Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteers.

Autor: Topletz-Erickson A; Clinical Pharmacology and Pharmacometrics, Seagen Inc., 21823 30th Drive SE, Bothell, WA, 98021, USA., Lee A; Translational ADME and PKPD, Seagen Inc., Bothell, WA, USA., Rustia EL; Clinical Development, Seagen Inc., Bothell, WA, USA.; Gilead Sciences, Seattle, WA, USA., Sun H; Translational ADME and PKPD, Seagen Inc., Bothell, WA, USA., Mayor JG; Clinical Development, Seagen Inc., Bothell, WA, USA., Abdulrasool LI; Clinical Development, Seagen Inc., Bothell, WA, USA., Walker L; Clinical Development, Seagen Inc., Bothell, WA, 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 Oct; Vol. 61 (10), pp. 1417-1426. Date of Electronic Publication: 2022 Aug 06.
DOI: 10.1007/s40262-022-01144-z
Abstrakt: Background and Objective: Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.
Methods: Parts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).
Results: Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC 0-inf ) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC 0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.
Conclusion: The potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.
Trial Registration: This trial (NCT03723395) was registered on October 29, 2018.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: