Drug Interaction Report

MONITOR: Coadministration with phenylbutyrate/taurursodiol (ursodoxicoltaurine) may alter the plasma concentrations of drugs that are substrates of CYP450 1A2, 2B6, and/or 3A4. Based on in vitro studies, phenylbutyrate/taurursodiol may decrease clearance via inhibition or increase clearance via induction of these isoenzymes, resulting in increased or decreased plasma concentrations of agents that are metabolized by one or more of these isoenzymes. Clinical and pharmacokinetic data are currently lacking.

MANAGEMENT: Caution is advised if phenylbutyrate/taurursodiol is used concomitantly with drugs that are substrates of CYP450 1A2, 2B6, and/or 3A4, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information for taurursodiol combined with sodium phenylbutyrate recommends avoiding coadministration with CYP450 1A2, 2B6, and/or 3A4 substrates for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever phenylbutyrate/taurursodiol is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of albendazole, which is rapidly converted by hepatocytes and intestinal mucosal cells into the active metabolite, albendazole sulfoxide (ABZSX), following absorption. The proposed mechanism is stimulation of gastric acid secretion, as the absorption of albendazole is thought to be pH-dependent. According to the product labeling, plasma concentrations of ABZSX are up to 5-fold higher on average when albendazole is administered with a fatty meal (fat content approximately 40 g) compared to administration in the fasted state. In one study of six healthy male volunteers, administration of a single 10 mg/kg oral dose of albendazole in combination with a high-fat meal (57 g fat, 1399 kcal) increased the mean ABZSX peak plasma concentration (Cmax) and systemic exposure (AUC) by 6.5- and 9.4-fold, respectively, and delayed the time to reach Cmax (Tmax) from 2.5 to 5.3 hours compared to administration in the fasted state with water. The elimination half-life was not affected.

MONITOR: Grapefruit juice may increase the oral bioavailability of albendazole, which is rapidly converted by hepatocytes and intestinal mucosal cells into the active metabolite, albendazole sulfoxide (ABZSX), following absorption. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In six healthy male volunteers, administration of a single 10 mg/kg oral dose of albendazole in combination with 250 mL of double-strength grapefruit juice increased the mean ABZSX peak plasma concentration (Cmax) and systemic exposure (AUC) by 3.2- and 3.1-fold, respectively, compared to administration with water. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: To ensure maximal oral absorption, albendazole should be taken with food. Grapefruit juice may also enhance the oral bioavailability of albendazole.

ADJUST DOSING INTERVAL: Coadministration with a high-fat meal may reduce the rate and extent of absorption of sodium phenylbutyrate. When a single 3 g-1 g dose of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) was administered to healthy volunteers in the presence of a high-fat, high-calorie meal (approximately 800 to 1000 calories; 500 to 600 calories from fat, 250 calories from carbohydrate, 150 calories from protein), sodium phenylbutyrate peak plasma concentration (Cmax) decreased by 75% and systemic exposure (AUC) decreased by 55%. The Cmax for taurursodiol was not significantly affected, but AUC was increased by 46%. The clinical significance of these changes has not been established. In premarketing studies, patients were advised to take the drug before a meal.

MANAGEMENT: The prescribing information recommends administration of sodium phenylbutyrate-taurursodiol before a meal or snack, particularly in patients of low body weight (less than 70 kg).