Abstract
Background
In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases.
Objectives
The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized.
Methods
This was a phase I, open-label, non-randomized, two-period crossover study in 20 healthy subjects aged 18–55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15.
Results
Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P < 0.001). A corresponding 25 % decrease in the geometric mean maximum plasma concentration (C max) of ponatinib was observed for ponatinib + lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration–time curve from time zero to infinity (AUC∞ 1,153 ng·h/mL for lansoprazole + ponatinib vs. 1,222 ng·h/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole.
Conclusions
Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max, overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH.
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Acknowledgments
This study was sponsored by ARIAD Pharmaceuticals, Inc. We thank Advion BioServices, Inc. for the bioanalytical assays. NIN, DJD, JD, and CDT are employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. DS is a paid consultant of ARIAD Pharmaceuticals, Inc. Professional writing assistance for this publication was provided by Melinda Ramsey, PhD, and Francesca Balordi, PhD, of Medicus International New York, and funded by ARIAD Pharmaceuticals, Inc.
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Narasimhan, N.I., Dorer, D.J., Davis, J. et al. Evaluation of the Effect of Multiple Doses of Lansoprazole on the Pharmacokinetics and Safety of Ponatinib in Healthy Subjects. Clin Drug Investig 34, 723–729 (2014). https://doi.org/10.1007/s40261-014-0225-y
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DOI: https://doi.org/10.1007/s40261-014-0225-y