title: Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants.
abstract: Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6β-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.
authors: Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, 180 Park Ave, Florham Park, NJ 07932, USA.
authors: Chiaki
authors: C
authors: Tanaka
authors: Ophelia Q P
authors: OQ
authors: Yin
authors: Tom
authors: T
authors: Smith
authors: Venkat
authors: V
authors: Sethuraman
authors: Karen
authors: K
authors: Grouss
authors: Lawrence
authors: L
authors: Galitz
authors: Robert
authors: R
authors: Harrell
authors: Horst
authors: H
authors: Schran
mesh_terms: D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D011743:Pyrimidines / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C498826:nilotinib; D007654:Ketoconazole; D012293:Rifampin; D006854:Hydrocortisone