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JAC Advance Access published online on April 4, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl112
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 16, 2006
Accepted March 12, 2006

Original article

The use of pharmacokinetically guided indinavir dose reductions in the management of indinavir-associated renal toxicity

Mark A. Boyd 1 *, Umaporn Siangphoe 2, Kiat Ruxrungtham 3, Peter Reiss 4, Apicha Mahanontharit 2, Joep M. A. Lange 4, Praphan Phanuphak 3, David A. Cooper 5, and David M. Burger 6

1 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Flinders University, Bedford Park 5042, South Australia, Australia
2 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
3 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
4 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Centre for Poverty-related Communicable Diseases, Academic Medical Centre, University of Amsterdam, and International Antiviral Therapy Evaluation Centre, Amsterdam, The Netherlands
5 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
6 Department of Clinical Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen University Centre for Infectious Diseases, Nijmegen, The Netherlands

* To whom correspondence should be addressed.
Mark A. Boyd, E-mail: mark.boyd{at}fmc.sa.gov.au


  Abstract

Objectives: Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therapeutic drug monitoring in patients with virological success but established nephrotoxicity on an indinavir-containing regimen.

Methods: We measured indinavir Ctrough/C2h, serum creatinine, pyuria, blood pressure (BP), weight and HIV RNA. The major endpoint of interest was the number of patients achieving a normal creatinine level 20 weeks following final indinavir dose adjustment. Primary analysis was by intention to treat (ITT).

Results: A total of 35 patients were enrolled; mean (SD) age 40.3 (5.8) years; mean (SD) BMI 21.5 (2.8) kg/m2. At baseline 6/35 (17%) had a serum creatinine concentration within normal limits, but were offered enrolment because of previous nephrotoxicity (nephrolithiasis and/or abnormal serum creatinine), and a screening pharmacokinetic profile associated with increased nephrotoxicity risk. By ITT analysis 11/35 (31%) had normal creatinine at study end (P = 0.18). Of the 29 patients with abnormal creatinine at baseline, 7/29 (24.1%) had normal creatinine at study end (P = 0.016). Patients had a median (IQR) indinavir per dose adjustment over the study of 400 (400-800) mg. We observed improvements in estimated creatinine clearance, pyuria, resting BP and indinavir pharmacokinetic profile. HIV RNA control was maintained with continued immune recovery despite lower indinavir doses.

Conclusions: Patients experiencing nephrotoxicity on an indinavir-containing regimen were safely maintained on indinavir by means of therapeutic drug monitoring. Parameters of renal function improved but did not return to baseline values, at least in the short-term.

Keywords: HIV; nephrotoxicity; pyuria; pharmacokinetics (PK); therapeutic drug monitoring; serum creatinine; creatinine clearance; blood pressure (BP); Thailand; resource-limited setting.
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