Drug Interactions between amoxicillin / clarithromycin / vonoprazan and atazanavir

GENERALLY AVOID: Concurrent use of inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) may decrease the oral bioavailability of atazanavir and substantially reduce its concentrations in plasma. Atazanavir solubility decreases with increasing pH, thus inhibition of gastric acid secretion may interfere with dissolution of the drug.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, use of PPIs or PCABs is not recommended in treatment-experienced patients receiving atazanavir with or without ritonavir or cobicistat. In treatment-naive patients receiving atazanavir with ritonavir or cobicistat, it is recommended that the dose of the PPI not exceed 20 mg/day of omeprazole, or equivalent, and doses should be separated by 12 hours. Some authorities recommend increasing the dose of atazanavir to 400 mg with 100 mg ritonavir when this combination is given with a PPI (UK). Atazanavir without ritonavir or cobicistat should not be coadministered with PPIs in treatment-naive patients.

ADJUST DOSE: Coadministration with atazanavir may significantly increase the plasma concentration of clarithromycin but decrease that of the active metabolite, 14-OH clarithromycin. The mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolism of clarithromycin. In 21 study subjects, atazanavir (400 mg once a day for 10 days) increased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of clarithromycin (500 mg once a day) by 50% and 94%, respectively, compared to administration of clarithromycin alone. In contrast, the Cmax and AUC of 14-OH clarithromycin were significantly reduced by 72% and 70%, respectively.

MANAGEMENT: Because increased plasma concentrations of clarithromycin may cause prolongation of the QT interval of the electrocardiogram, a dose reduction of clarithromycin by 50% is recommended for patients with moderate renal insufficiency (CrCl 30 to 60 mL/min) and a dose reduction by 75% is recommended for patients with severe renal insufficiency (CrCl less than 30 mL/min). The daily dose of clarithromycin should not exceed 1000 mg during concomitant use with protease inhibitors. In addition, because plasma concentrations of the active metabolite is significantly reduced, alternative therapy should be considered for indications other than infections due to Mycobacterium avium complex. Some authorities recommend avoiding the use of the fixed combination atazanavir-cobicistat with clarithromycin.

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.