Dinko Rekić (1), Daniel Röshammar (2), Martin Bergstrand (3), Joel Tarning (4),(5), Vidar Ormaasen (6), Michael Ashton (1), Magnus Gisslén (7) and Angela Äbelö (1)
Institution: (1) Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. (2) AstraZeneca R&D Mölndal, Sweden, (3) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (4) Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (5) Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK, (6) Department of Infectious Diseases, Division of Internal Medicine, Oslo University Hospital, Oslo, Norway, (7) Department of Infectious Diseases, Sahlgrenska University Hospital, University of Gothenburg, Sweden
Objectives: Atazanavir increases bilirubin levels in patients in a concentration dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work a previously developed nomogram, based on a indirect response bilirubin PK/PD model, for detection of sub-optimal atazanavir exposure is validated against an external patient population [1].
Methods: The bilirubin nomogram was validated against an external dataset of 98 matching bilirubin and atazanavir samples from 76 HIV-1 infected patients. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. Additionally the use of the nomogram to detect non-adherence was investigated by simulation.
Results: The bilirubin nomogram predicted underexposure in the external patient population with a sensitivity of 100% (95% CI: 28-100) and a specificity of 91% (95% CI: 84-96). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during the period of non-adherence they had lower predictive power to detect past non-adherence episodes. The nomogram had significantly higher negative predictive value (98% [95% CI: 97-99]) compared to atazanavir measurement (91% [95% CI: 89-92]) in detecting non-adherence in patient secretly taking a dose just before a monitoring event after a period of non-adherence.
Conclusions: Using the bilirubin nomogram for detection of sub-optimal atazanavir exposure in patients is a cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings especially so in resource-limited areas.
References: [1] Rekić, D., Clewe, O., Röshammar, D., Flamholc, L., Sönnerborg, A., Ormaasen, V., Gisslén, M., et al. (2011). Bilirubin-A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy. The AAPS journal, 13(4), 598-605. Springer New York.
Disclosure
Daniel Röshammar is a current employee of AstraZeneca. However, this work is not sponsored by AstraZeneca or any other pharmaceutical company.
Reference: PAGE 21 (2012) Abstr 2510 [www.page-meeting.org/?abstract=2510]
Poster: Infection