Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects

Abstract

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, C(max) 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, C(max) 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.

Figure 1

Mean plasma concentrations of lapatinib (LAP) from a 100-mg dose given alone (▵) and after treatment with ketoconazole (KTZ) (▴), and from a 250-mg dose given alone (○) and after treatment with carbamazepine (CBZ) (•). LAP (—○—); LAP + CBZ (—•—); LAP (—▵—); LAP + KTZ (—▴—)

Figure 2

Individual changes in lapatinib AUC due to carbamazepine (CBZ) induction (left) and ketoconazole (KTZ) inhibition (right) of CYP3A4