Bilirubin—A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy

Abstract

Abstract. The objective of this work was to examine the atazanavir-bilirubin relationship using a populationbased 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 firstorder 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.

Atazanavir–bilirubin interaction: a pharmacokinetic–pharmacodynamic model

“…However, despite having nomograms for the calculation of exposition to ATZ based on the turnover concept and indirect response model, which support the conventional model in this area,20 the data obtained by applying our present model were not consistent with those obtained by applying nonograms published by other authors 9,18–20…”

“…With respect to the model for the quantification of ATZ-bilirubin interaction, previous studies have shown a positive correlation between ATZ exposure and hyperbilirubinemia that allow us to use BIL as a marker of ATZ exposure 18–20…”

“…Thus, because this model is only dependent on concentration increments of interacting drugs (from drug concentration at the start of the interaction to drug concentration at SS) and is not a kinetic model, where the concentration is expressed as a function of time, the present model is only applicable once SS is reached as for an adherence marker. Also, our model is independent of the pharmacokinetic model used whereas the models based on the turnover concept, where a drug can inhibit or stimulate the production or elimination of a given variable, by contrast, are linked to a pharmacokinetic model and are applicable at any time with the plasma concentration of the drug as a function of time 19,20…”

Predictors of first-line antiretroviral therapy discontinuation due to drug-related adverse events in HIV-infected patients: a retrospective cohort study

“…In our population, we did not observe any association with the explored parameters; however, the relevant proportion of missing data could have influenced such finding masking the real effects in terms of increased/reduced hazard of adverse events occurrence. Moreover, only baseline markers were analyzed, while the effect of current markers may be crucial, for instance the raise levels of bilirubin during atazanavir-containing antiretroviral therapy [28]. We decided not to perform a time-dependent analysis given the high rate of missing information in the baseline variables.…”

Adherence Profiles and Therapeutic Responses of Treatment-Naive HIV-Infected Patients Starting Boosted Atazanavir-Based Therapy in the ANRS 134-COPHAR 3 Trial

“…This might be due to the stringent algorithm that we used to classify self-reported adherence in the questionnaire and the difference between perceived adherence and objective adherence. Bilirubin level, which is more objective, has been linked to adherence to atazanavir (25,26). Of note, our data set served for external validation of the use of bilirubin level to detect suboptimal atazanavir exposure, as reported elsewhere (27).…”