JAC Advance Access published online on November 6, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp408
Original research |
Factors influencing lopinavir and atazanavir plasma concentration
1 MRC Clinical Trials Unit, London, UK 2 University of Liverpool, Liverpool, UK 3 University College Medical School, Royal Free Campus, London, UK 4 Imperial College Healthcare NHS Trust, London, UK 5 Department of Virology, University College London, London, UK 6 North Middlesex University Hospital NHS Trust, London, UK 7 Chelsea and Westminster NHS Trust, London, UK 8 Lothian University Hospitals NHS Trust, Edinburgh, UK 9 Brighton and Sussex University Hospitals NHS Trust, Brighton, UK 10 Barts and The London NHS Trust, London, UK 11 Homerton University Hospital NHS Trust, London, UK 12 Royal Free NHS Trust, London, UK 13 King's College Hospital, London, UK
Received 31 July 2009; returned 25 August 2009; revised 7 October 2009; accepted 11 October 2009
* Corresponding author. MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. Tel: +44-207-670-4802; Fax: +44-207-670-4818; E-mail: ws{at}ctu.mrc.ac.uk
Background: The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.
Methods: Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.
Results: Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).
Conclusions: This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.
Key Words: pharmacokinetics , rifabutin , drug interactions
Members of the UK CHIC Steering Committee are given in the Acknowledgements section.