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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.