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Medline ® Abstract for Reference 60

of 'Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia'

60
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Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib.
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Yin OQ, Gallagher N, Fischer D, Demirhan E, Zhou W, Golor G, Schran H
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J Clin Pharmacol. 2010 Aug;50(8):960-7. Epub 2010 May 24.
 
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.
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Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, 180 Park Ave, Florham Park, NJ 07932, USA. Ophelia.yin@novartis.com
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