Abstract
We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies. In Study 1, subjects with normal hepatic fiction or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group).
In Study 2, patiens with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days. In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, Langer half-life, and reduced plasma metabolite levels.
In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between Gross in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts.
We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.