RESUMO
OBJECTIVE: Famotidine given at a dose of 80 mg/day is effective in preventing NSAID-induced gastropathy. The aim of this proof of concept study was to compare twice a day (BID) vs 3-times a day (TID) administration of this total dose of famotidine on intragastric pH in healthy volunteers. RESEARCH DESIGN AND METHODS: Two analyses were undertaken: (1) a 13 subject controlled cross-over 24-h intragastric pH evaluation of the BID and TID administration of 80 mg/day of famotidine, as well as measures for drug accumulation over 5 days (EudraCT, number 2006-002930-39); and (2) a pharmacokinetic (PK)/pharmacodynamic (PD) model which predicted steady-state famotidine plasma concentrations and pH of the two regimens. RESULTS: For the cross-over study, gastric pH was above 3.5 for a mean of 20 min longer for TID dosing compared to BID dosing on Day 1. On Day 5, the mean time above this threshold was higher with the BID regimen by â¼25 min. For pH 4, subjects' gastric pH was above this pH value for a mean of 25 min longer for TID dosing compared to BID dosing on Day 1. For Day 5, the pH was above 4 for â¼45 min longer with the TID regimen as compared with the BID regimen. The mean 24-h gastric pH values when taken in the upright position trended higher for the TID dosing period compared to the BID regimen on Day 1. The steady-state simulation model indicated that, following TID dosing, intragastric pH will be above 3 for 24 h vs 16 h for the BID regimen. There was no evidence for plasma accumulation of famotidine with TID dosing as compared to BID dosing from either analysis. CONCLUSION: The data indicate that overall more time is spent above the acidic threshold pH values when 80 mg/day of famotidine is administered TID vs BID. Key limitations included small study size with a short duration and lack of a baseline examination, but was compensated for by the cross-over and PK/PD modeling design. Although most of the comparisons in this proof of concept study were not statistically significant these results have important implications for future research on gastric acid lowering agents used for the prevention of NSAID-induced gastropathy.
RESUMO
BACKGROUND & AIMS: The safety of selective cyclooxygenase-2 inhibitors in patients with ulcerative colitis in remission is unknown. METHODS: We performed a placebo-controlled pilot trial to evaluate the safety of celecoxib in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy. A total of 222 patients with ulcerative colitis in remission were randomized to receive oral celecoxib 200 mg or placebo twice daily for 14 days. Remission was defined as a total Mayo Clinic score of 2 points or less and an endoscopic score of 1 point or less. Disease exacerbation was defined as a total Mayo Clinic score of 5 points or more and an increase in the endoscopic score of 1 point or more. The primary analysis was disease exacerbation through day 14 among patients who underwent randomization, had at least 1 dose of study drug, and had both endoscopy and Mayo Clinic disease activity index scores at the baseline and final assessments. RESULTS: Three percent of patients in the celecoxib group experienced disease exacerbation through day 14, as compared with 4% in the placebo group (P = .719). Eleven percent of patients in each group experienced a bowel-related adverse event (P > .20). CONCLUSIONS: Therapy with celecoxib for up to 14 days did not have a greater relapse rate than placebo in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy.