Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Lapatinib is an orally administered tyrosine kinase inhibitor indicated for use in combination with capecitabine to treat advanced or metastatic breast cancers that overexpress ErbB2 in patients previously treated with anthracyclines, taxanes and trastuzumab. • In vitro studies have suggested that lapatinib is metabolized primarily by CYP3A4, that it is a substrate of the efflux transporter ABCB1, and that it is a modest inhibitor of both CYP3A4 and ABCB1. • However, no data regarding the in vivo metabolism of lapatinib have as of yet been reported. WHAT THIS STUDY ADDS • The in vivo pharmacokinetics of lapatinib in healthy subjects was determined in the presence of a potent inhibitor (ketoconazole) or inducer (carbamazepine) of CYP3A4. • The results indicated that systemic exposure to lapatinib was significantly altered by inhibition or induction of CYP3A4. • Thus, dose adjustments may be required when lapatinib is administered orally concomitantly with drugs that potently alter CYP3A4 activity. AIMS To characterize the impact of potent CYP3A4 inhibition and induction on lapatinib pharmacokinetics. METHODS Two studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.i.d. for 7 days on a single 100-mg dose of lapatinib in 22 healthy subjects. The other study examined the effect of carbamazepine titrated up to 200 mg b.i.d. over 20 days on a single 250-mg dose of lapatinib in 24 healthy subjects. RESULTS Ketoconazole altered lapatinib AUC, Cmax and half-life, with geometric mean [95% confidence interval (CI)] increases of 3.57-fold (3.07, 4.15), 2.14-fold (1.74, 2.64) and 1.66-fold (1.50, 1.84), respectively, but had no effect on absorption rate. Carbamazepine altered lapatinib AUC, Cmax and absorption rate, with geometric mean (95% CI) decreases of 72% (68, 77), 59% (49, 66) and 28% (4, 46), respectively, but had no effect on half-life. CONCLUSIONS Systemic exposure to lapatinib was significantly altered by potent inhibition and induction of CYP3A4. Dose adjustments may be required when lapatinib is administered with orally administered drugs that potently alter the activity of this enzyme.