Pharmacokinetics Of Tucatinib In Healthy And Hepatically-Impaired Volunteers.

Abstract Background: Tucatinib (TUKYSA®) is a selective HER2-targeted tyrosine kinase inhibitor indicated in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen, including patients with brain metastases. Tucatinib is cleared via CYP2C8-mediated metabolism, to a lesser extent by CYP3A, and biliary excretion. Impaired hepatic function (HI) can cause alterations in drug disposition and pharmacokinetics (PK), thus characterizing PK in subjects with HI was necessary to inform dosing recommendations. ONT-380-009 was a clinical study conducted to evaluate the PK of tucatinib in volunteers with HI based on Child-Pugh (CP) score compared to matched healthy subject controls. Methods: Volunteers (N=37) at 4 centers were enrolled in the study. Subjects with mild (CP Class A; n=8), moderate (CP Class B; n=8) or severe (CP Class C; n=6) HI were matched to subjects with normal hepatic function (n=15) by age, BMI and sex. Tucatinib was administered as a single 300 mg oral dose. Plasma samples were collected for PK analysis and tucatinib concentrations measured using validated LC-MS/MS methods. The PK and safety profiles between each HI group and matched controls were compared. Results: Tucatinib single dose PK was similar between subjects with mild HI and matched controls (AUCinf and Cmax geometric mean ratios (GMR) [90% CI] were 99.0% [76.3%, 128%] and 104% [61.6%, 175%], respectively). Tucatinib plasma exposures were generally higher in subjects with moderate or severe HI compared to matched controls (AUCinf GMR [90% CI] were 115% [65.3%, 202%] and 161% [67.3%, 385%], respectively; Cmax GMR [90% CI] were 88.5% [42.1%, 186%] and 117% [36.6%, 377%], respectively). Changes were highly variable, and ratios crossed 1.0 (or 100%). The observed trend of increased plasma exposure for tucatinib by degree of HI did not reach statistical significance due to high inter-subject variability. Three subjects experienced a total of two Grade 1 (nausea, dermatitis) and one Grade 2 (increased transaminases) treatment-emergent adverse events (TEAEs) in the study, two of which were considered tucatinib-related. All three TEAEs recovered. No TEAEs were observed in patients with moderate or severe hepatic impairment. Conclusions: Subjects with mild HI had similar tucatinib exposures compared to subjects with normal hepatic function. Tucatinib exposure was generally increased in subjects with moderate and severe HI, however GMR values were less than 2-fold and exhibited large inter-subject variability. Overall, a single 300 mg oral dose of tucatinib was considered safe and well tolerated in this study for subjects with normal hepatic function or with mild, moderate, or severe HI. The 1.6-fold GMR AUCinf increase in severe HI subjects support dose reduction from 300 mg BID to 200 mg BID in those subjects; no dose adjustment is recommended for subjects with mild or moderate HI. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, JoAl G. Mayor, Hao Sun, Layth I. Abdulrasool, Evelyn L. Rustia, Luke Walker, Christopher J. Endres. Pharmacokinetics of tucatinib in healthy and hepatically-impaired volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1371.