This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kakuda, T. N.
Right arrow Articles by Fletcher, C. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kakuda, T. N.
Right arrow Articles by Fletcher, C. V.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 2001, p. 236-242, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.236-242.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacological Basis for Concentration-Controlled Therapy with Zidovudine, Lamivudine, and Indinavir

Thomas N. Kakuda,1 Linda M. Page,1 Peter L. Anderson,1 Keith Henry,2 Timothy W. Schacker,3 Frank S. Rhame,4 Edward P. Acosta,1 Richard C. Brundage,1 and Courtney V. Fletcher1,*

Departments of Experimental and Clinical Pharmacology1 and Infectious Diseases,3 University of Minnesota Academic Health Sciences Center, and HIV and AIDS Program, Regions Hospital,2 St. Paul, and Abbott Northwestern Hospital, Minneapolis,4 Minnesota

Received 6 July 1999/Returned for modification 14 December 1999/Accepted 12 October 2000

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.

* Corresponding author. Mailing address: University of Minnesota, 7-151 WDH, 308 Harvard St., S.E., Minneapolis, MN 55455. Phone: (612) 624-6489. Fax: (612) 625-9931. E-mail: fletc001{at}tc.umn.edu.

Antimicrobial Agents and Chemotherapy, January 2001, p. 236-242, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.236-242.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Anderson, P. L., King, T., Zheng, J.-H., MaWhinney, S. (2008). Cytokine and sex hormone effects on zidovudine- and lamivudine-triphosphate concentrations in vitro. J Antimicrob Chemother 62: 738-745 [Abstract] [Full Text]  
  • Csajka, C., Marzolini, C., Fattinger, K., Decosterd, L. A., Telenti, A., Biollaz, J., Buclin, T. (2004). Population Pharmacokinetics of Indinavir in Patients Infected with Human Immunodeficiency Virus. Antimicrob. Agents Chemother. 48: 3226-3232 [Abstract] [Full Text]  
  • Holland, D. T., DiFrancesco, R., Stone, J., Hamzeh, F., Connor, J. D., Morse, G. D. (2004). Quality Assurance Program for Clinical Measurement of Antiretrovirals: AIDS Clinical Trials Group Proficiency Testing Program for Pediatric and Adult Pharmacology Laboratories. Antimicrob. Agents Chemother. 48: 824-831 [Abstract] [Full Text]  
  • Pfister, M., Labbe, L., Hammer, S. M., Mellors, J., Bennett, K. K., Rosenkranz, S., Sheiner, L. B. (2003). Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob. Agents Chemother. 47: 130-137 [Abstract] [Full Text]  
  • Hsu, A., Isaacson, J., Brun, S., Bernstein, B., Lam, W., Bertz, R., Foit, C., Rynkiewicz, K., Richards, B., King, M., Rode, R., Kempf, D. J., Granneman, G. R., Sun, E. (2003). Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients. Antimicrob. Agents Chemother. 47: 350-359 [Abstract] [Full Text]  
  • Shulman, N., Zolopa, A., Havlir, D., Hsu, A., Renz, C., Boller, S., Jiang, P., Rode, R., Gallant, J., Race, E., Kempf, D. J., Sun, E. (2002). Virtual Inhibitory Quotient Predicts Response to Ritonavir Boosting of Indinavir-Based Therapy in Human Immunodeficiency Virus-Infected Patients with Ongoing Viremia. Antimicrob. Agents Chemother. 46: 3907-3916 [Abstract] [Full Text]  
  • Khoo, S. H., Hoggard, P. G., Williams, I., Meaden, E. R., Newton, P., Wilkins, E. G., Smith, A., Tjia, J. F., Lloyd, J., Jones, K., Beeching, N., Carey, P., Peters, B., Back, D. J. (2002). Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors. Antimicrob. Agents Chemother. 46: 3228-3235 [Abstract] [Full Text]  
  • van Praag, R. M. E., van Weert, E. C. M., van Heeswijk, R. P. G, Zhou, X.-J., Sommadossi, J.-P., Jurriaans, S., Lange, J. M. A., Hoetelmans, R. M. W., Prins, J. M. (2002). Stable Concentrations of Zidovudine, Stavudine, Lamivudine, Abacavir, and Nevirapine in Serum and Cerebrospinal Fluid during 2 Years of Therapy. Antimicrob. Agents Chemother. 46: 896-899 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»