Evaluation of the Effect of Multiple Doses of Lansoprazole on the Pharmacokinetics and Safety of Ponatinib in Healthy Subjects

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.