Drug Interactions between amoxicillin / clarithromycin / omeprazole and docetaxel

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 or dual CYP450 3A4 and P-glycoprotein (P-gp) inhibitors may significantly increase the plasma concentrations of docetaxel, which is a substrate of both CYP450 3A4 and P-gp. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a suspected interaction with amiodarone was described in a case report involving a 77-year-old woman with HER2-positive invasive ductal breast cancer on long-term amiodarone therapy who developed increasing abdominal discomfort and skin lesions during 4 cycles of paclitaxel (80 mg/m2 weekly) and trastuzumab. A subsequent switch to docetaxel (100 mg or 75 mg/m2 weekly) led to the development of severe skin and mucosal toxicity, requiring hospitalization 8 days after the first docetaxel dose was administered. Analysis of two blood samples taken 9 and 10 days after docetaxel administration showed an approximately fivefold increase in its AUC as well as the presence of paclitaxel in unquantifiable levels, 20 and 21 days after it was last administered. In another case report, a 79-year-old man was hospitalized with fever, diarrhea, and grade 4 stomatitis and neutropenia after receiving a third cycle of docetaxel (35 mg/m2 on days 1 and 8 every 21 days) for metastatic androgen-independent prostate cancer while on dronedarone therapy (400 mg twice daily), which had been commenced 24 days earlier due to recurrence of atrial fibrillation. Docetaxel was still detectable in a plasma sample taken 24 days after it was last administered, at a concentration of approximately 2.4 ng/mL, even though its terminal half-life is about 12 hours. Unfortunately, the patient died after deterioration of his condition and multiple infectious complications. The authors of these case reports propose that, in addition to CYP450 3A4 inhibition, P-gp inhibition due to amiodarone and dronedarone may also have contributed to the interaction.

MANAGEMENT: Concomitant use of docetaxel with CYP450 3A4 inhibitors, particularly potent inhibitors or dual CYP450 3A4 and P-gp inhibitors such as itraconazole, ketoconazole, posaconazole, conivaptan, ceritinib, idelalisib, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics, should generally be avoided. Some authorities recommend avoiding concomitant use of docetaxel during and for 2 weeks after treatment with itraconazole. If concomitant use is required, a reduced dosage of docetaxel should be considered. Based on extrapolation from the pharmacokinetic study in 7 cancer patients, a 50% reduction in the docetaxel dose may be reasonable. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

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.