title: Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib.
abstract: This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C(max)) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).
authors.affiliation: Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tanaka
authors.forename: O Q P
authors.initials: OQ
authors.lastname: Yin
authors.forename: V
authors.initials: V
authors.lastname: Sethuraman
authors.forename: T
authors.initials: T
authors.lastname: Smith
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Grouss
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: F
authors.initials: F
authors.lastname: Giles
authors.forename: O G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: L
authors.initials: L
authors.lastname: Galitz
authors.forename: H
authors.initials: H
authors.lastname: Schran
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004041:Dietary Fats; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D016044:Fusion Proteins, bcr-abl / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004041:Dietary Fats; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib