Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.
OBJECTIVE
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.
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Inc., Research Triangle Park, NC, USA. deborah.a.smith@gsk.com
Deborah A
DA
Smith
Kevin M
KM
Koch
Nikita
N
Arya
Carolyn J
CJ
Bowen
Jill M
JM
Herendeen
Andrew
A
Beelen
D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002220:Carbamazepine / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
D018712:Analgesics, Non-Narcotic; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D002220:Carbamazepine; D007654:Ketoconazole