title: Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.
abstract: Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: Hefei
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sheng
authors.forename: Jin H
authors.initials: JH
authors.lastname: Ko
authors.forename: Cheng
authors.initials: C
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Petra
authors.initials: P
authors.lastname: Priess
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.forename: Steven
authors.initials: S
authors.lastname: Novick
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C498826:nilotinib; D008874:Midazolam
keywords: CYP3A inhibitor; drug-drug interaction; midazolam; nilotinib; pharmacokinetics