Drug Interactions between amoxicillin / clarithromycin / omeprazole and cabazitaxel

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.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.