JAC Advance Access originally published online on April 4, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1161-1167; doi:10.1093/jac/dkl112
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The use of pharmacokinetically guided indinavir dose reductions in the management of indinavir-associated renal toxicity
1 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre Bangkok, Thailand 2 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales Sydney, Australia 3 Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Flinders University Bedford Park 5042, South Australia, Australia 4 Faculty of Medicine, Chulalongkorn University Bangkok, Thailand 5 Centre for Poverty-related Communicable Diseases, Academic Medical Centre, University of Amsterdam, and International Antiviral Therapy Evaluation Centre Amsterdam, The Netherlands 6 Department of Clinical Pharmacy, Radboud University Medical Centre Nijmegen, The Netherlands 7 Nijmegen University Centre for Infectious Diseases Nijmegen, The Netherlands
Received 16 January 2006; returned 14 February 2006; revised 28 February 2006; accepted 12 March 2006
*Correspondence address. Room 5D304.1, Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Flinders University, Bedford Park 5042, South Australia, Australia. Tel: +61-8-8204-4948; Fax: +61-8-8204-4733; E-mail: mark.boyd{at}fmc.sa.gov.au
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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