The Effect of Food on the Relative Bioavailability of Rapidly Dissolving Immediate-Release Solid Oral Products Containing Highly Soluble Drugs

Abstract

The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.

Current Methods for Predicting Human Food Effect

“…Food can impact the pharmacokinetics of a drug product through several mechanisms, such as delay in gastric emptying, stimulation of bile flow, changes in gastrointestinal (GI) pH, alterations in luminal metabolism, or interactions of the drug with the food itself (1,2). The drug absorption process can be affected by many factors, including calorie content (low vs high calorie meals), nutrient composition (protein, carbohydrate-rich or high-fat meals), volume, temperature of the meal itself, and fluid ingestion.…”

Cyclization-activated Prodrugs

“…The prodrug approach has been widely used to improve delivery of drugs to their site of action by modulation of physico-chemical properties that affect absorption or by targeting to specific enzymes or membrane transporters [2,[3][4][5]. Most of the prodrugs that are now in clinical use require enzymatic catalysis in order to be converted into the parent drug.…”

“…Most of the prodrugs that are now in clinical use require enzymatic catalysis in order to be converted into the parent drug. This is particularly true for those prodrugs designed to liberate the parent drug in the blood stream following gastro-intestinal absorption: they are typically ester derivatives of drugs containing carboxyl or hydroxyl groups, which are readily converted into the parent drug by esterasecatalyzed hydrolysis [5]. However, applying enzymatic activation for other functional groups may result in high chemical reactivity that precludes either liquid or solid formulation of the prodrug (e.g.…”

Drug release from matrix tablets: physiological parameters and the effect of food

“…The differences in bioavailability when drug is administered in fed state versus the fasted state could be partly attributed to this compositional difference of the fed and fasted intestinal fluids [4]. This is as a result of interactions which may occur between the oral formulation of the drug and the food administered [86][87][88][89][90].…”