive SE, Bothell, WA, 98021, USA. CEndres@seagen.com.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2022 Dec; Vol. 61 (12), pp. 1761-1770. Date of Electronic Publication: 2022 Dec 05.
DOI: 10.1007/s40262-022-01183-6
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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