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

Abstract

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 (AUC0-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 AUC0-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.

Conflict of interest statement

This study was funded by Seagen Inc. The authors wrote the article with the assistance of a medical writer funded by the sponsor. All the authors had full access to the relevant data, vouch for the completeness and accuracy of the data and for adherence of the trial to the protocol, assume final responsibility for the content of the article, and for the decision to submit the article for publication. A. Topletz-Erickson, A. Lee, E.L. Rustia, H. Sun, J.G. Mayor, L.I. Abdulrasool, L. Walker, and C.J. Endres are employees of Seagen and hold stocks and shares in Seagen. No authors are Fellows of the American College of Clinical Pharmacology.

© 2022. The Author(s).

Figures

Fig. 1

Study schematics for assessing A the effect of comedications on tucatinib plasma exposure, and B the effect of steady-state tucatinib on the plasma exposure of co-administered drugs. BID twice daily, D day, ITZ itraconazole, MDZ midazolam, PK pharmacokinetics, QD once daily, RIF rifampin, TUC tucatinib

Fig. 2

Tucatinib plasma concentration profiles (A, D, G), AUC0–inf values (B, E, H), and Cmax values (C, F, I) in the absence and presence of steady-state itraconazole (A–C), rifampin (D–F), or gemfibrozil (G–I). Solid lines inside the box plots represent the median. The boxes represent the 25th and 75th percentile and the whiskers represent the minimum and maximum values. AUC0–inf area under the concentration–time curve from time 0 extrapolated to infinity, Cmax maximum observed concentration, CYP cytochrome P450, GEM gemfibrozil, ITZ itraconazole, RIF rifampin

Fig. 3

Plasma concentration profiles, AUC0–inf values, and Cmax values of midazolam (A–C), repaglinide (D–F), tolbutamide (G–I), or digoxin (J–L) in the absence and presence of steady-state tucatinib. Solid lines inside the box plots represent the median. The boxes represent the 25th and 75th percentile and the whiskers represent the minimum and maximum values. AUC0–inf area under the concentration–time curve from time 0 extrapolated to infinity, Cmax maximum observed concentration, CYP cytochrome P450, MDZ midazolam, P-gp P-glycoprotein, TUC tucatinib