Drug Interactions between pexidartinib and praziquantel

ADJUST DOSING INTERVAL: The presence of food may increase the absorption and toxicity of pexidartinib. Administration of pexidartinib with a high-fat meal increased peak plasma concentration (Cmax) and systemic exposure (AUC) by 100% and prolonged the time to reach peak plasma concentration (Tmax) by 2.5 hours.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentration and risk of adverse effects of pexidartinib, including potentially fatal hepatotoxicity. The mechanism is inhibition of CYP450 3A4-mediated metabolism of pexidartinib by certain compounds present in grapefruits. Concomitant administration of itraconazole, a strong CYP450 3A4 inhibitor, increased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 70%, respectively.

MANAGEMENT: Pexidartinib should be administered on an empty stomach, at least one hour before or two hours after a meal or snack. Consumption of grapefruit or grapefruit juice should generally be avoided during pexidartinib therapy. If concomitant use is unavoidable, the dose of pexidartinib should be reduced according to the manufacturer's recommendations. If concomitant use of grapefruit or grapefruit juice is discontinued, the dose of pexidartinib may be increased (after 3 plasma half-lives of a strong CYP450 3A4 inhibitor) to the dose that was used prior to consumption of grapefruit or grapefruit juice.

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.