Investigation of the impact of hepatic impairment on the pharmacokinetics of dacomitinib.

ABSTRACT

Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment.