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

Rekic, Dinko; Clewe, Oskar; Roshammar, Daniel; Flamholc, Leo LU ; Sonnerborg, Anders; Ormaasen, Vidar; Gisslen, Magnus; Abelo, Angela and Ashton, Michael (2011) In AAPS Journal 13(4). p.598-605
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 mu mol/L (95%... (More)
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 mu mol/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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atazanavir, bilirubin, HIV/AIDS, pharmacodynamics, pharmacokinetics
in
AAPS Journal
volume
13
issue
4
pages
598 - 605
publisher
American Association of Pharmaceutical Scientists
external identifiers
  • wos:000297358100008
  • scopus:83555168318
ISSN
1550-7416
DOI
10.1208/s12248-011-9299-0
language
English
LU publication?
yes
id
3f4283d7-9d73-4284-84a1-581dc0c91f45 (old id 2272686)
date added to LUP
2012-01-02 09:50:23
date last changed
2017-09-24 04:03:54
@article{3f4283d7-9d73-4284-84a1-581dc0c91f45,
  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 mu mol/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.},
  author       = {Rekic, Dinko and Clewe, Oskar and Roshammar, Daniel and Flamholc, Leo and Sonnerborg, Anders and Ormaasen, Vidar and Gisslen, Magnus and Abelo, Angela and Ashton, Michael},
  issn         = {1550-7416},
  keyword      = {atazanavir,bilirubin,HIV/AIDS,pharmacodynamics,pharmacokinetics},
  language     = {eng},
  number       = {4},
  pages        = {598--605},
  publisher    = {American Association of Pharmaceutical Scientists},
  series       = {AAPS Journal},
  title        = {Bilirubin-A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy},
  url          = {http://dx.doi.org/10.1208/s12248-011-9299-0},
  volume       = {13},
  year         = {2011},
}