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 Zhou, X.-J.
Right arrow Articles by The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhou, X.-J.
Right arrow Articles by The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators,

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 1999, p. 121-128, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Population Pharmacokinetics of Nevirapine, Zidovudine, and Didanosine in Human Immunodeficiency Virus-Infected Patients

Xiao-Jian Zhou,1 Lewis B. Sheiner,2 Richard T. D'Aquila,3 Michael D. Hughes,4,5 Martin S. Hirsch,3 Margaret A. Fischl,6 Victoria A. Johnson,1 Maureen Myers,7 Jean-Pierre Sommadossi,1,* and The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigatorsdagger

Departments of Pharmacology and Medicine, Divisions of Clinical Pharmacology and Infectious Diseases, Birmingham Veterans Affairs Medical Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama1; Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco, San Francisco, California2; Infectious Disease Unit and AIDS Research Center, Massachusetts General Hospital, Harvard Medical School,3 and Harvard School of Public Health,4 Boston, Massachusetts; London School of Hygiene and Tropical Medicine, London, United Kingdom5; University of Miami School of Medicine, Miami, Florida6; and Boehringer-Ingelheim Pharmaceuticals, Ridgefield, Connecticut7

Received 1 December 1997/Returned for modification 2 May 1998/Accepted 10 September 1998

The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL, VSS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of VSS. The average individual oral CL, VSS, and V of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and VSS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (FTRIPLE = 1.05 and FDOUBLE = 1 by definition), but the F of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.

* Corresponding author. Mailing address: Department of Pharmacology, Division of Clinical Pharmacology, University of Alabama at Birmingham School of Medicine, Volker Hall G019, 1670 University Blvd., Birmingham, AL 35294-0019. Phone: (205) 934-8226. Fax: (205) 975-4871. E-mail: Jean-Pierre.Sommadossi{at}CCC.UAB.EDU.

dagger Listed in Appendix.

Antimicrobial Agents and Chemotherapy, January 1999, p. 121-128, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Hurwitz, S. J., Asif, G., Kivel, N. M., Schinazi, R. F. (2008). Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model. Antimicrob. Agents Chemother. 52: 4241-4250 [Abstract] [Full Text]  
  • Molto, J., Valle, M., Miranda, C., Cedeno, S., Miranda, J., Santos, J. R., Negredo, E., Vilaro, J., Costa, J., Clotet, B. (2008). Once- or twice-daily dosing of nevirapine in HIV-infected adults: a population pharmacokinetics approach. J Antimicrob Chemother 62: 784-792 [Abstract] [Full Text]  
  • Ofotokun, I., Chuck, S. K., Binongo, J. N., Palau, M., Lennox, J. L., Acosta, E. P. (2007). Lopinavir/Ritonavir Pharmacokinetic Profile: Impact of Sex and Other Covariates Following a Change From Twice-Daily to Once-Daily Therapy. J Clin Pharmacol 47: 970-977 [Abstract] [Full Text]  
  • Zhou, H. (2006). Population-based assessments of clinical drug-drug interactions: qualitative indices or quantitative measures?. J Clin Pharmacol 46: 1268-1289 [Abstract] [Full Text]  
  • Cooper, D. A. (2002). Update on Didanosine. J Int Assoc Physicians AIDS Care (Chic Ill) 1: 15-25 [Abstract]  
  • Hader, S. L., Smith, D. K., Moore, J. S., Holmberg, S. D. (2001). HIV Infection in Women in the United States: Status at the Millennium. JAMA 285: 1186-1192 [Abstract] [Full Text]  
  • Izzedine, H., Launay-Vacher, V., Aymard, G., Legrand, M., Deray, G. (2001). Pharmacokinetic of nevirapine in haemodialysis. Nephrol Dial Transplant 16: 192-193 [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»