Effect of Sustained Elevated Gastric pH Levels on Gefitinib Exposure.
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 Cmaxfor 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 tmaxwas delayed from 5 to 6 hours. Mean t1/2was 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.
Early Clinical Development, Innovative Medicines and Early Development Bio Tech Unit, Quantitative Clinical Pharmacology, AstraZeneca, Gaithersburg, MD, USA.
Weifeng
W
Tang
Early Clinical Development, Innovative Medicines and Early Development Bio Tech Unit, Quantitative Clinical Pharmacology, AstraZeneca, Cambridge, UK.
Helen
H
Tomkinson
Early Clinical Development, Innovative Medicines and Early Development Bio Tech Unit, Quantitative Clinical Pharmacology, AstraZeneca, Boston, MA, USA.
Eric
E
Masson
D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D000077156:Gefitinib; D064368:Healthy Volunteers; D006635:Histamine H2 Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016018:Least-Squares Analysis; D008297:Male; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011897:Random Allocation; D011899:Ranitidine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013270:Stomach / Q000737:chemistry*
D006635:Histamine H2 Antagonists; D011799:Quinazolines; D011899:Ranitidine; D000077156:Gefitinib
bioavailability; gastric pH; gefitinib; pharmacokinetics; ranitidine