Drug Interaction Report

MONITOR: Coadministration with isavuconazonium sulfate (prodrug of isavuconazole) may increase the plasma concentrations of drugs that are substrates of CYP450 3A4 and/or P-glycoprotein (P-gp). The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity and/or P-gp-mediated efflux of these drugs by isavuconazole. In pharmacokinetic studies, isavuconazole increased the systemic exposure (AUC) of sensitive CYP450 3A4 substrates midazolam, sirolimus, and tacrolimus by approximately 2-fold, thus it can be considered a moderate inhibitor of the isoenzyme.

MANAGEMENT: Caution is advised when isavuconazonium sulfate is used concomitantly with drugs that are substrates of the CYP450 3A4 isoenzyme or the P-gp transport protein, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever isavuconazonium sulfate is added to or withdrawn from therapy.

ADJUST DOSING INTERVAL: Administration with food increases the oral bioavailability of praziquantel. The mechanism has not been described. In nine healthy volunteers, administration of praziquantel (1800 mg single oral dose) following a high-fat meal increased the mean praziquantel peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 243% and 180%, respectively, compared to administration under fasting conditions. Administration with a high-carbohydrate meal increased these values by 515% and 271%, respectively, compared to fasting. Overall, the relative bioavailability was increased by a factor of 2.72 and 3.98 with the high-fat and high-carbohydrate meals, respectively. The time to reach peak concentration (Tmax) and elimination half-life (T1/2) were not significantly altered.

Coadministration with grapefruit juice may increase the oral bioavailability of praziquantel. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. In 18 healthy volunteers, administration of praziquantel (1800 mg single oral dose) with 250 mL of commercially squeezed grapefruit juice resulted in increases in the mean praziquantel Cmax and AUC of 63% and 90%, respectively, compared to administration with water. The Tmax and T1/2 were not significantly altered. The pharmacokinetics of praziquantel were subject to a high degree of interpatient variability with and without grapefruit juice.

MANAGEMENT: To ensure maximal oral absorption, praziquantel should be administered with meals. Administration with grapefruit juice may further increase pharmacologic effects of praziquantel, including adverse effects such dizziness, abdominal discomfort, and nausea.