Bilirubin—A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy
The objective of this work was to examine the atazanavir–bilirubin relationship using a population-based approach and to assess the possible application of bilirubin as a readily available marker of atazanavir exposure. A model of atazanavir exposure and its concentration-dependent effect on bilirubin levels was developed based on 200 atazanavir and 361 bilirubin samples from 82 patients receiving atazanavir in the NORTHIV trial. The pharmacokinetics was adequately described by a one-compartment model with first-order absorption and lag-time. The maximum inhibition of bilirubin elimination rate constant (I max) was estimated at 91% (95% CI, 87–94) and the atazanavir concentration resulting in half of I max (IC50) was 0.30 μmol/L (95% CI, 0.24–0.37). At an atazanavir/ritonavir dose of 300/100 mg given once daily, the bilirubin half-life was on average increased from 1.6 to 8.1 h. A nomogram, which can be used to indicate suboptimal atazanavir exposure and non-adherence, was constructed based on model simulations.