Case Study in Optimal Dosing in Duodenal Ulcer

Duodenal ulcers occur in the duodenum – the upper portion of the small intestine as it leaves the stomach. A duodenal ulcer is characterized by the presence of a well-demarcated break in the mucosa that may extend into the muscularis propria [Thompson et al, 2010]. Cimetidine (C) was the first H2-Receptor Antagonist to receive regulatory approval (in the late 1970s) for the treatment of duodenal ulcers. When it was being developed it was widely held that duodenal ulcers were caused by excessive gastric acid production. In fact the prevailing medical opinion was no acid, no ulcer. Sir James Black and colleagues at SmithKline and French Laboratories are credited with the discovery of C. They discovered that histamine released by the H2-receptor stimulated the production of gastric acid, and that C by blocking the release of this histamine would suppress both normal and food stimulated gastric acid secretion [Nayak & Ketteringham, 1986]. In a reduced acidic environment, ulcers would be able to heal. The first C regimen approved for the treatment of duodenal ulcers in the United Kingdom was 1000 mg per day, given as: 200 mg at breakfast, lunch and dinner, and 400 mg at bed time, for up to 4 weeks. The first regimen approved in the United States for this indication was 1200 mg per day, given as: 300 mg q.i.d. for up to 4 weeks. Subsequently, other indications were obtained, and dosing regimens modified; for example, 800 mg per day, given as 400 mg bid. In the mid 1980's, based upon data from gastric acid anti-secretory studies at various doses and frequencies of dosing, there was reason to believe that a single night time (hs) dose of 800 mg of C for up to 4 weeks would be the clinically optimal regimen for treating patients with duodenal ulcers. A large, landmark, dose comparison clinical trial [Dickson et al, 1985; Peace et al, 1985; Valenzuela et al, 1985; Young et al, 1989] was undertaken to confirm the effectiveness of 800 C mg hs in the treatment of duodenal ulcers for up to four weeks. When the author was first consulted by the project physician and regulatory affairs expert, the clinical development plan consisted of two, randomized, double-blind, placebo controlled, pivotal proof of efficacy trials with single nighttime dosing for four weeks: