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Antimicrobial Agents and Chemotherapy, October 2007, p. 3516-3522, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.01626-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Intracellular Pharmacokinetics of Once versus Twice Daily Zidovudine and Lamivudine in Adolescents{triangledown} ,{ddagger}

Patricia M. Flynn,1,2*,{dagger} John Rodman,3,{dagger} Jane C. Lindsey,4 Brian Robbins,1 Edmund Capparelli,5 Katherine M. Knapp,1,2 Jose F. Rodriguez,6,7 James McNamara,8 Leslie Serchuck,9 Barbara Heckman,10 Jaime Martinez,11 the PACTG P1012 Team

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee,1 Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee,2 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee,3 Statistical & Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts,4 Pediatric Pharmacology Research Unit, University of California, San Diego, California,5 Department of Biochemistry, University of Puerto Rico, San Juan, Puerto Rico,6 Puerto Rico Forensic Sciences Institute, San Juan, Puerto Rico,7 National Institute of Allergy and Infectious Diseases,8 National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland,9 Frontier Science & Technology Research Foundation, Amherst, New York,10 Department of Pediatrics, Stroger Hospital of Cook County/CORE Center, Chicago, Illinois,11

Received 29 December 2006/ Returned for modification 15 February 2007/ Accepted 19 July 2007

Zidovudine (ZDV) and lamivudine (3TC) metabolism to triphosphates (TP) is necessary for antiviral activity. The aims of this study were to compare ZDV-TP and 3TC-TP concentrations in adolescents receiving twice daily (BID) and once daily (QD) regimens and to determine the metabolite concentrations of ZDV and 3TC during chronic therapy on a QD regimen. Human immunodeficiency virus-infected patients (12 to 24 years) taking ZDV (600 mg/day) and 3TC (300 mg/day) as part of a highly active antiretroviral therapy regimen received QD and BID regimens of ZDV and 3TC for 7 to 14 days in a crossover design. Serial blood samples were obtained over 24 h on the QD regimen. Intracellular mono-, di-, and triphosphates for ZDV and 3TC were measured. The median ratio of BID/QD for ZDV-TP predose concentrations was 1.28 (95% confidence interval [CI] = 1.00 to 2.45) and for 3TC-TP was 1.12 (95% CI = 0.81 to 1.96). The typical population estimated half-lives (± the standard error of the mean) were 9.1 ± 0.859 h for ZDV-TP and 17.7 ± 2.8 h for 3TC-TP. Most patients had detectable levels of the TP of ZDV (24 of 27) and 3TC (24 of 25) 24 h after dosing, and half-lives on a QD regimen were similar to previously reported values when the drugs were given BID. Lower, but not significantly different, concentrations of ZDV-TP were demonstrated in the QD regimen compared to the BID regimen (P = 0.056). Although findings were similar between the BID and QD groups, the lower concentrations of ZDV and the number of patients below the level of detection after 24 h suggests that ZDV should continue to be administered BID.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105. Phone: (901) 495-2338. Fax: (901) 495-5068. E-mail: pat.flynn{at}stjude.org

{triangledown} Published ahead of print on 30 July 2007.

{ddagger} This study is presented in honor of John Rodman, who passed away in April 2006.

{dagger} P.M.F. and J.R. contributed equally to this study.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3516-3522, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.01626-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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