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

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Abstract

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.

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Acknowledgements

The NORTHIV study was supported by grants from the Sahlgrenska Academy at the University of Gothenburg (ALFGBG-11067), the Research Foundation of Swedish Physicians Against AIDS, The Health & Medical Care Committee of the Region Västra Götaland (VGFOUREG 2591), the Swedish Research Council (2007-7092) and the Stockholm County Council ALF-grant (581513). We thank Dr. Filip Josephson for valuable discussions concerning bilirubin kinetics and Gilbert’s syndrome.

Disclosure

Daniel Röshammar is a current employee of AstraZeneca. However, this work is not sponsored by AstraZeneca or any other pharmaceutical company.

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Authors and Affiliations

  1. Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Po Box 431, 405 30, Gothenburg, Sweden

    Dinko Rekić, Oskar Clewe, Angela Äbelö & Michael Ashton

  2. AstraZeneca R&D Mölndal, Mölndal, Sweden

    Daniel Röshammar

  3. Department of Infectious Diseases, Malmö University Hospital, Malmö, Sweden

    Leo Flamholc

  4. Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden

    Anders Sönnerborg

  5. Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway

    Vidar Ormaasen

  6. Department of Infectious Diseases, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden

    Magnus Gisslén

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  1. Dinko Rekić
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Correspondence to Dinko Rekić.

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Rekić, D., Clewe, O., Röshammar, D. et al. Bilirubin—A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy. AAPS J 13, 598–605 (2011). https://doi.org/10.1208/s12248-011-9299-0

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  • DOI: https://doi.org/10.1208/s12248-011-9299-0

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