Intracellular Pharmacokinetics of Once versus Twice Daily Zidovudine and Lamivudine in Adolescents

Author:

Flynn Patricia M.12,Rodman John3,Lindsey Jane C.4,Robbins Brian1,Capparelli Edmund5,Knapp Katherine M.12,Rodriguez Jose F.67,McNamara James8,Serchuck Leslie9,Heckman Barbara10,Martinez Jaime11

Affiliation:

1. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee

2. Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee

3. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee

4. Statistical & Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts

5. Pediatric Pharmacology Research Unit, University of California, San Diego, California

6. Department of Biochemistry, University of Puerto Rico, San Juan, Puerto Rico

7. Puerto Rico Forensic Sciences Institute, San Juan, Puerto Rico

8. National Institute of Allergy and Infectious Diseases

9. National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland

10. Frontier Science & Technology Research Foundation, Amherst, New York

11. Department of Pediatrics, Stroger Hospital of Cook County/CORE Center, Chicago, Illinois

Abstract

ABSTRACT 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.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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