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Clin Pharmacol Drug Dev. 2017 Sep;6(5):517-523. doi: 10.1002/cpdd.337. Epub 2017 Feb 8.

Effect of Sustained Elevated Gastric pH Levels on Gefitinib Exposure.

Author information

1
Early Clinical Development, Innovative Medicines and Early Development Bio Tech Unit, Quantitative Clinical Pharmacology, AstraZeneca, Gaithersburg, MD, USA.
2
Early Clinical Development, Innovative Medicines and Early Development Bio Tech Unit, Quantitative Clinical Pharmacology, AstraZeneca, Cambridge, UK.
3
Early Clinical Development, Innovative Medicines and Early Development Bio Tech Unit, Quantitative Clinical Pharmacology, AstraZeneca, Boston, MA, USA.

Abstract

This open-label, randomized, phase 1 crossover study investigated the effect of elevated gastric pH level (>5) on the relative bioavailability and pharmacokinetic profile of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Healthy male volunteers (n = 26) were randomized to gefitinib 250 mg (fasted), either alone on day 1 (unmodified gastric pH) or 1 hour following the second of 2 oral doses of the H2 -receptor antagonist ranitidine 450 mg (elevated gastric pH). After a 3-week washout period, volunteers crossed to the other treatment. The geometric least-squares (GLS) mean AUC0-∞ and Cmax for gefitinib were reduced by 47% and 71%, respectively, under conditions of sustained elevated gastric pH; for both parameters, the 90%CI for the ratio of the GLS means lay below the prespecified lower limit. Median tmax was delayed from 5 to 6 hours. Mean t1/2 was similar under both gastric pH conditions. No serious adverse events were reported. The bioavailability of a single oral gefitinib 250-mg dose was reduced by approximately 50% when gefitinib was administered under conditions of sustained elevated gastric pH.

KEYWORDS:

bioavailability; gastric pH; gefitinib; pharmacokinetics; ranitidine

PMID:
28176470
DOI:
10.1002/cpdd.337
[Indexed for MEDLINE]

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