Drug Interactions between amoxicillin / omeprazole / rifabutin 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 concentrations of rifabutin and its active 25-O-desacetyl metabolite. The mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of rifabutin. In 3 study subjects, atazanavir (600 mg once a day for 10 days) increased the mean steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of rifabutin (300 mg once daily for 10 days followed by 150 mg once a day for 10 days) by 18%, 110% and 243%, respectively. The Cmax, AUC and Cmin of the 25-O-desacetyl metabolite were 8, 22, and 75 times the values observed with rifabutin alone. In another study, 7 subjects administered atazanavir/ritonavir (300 mg/100 mg once daily for 17 days) also increased Cmax, AUC and Cmin of rifabutin (150 mg twice weekly for 15 days) by 149%, 48% and 40%, respectively.

MANAGEMENT: Use of atazanavir-cobicistat with rifabutin is considered contraindicated by some authorities (Australia). However, if concomitant use of atazanavir-cobicistat, or atazanavir-ritonavir with rifabutin is needed, some authorities recommend a reduction in the rifabutin dosage of up to 75% (e.g., 150 mg every other day or three times per week). A further dosage reduction of rifabutin to 150 mg twice weekly may be necessary for patients in whom the 150 mg three times per week dose is not tolerated. Patients should be monitored for rifabutin toxicity such as leucopenia, uveitis, arthralgias and skin discoloration. Current guidelines should be consulted for the appropriate treatment of tuberculosis in HIV infected patients.