Effects of Food on Clinical Pharmacokinetics

Abstract

Food-drug interactions can be associated with alterations in the pharmacokinetic and pharmacodynamic profile of various drugs that may have clinical implications. The various phases in which food may interact with a coadministered drug are: (i) before and during gastrointestinal absorption; (ii) during distribution; (iii) during metabolism; and (iv) during elimination. Absorption and metabolism are the phases where food has most effect, and this review will focus on those areas. It will also review the variable and complex effects of antacids and metal ions on drug absorption. Mechanisms related to food effects on drug absorption have been described under 5 categories: those causing decreased, delayed, increased or accelerated absorption, and those in which food has no significant effect. Among the major variables that interface between differential effects of food and postprandial bioavailability are: (i) the physicochemical characteristics and enantiomorphic composition of the drug; (ii) timing of meals in relation to time of drug administration; (iii) size and composition of meals (especially fat, protein and fibre); and (iv) dose size. However, the influence of food is largely a matter of the design of the pharmaceutical formulation. In addition, the mechanism of 'food effect' may involve physiological and sensory responses to food, such as changes in gastrointestinal milieu and gastric emptying rate, reflex action, and may also involve the site and route (either portal or lymphatic) of drug absorption. Mixing drugs with fruit juice, such as grapefruit and orange juice, and acidic beverages, such as commercial soft drinks, may affect absorption because of decreases in gastric pH, which could offer a therapeutic advantage in certain clinical conditions, such as patients with HIV disease and cancer. The increased bioavailability caused by the concomitant intake of grapefruit juice results from the inhibition of intestinal cytochrome P450(CYP)3A4, but not hepatic CYP3A4 or colon CYP3A5, which probably involves the bioflavonoid naringenin and furanocoumarins. Although there is a vast amount of literature, there is still no rational scientific basis to predict the effect of food for a particular chemical entity or a chemical class of therapeutic agents. A mechanistic understanding of the effects of food may serve as a key to the pharmacokinetic optimisation of patient therapy, both in outpatients and hospitalised patients of various age groups.

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

“…Pharmacokinetic reactions, in which food affects the absorption, distribution, metabolism, or elimination of a drug, are the most commonly observed food-drug interactions [16]. For example, concomitant intake of food can affect the rate and extent of drug absorption from the gastrointestinal tract, resulting in reduced, delayed, increased, or accelerated drug absorption [17]. In addition, the influence of food is largely dependent on the pharmaceutical formulation of a specific drug, such that food intake with some extended-release drug formulations can substantially alter the release of the drug, which ultimately alters the drug absorption time profile and, thus, the overall clinical effect [17].…”

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

“…For example, food intake triggers physiological changes in the gastric pH, changes in GI motility, etc., which can have profound impact on drug absorption (40). Food can also impact specific transporters that are involved in absorption of a drug.…”

The Effect of Food on the Absorption of Abiraterone Acetate from a Fine Particle Dosage Form: A Randomized Crossover Trial in Healthy Volunteers

“…Taking lipophilic drugs with a high-fat meal is also known to increase their rate of dissolution [6]. Abiraterone acetate (AA), an orally available, highly lipophilic drug [7], is approved for the treatment of metastatic castration-resistant prostate cancer.…”

“…For example, Chi et al reported that in healthy subjects administered the OAA formulation, the area under the plasma concentration-time curve (AUC) and maximum measured plasma concentration (C max ) of abiraterone, the active metabolite of AA, increased by 10-and 17-fold, respectively, when given shortly after a high-fat meal relative to the fasted state [10]. Biorelevant in vitro studies suggest that intestinal fluids, such as bile salt [6,10] produced during the fed state, may facilitate the absorption of abiraterone, thus producing the food effect observed in pharmacokinetic trials [9]. The large bioavailability changes recognized in the reference product with regard to meal fat content [10] may lead to differences in safety, tolerability, and efficacy.…”