A clinical study to examine the potential effect of lansoprazole on the pharmacokinetics of bosutinib when administered concomitantly to healthy subjects.

BACKGROUND: Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect bosutinib absorption.
OBJECTIVES: The objectives of this study were to evaluate the effect of lansoprazole, a gastric proton pump inhibitor, on the pharmacokinetics and safety of bosutinib.
METHODS: This open-label, non-randomized, phase I study involved inpatients and outpatients at a single site. The study participants were healthy men or women of non-childbearing potential aged 18-50 years. Each subject received bosutinib 400 mg on Day 1, lansoprazole 60 mg on Day 14, and bosutinib 400 mg co-administered with lansoprazole 60 mg on Day 15 under fasting conditions. The main outcome measure was the effect of multiple doses of lansoprazole on the pharmacokinetic profile of a single oral dose of bosutinib.
RESULTS: A total of 24 healthy male subjects were enrolled. Co-administration with lansoprazole decreased the mean maximum plasma concentration (C(max)) of bosutinib from 70.2 to 42.9 ng/mL, and the total area under the plasma concentration-time curve (AUC) from 1,940 to 1,470 ng·h/mL. Log-transformed bosutinib pharmacokinetic parameters indicated significant between-treatment differences; the least squares geometric mean ratio for C(max) was 54 % (95 % CI 42-70) and for AUC was 74 % (95 % CI 60-90). Mean apparent total body clearance from plasma after oral administration increased from 237 to 330 L/h, and the median time to reach Cmax increased from 5 to 6 h, although this change may be related to decreased bosutinib absorption when combined with lansoprazole. When co-administered with lansoprazole, bosutinib maintained an acceptable safety profile, which was primarily characterized by diarrhea (33 %), headache (21 %), and nausea (13 %). One subject experienced serious adverse events of diverticulitis, gastritis, and duodenitis after co-administration; however, no participant withdrew because of toxicity.
CONCLUSIONS: This study demonstrated that bosutinib absorption may be reduced when co-administered with lansoprazole or other proton pump inhibitors. Caution should be used with such drug combinations, as subtherapeutic exposure of bosutinib may limit its clinical antitumor activity; short-acting antacids are recommended instead.