Drug Interaction Report

MONITOR: Coadministration with cobicistat may increase the plasma concentrations of most HMG-CoA reductase inhibitors (i.e., statins) to varying degrees. Cobicistat is a potent inhibitor of CYP450 3A4 and can significantly increase exposure to statins that are primarily metabolized by the isoenzyme (e.g., atorvastatin, lovastatin, simvastatin). Cobicistat may also inhibit the OATP 1B1- and 1B3- mediated hepatic uptake of statins, thus even those that are not metabolized by CYP450 3A4 may be affected. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

MANAGEMENT: Caution is advised when statins are prescribed with cobicistat-containing regimens. The lowest starting dosage of the statin is recommended, then titrated as needed based on clinical response and tolerance. Some statins such as lovastatin and simvastatin are contraindicated for use with cobicistat. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.