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.

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.