Drug Interaction Report

GENERALLY AVOID: Coadministration with potent CYP450 3A4 inhibitors may significantly increase the plasma concentrations and toxicity of cabazitaxel, which is primarily metabolized via the isoenzyme. A drug interaction study of cabazitaxel in patients with advanced cancers (n=23), revealed that repeated administration of the potent CYP450 3A4 inhibitor ketoconazole (400 mg orally once daily), decreased the clearance and increased the systemic exposure (AUC) of cabazitaxel (5 mg/m2 intravenous) by 20% and 25%, respectively. However, one case report reviewing the coadministration of cabazitaxel (22.5 mg/m2 intravenous every 3 weeks) with lower doses of a different potent CYP450 3A4 inhibitor, clarithromycin (400 mg daily) in a 75-year-old male with castration-resistant prostate cancer did not reveal a significant change in cabazitaxel's plasma concentrations when compared to previously reported levels. This patient did experience an increase in cabazitaxel toxicity (general malaise, anorexia, dehydration), but investigators ultimately felt that this resulted from a decrease in the patient's ability to tolerate cabazitaxel.

MANAGEMENT: Given the narrow therapeutic index of cabazitaxel, concomitant use with potent CYP450 3A4 inhibitors should generally be avoided. If coadministration is clinically necessary, a 25% reduction in cabazitaxel's dose should be considered. Some authorities also recommend close monitoring for toxicity (e.g., bone marrow suppression, nausea, vomiting, severe diarrhea, peripheral neuropathy, cystitis, renal failure, pneumonitis) during coadministration. On the other hand, one publication indicated that doses of clarithromycin which result in trough concentrations around 70 ng/mL may not significantly affect cabazitaxel's plasma concentrations. Limitations such as this being a single-patient case report, lack of serial blood sampling, and unusual dosing for clarithromycin should be taken into consideration when evaluating this interaction in practice. The labeling of the inhibitor should be consulted as some inhibitors may continue to have effects on CYP450 3A4 even after the agent has been discontinued. For example, some manufacturers of itraconazole recommend avoiding concomitant use of cabazitaxel during and for 2 weeks after itraconazole treatment.

ADJUST DOSING INTERVAL: Food may reduce the systemic bioavailability of amprenavir from fosamprenavir oral suspension. The mechanism of interaction has not been described. According to the product labeling, administration of fosamprenavir oral suspension (1400 mg single dose) with a high-fat meal (967 kcal, 67 g fat, 33 g protein, 58 g carbohydrate) reduced amprenavir peak plasma concentration (Cmax) by 46% and systemic exposure (AUC) by 28% compared to administration in a fasted state. The time to reach peak plasma level (Tmax) was delayed by 0.72 hours. In contrast, the same high-fat meal did not affect the pharmacokinetics of amprenavir from fosamprenavir tablets.

MANAGEMENT: Fosamprenavir suspension should be administered on an empty stomach in adults, but with food in pediatric patients to aid palatability and compliance. If emesis occurs within 30 minutes after dosing the suspension, the dose should be repeated. Fosamprenavir tablets may be taken with or without food.