Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers.

Chelation interactions between drugs/supplements that contain large amounts of multivalent ions and the fluoroquinolones have been known for quite some time. However, there has been a lack of taking this interaction into account when they may be coadministered with foods that have been fortified with amounts of multiple multivalent ions that equal or exceed many supplement products. A previous study demonstrated that 12 ounces of calcium-fortified orange juice significantly decreased the bioequivalence of a dose of ciprofloxacin. This study examined, in 16 healthy volunteers, whether 12 ounces of orange juice with and without calcium fortification would demonstrate the same chelation interaction with single doses of levofloxacin. The results of the study demonstrated that both types of juice decreased levofloxacin Cmax values by 14% to 18% and prolonged tmax values by approximately 50%, with calcium-fortified orange juice decreasing Cmax enough to lose bioequivalence as compared to the control arm (89% [78.1%, 99.8%]). Due to the lack of change in overall exposure, it is thought that rather than a chelation interaction, levofloxacin and components of the orange juices competed for intestinal transport mechanisms such as P-glycoprotein and organic anion-transporting polypeptides, which resulted in the discovered interaction. These results further confirm the need to adjust regulatory studies to include bioequivalence/bioavailability studies that contain fortified foods more than high-calorie/high-fat foods to better reflect current American consumption habits.

Lack of bioequivalence of gatifloxacin when coadministered with calcium-fortified orange juice in healthy volunteers.

Previous work has demonstrated that the chelation interaction seen with ciprofloxacin when it is coadministered with antacids also happens when it is coadministered with calcium-fortified foods. This study was conducted to study whether this was a drug-specific finding or whether the interaction occurs with other members of the fluoroquinolone class of drugs. Sixteen healthy volunteers received single 400-mg oral doses of gatifloxacin with 12 ounces each of water, nonfortified orange juice, and calcium-fortified orange juice and had plasma samples drawn for assay over the subsequent 48 hours. Results demonstrated significant increases in total oral clearance (15%) and volume of distribution (13%) along with a matching significant decrease (12%) in exposure (AUC) when gatifloxacin was taken with the fortified juice. Although not statistically significant, peak concentrations decreased by 15% and were reached (tmax) approximately 38% later when gatifloxacin was coadministered with the calcium-fortified juice. Bioavailability testing indicated that although the 90% confidence intervals (CIs) for the ratio of the geometric means of the calcium-fortified juice and water arms' AUC stayed within the range of 80% to 125%, those for Cmax did not. This study demonstrated a chelation or adsorption interaction between the fortified juice and gatifloxacin that reached regulatory significance. As a result, clinicians may wish to instruct patients to take gatifloxacin either with nonfortified foods or on an empty stomach.

Is it really OK to take this with food? Old interactions with a new twist.

In response to consumers' increased interest in preventive health care, the food industry is producing a variety of foods fortified with calcium, iron, and other minerals and vitamins. This well-meaning idea of food fortification is troubling in the context of clinical pharmacology. The recommended Food and Drug Administration (FDA) meal used in food-drug interaction studies is a high-fat, high-calorie meal with little nutritive value. While some drugs may appear to be safe when taken with food, this may not be true when fortified foods are considered. The mechanisms causing drug-fortified food interactions are the some well-known mechanisms that cause other drug-mineral interactions. Certain drugs may exhibit decreased absorption due to chelation and adsorption. Other drugs may have decreased absorption or increased excretion due to changes in gastric and/or urinary pH. The results of such interactions may be clinically insignificant or severe, including treatment failure, frequent dose changes, antibiotic resistance, and increased morbidity and mortality. Revisions of current regulatoryguidelines are necessary to take into account this potentially major source of "new" drug interactions.