Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib

• Published in: Journal of clinical oncology Vol. 27; no. 15_suppl; p. 7053
• Main Authors: Gallagher, N. J., Fischer, D., Demirhan, E., Zhou, W., Golor, G., Schran, H., Yin, O.
• Format: Journal Article
• Language: English
• Published: 20.05.2009
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2009.27.15_suppl.7053

Abstract only 7053 Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP patients resistant or intolerant to prior therapy including imatinib. The solubility of nilotinib is pH dependent, with lower solubility at higher pH. We evaluated whether esomeprazole, a potent proton pump inhibitor (PPI) that can significantly increase gastric pH, could affect the oral absorption and pharmacokinetics of nilotinib in healthy subjects. Methods: Twenty-two subjects (6 F, 16M, age range 18–64 years) were enrolled to receive nilotinib alone or in the presence of steady-state esomeprazole during two treatment periods. Nilotinib was given as a single oral 400 mg dose on days 1 and 13, and esomeprazole 40 mg once-daily on day 8 through day 13. Serial blood samples were collected up to 72 hours after nilotinib dosing for determination of nilotinib serum concentrations by a validated liquid chromatography-tandem mass spectrometry assay. Gastric pH was monitored in all subjects at baseline (prior to nilotinib and esomeprazole dosing), before and during the first 4 hrs of esomeprazole steady state dosing (fifth dose on Day 12). Results: When coadministered with esomeprazole, nilotinib C max was decreased by 27% (397±89 vs 303±157ng/mL) and AUC 0-∞ decreased by 34% (11515±6140 vs 7164±3752ng*hr/mL) respectively. The median time to reach nilotinib C max was slightly prolonged from 4.0 hrs to 6.0 hrs, but its elimination half-life was not altered (17.3±10.7 vs 15.9±6.6 hrs). Median gastric pH was increased from 0.8 at baseline to 2.0 at pre-dose, and to 3.9, 5.8, 5.5, and 5.7 at 1, 2, 3, and 4 hrs after esomeprazole dosing. Administration of nilotinib alone or in combination with esomeprazole was generally well tolerated in the study subjects. Conclusions: The study results demonstrate a modest reduction in the rate and extent of nilotinib absorption when co-administered with esomeprazole. Such an effect is unlikely to cause a significant clinical consequence for nilotinib therapy, and thus nilotinib can be used with esomeprazole or other PPIs without the risk of substantial decrease in nilotinib systemic exposure. [Table: see text]