Gastric Acid Related Disorders

Gastric acid-related disorders include heartburn, gastric and duodenal ulcers, symptomatic gastroesophageal reflux disease (GERD), erosive esophagitis, and pathological hypersecretory conditions such as ZollingerEllison syndrome. The conventional treatment for these acid-related disorders is the suppression of gastric acid secretion by H2 blockers and proton pump inhibitors (PPIs). PPIs are currently the drugs of choice in the management of acid-related disorders. The use of antisecretory agents in combination with antibiotics is beneficial in the healing of H-pylori related peptic ulcers. The approved H2 blockers in the United States include cimetidine, ranitidine, famotidine, and nizatidine. Approved PPIs include omeprazole, esomeprazole (enantiomer of omeprazole), pantoprazole, lansoprazole, and rabeprazole.

H2 blockers principally act via competitive inhibition of H2 receptors located on the parietal cells of the stomach. PPIs suppress gastric acid secretion by irreversibly inhibiting the gastric H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell, thus blocking the final step of acid production. Both H2 blockers and PPIs cause dose-related suppression of basal gastric acid secretion. However, the two classes of drugs differ markedly in their pharmacodynamic profiles. The antisecretory effect of H2 blockers has a rapid onset and a relatively short duration. On the other hand, although PPIs generally have short plasma elimination halflives of about 1-2 hours, the antisecretory effect lasts for up to 3-5 days after drug administration [30]. The prolonged effect of PPIs is attributed to their mechanism of action, which involves irreversible inhibition of the proton pump. The rate-limiting step in the antisecretory action of PPIs is the turnover of the proton pump, which is reported to have a half-life of about 50 hours.

Studies in healthy volunteers can provide a preliminary evaluation of the potential efficacy of antisecretory agents and also dose-response information. Administration of pentagastrin or peptone meal provides acid stimulation in these studies. Thus, early Phase I studies designed to characterize the pharmacokinetics of the drug product can evaluate the pharmacodynamic effect as well. Pharmacodynamic biomarkers such as median 24-hour pH, % time gastric pH >3, and % time gastric pH >4 are common efficacy biomarkers for antisecretory agents. Use of these biomarkers has arisen from studies that utilized meta-analyses to determine the degree and duration of acid inhibition necessary for optimal healing of various acid-related disorders. The findings suggest that gastric pH has to be elevated above 3.0 for about 16-18 hours a day for treatment of duodenal ulcer, while gastric pH needs to be elevated above 4.0 for 16-18 hours a day for treatment of esophagitis. However, the clinical relevance of the above biomarkers is not established. Thus, if favorable data are obtained in healthy volunteers, then similar studies are carried out in patients to further characterize the gastric acid antisecretory effect. Subsequently, full clinical efficacy and safety studies can be initiated with clinical endpoints as the outcome (e.g., % of patients healed in active duodenal ulcer trial).

There is extensive literature that describes exposure-response relationships for H2 blockers. In general, a direct correlation appears to exist between plasma concentrations of H2 blockers and the acid inhibitory activity, which may be attributed to the competitive nature of drug-receptor interaction associated with H2 blockers [31]. Exposure-response analyses relying on the sigmoid Emax model have been successful in predicting the time course of acid inhibitory activity for H2 blockers [32].

Apparent exposure-response relationships are reported for most PPIs [31-35]. Katashima et al. [33] analyzed the relationship between plasma concentrations and the inhibitory effects of the PPIs omeprazole, lansoprazole, and pantoprazole on gastric acid secretion in healthy human subjects using a model that assumed a linear relationship between the fraction of inactive gastric proton pumps and the acid inhibitory effect. The authors concluded that the potency of the acid inhibitory activity of pantoprazole was weaker than that of omeprazole and lansoprazole, but the apparent recovery half-life of pantoprazole (45.9 hours) was slower than that of either omeprazole (27.5 hours) or lansoprazole (12.9 hours). It is noteworthy that while the model reasonably predicted the gastric acid inhibitory effects of studied PPIs, it may not have an actual mechanistic basis. More recently, Perron et al. [34] analyzed the exposure-response relationship for pantoprazole (10-80mg, IV & oral) in healthy human subjects using an indirect response model. The model reasonably described the time course of acid secretion at all studied doses. The authors concluded that maximum acid inhibition was related to the extent of exposure to pantoprazole. In addition, the time to maximum acid inhibition decreased with higher doses. Further work is needed in the area of exposure-response modeling of PPIs to fully characterize the time course of gastric acid inhibition exerted by PPIs. More importantly, further investigation is needed to explore the nature of the relationship between gastric acid inhibition and clinical efficacy in acid-related gastrointestinal disorders.

Pharmacodynamic data on antisecretory activity are useful in special populations and other situations in which clinical efficacy trials are not feasible. For example, measurement of antisecretory activity in pediatric patients is feasible and can be used in lieu of large clinical studies with efficacy endpoints. Pharmacodynamic data on antisecretory activity can also be obtained in special populations such as hepatic and renal impairment patients. The need for dosage adjustment in these special populations can be made by taking into account both pharmacokinetics and pharmacodynamcis. For many other disease states, the need for dosage adjustments in special populations are made based on pharmacokinetic data alone.

Two key clinical pharmacology issues arise with antisecretory treatment. The first issue is the potential effect of these agents on the absorption of coadministered drugs. Because these drugs markedly elevate the pH in the stomach, they may affect the pharmacokinetics of a coadministered drug with pH-dependent absorption or a modified-release drug product with pH-dependent drug release. For example, in normal subjects, coadministration of rabeprazole 20 mg once daily resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in digoxin AUC and Cmax of 19% and 29%, respectively [36]. Consequently, one may need to alter the time of drug administration or adjust the dose of the coadministered drug. The second issue is the effect of CYP2C19 phenotype on pharmacokinetics. Omeprazole, lansoprazole, pantoprazole, and esomeprazole are metabolized by CYP2C19, an enzyme that exhibits genetic polymorphism; approximately 3% of Caucasians and 17-23% of Asians are poor metabolizers. One can use exposure-response information to determine the need for dosage adjustment in these patients.

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