title: Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib.
abstract: Nilotinib (Tasigna), a highly selective and potent BCR-ABL tyrosine kinase inhibitor (TKI), is administered orally and has pH-dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty-two participants (6 women, 16 men, mean age of 44.9 +/- 12.9 years) were enrolled to receive nilotinib as a single oral 400-mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after nilotinib dosing, and nilotinib serum concentrations were determined by a validated liquid chromatography/tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, nilotinib C(max) was decreased by 27% and AUC(0-infinity) decreased by 34%. Nilotinib t(max) was prolonged from 4.0 to 6.0 hours, but t(1/2) was not altered. Mean gastric pH was 1.0 +/- 0.5 at baseline and increased to 2.79 +/- 2.50, 3.98 +/- 2.27, 5.30 +/- 1.70, 5.38 +/- 1.26, and 5.31 +/- 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors.
authors.affiliation: Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, 180 Park Ave, Florham Park, NJ 07932, USA. Ophelia.yin@novartis.com
authors.forename: Ophelia Q P
authors.initials: OQ
authors.lastname: Yin
authors.forename: Neil
authors.initials: N
authors.lastname: Gallagher
authors.forename: Deirdre
authors.initials: D
authors.lastname: Fischer
authors.forename: Eren
authors.initials: E
authors.lastname: Demirhan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Georg
authors.initials: G
authors.lastname: Golor
authors.forename: Horst
authors.initials: H
authors.lastname: Schran
mesh_terms: D000328:Adult; D019540:Area Under Curve; D064098:Esomeprazole / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D054328:Proton Pump Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D064098:Esomeprazole