Document Detail


Age-related differences in plasma and intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults.
MedLine Citation:
PMID:  23032419     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
INTRODUCTION: There is limited pediatric information on the complex relationships among the dose of tenofovir disoproxil fumarate (TDF), plasma concentrations of tenofovir (TFV), and intracellular TFV diphosphate (TFV-DP) concentrations. Our objectives were to describe TFV-DP pharmacokinetics in children and adolescents and investigate the effect of age on TFV and TFV-DP concentrations.
METHODS: TFV-DP pharmacokinetics were determined in 47 children and adolescents. TFV and TFV-DP were quantified with validated liquid chromatography/tandem mass spectrometry methods. Data were pooled with other studies in HIV-infected adults (N = 55). Nonlinear mixed effects modeling was used to develop the population model and explore the influence of covariates on TFV. A two-compartment model, partitioned for slow and fast absorbers by age, with weight allometrically scaled for children and adolescents, best described TFV pharmacokinetics. An indirect stimulation of response model best described TFV-DP formation.
RESULTS: Apparent oral TFV clearance was significantly faster in patients less than 25 versus 25 years or more. The most significant covariate on apparent TFV oral clearance and central distribution volume was creatinine clearance. The TFV plasma concentration producing 50% of maximal TFV-DP concentrations was almost two-fold lower in patients less than 25 versus 25 years or more. The estimated intracellular TFV-DP half-life for these groups was 70 and 87 h, respectively.
CONCLUSION: These data demonstrate that children and adolescents receiving standard TDF dosing of 300 mg once daily achieve higher intracellular TFV-DP concentrations than adults, despite lower plasma TFV concentrations. This age-related difference appears to arise from an increased sensitivity to formation of TFV-DP.
Authors:
Gautam Baheti; Jennifer R King; Edward P Acosta; Courtney V Fletcher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  AIDS (London, England)     Volume:  27     ISSN:  1473-5571     ISO Abbreviation:  AIDS     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-06-13     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  8710219     Medline TA:  AIDS     Country:  England    
Other Details:
Languages:  eng     Pagination:  221-5     Citation Subset:  IM; X    
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MeSH Terms
Descriptor/Qualifier:
Adenine / administration & dosage,  analogs & derivatives*,  pharmacokinetics
Adolescent
Adult
Age Factors
Anti-HIV Agents / administration & dosage,  pharmacokinetics*
Biological Availability
Child
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Female
HIV Infections / metabolism*
HIV-1 / drug effects,  metabolism
Humans
Male
Organophosphonates / administration & dosage,  pharmacokinetics*
Reverse Transcriptase Inhibitors / administration & dosage,  pharmacokinetics*
Tandem Mass Spectrometry
Grant Support
ID/Acronym/Agency:
P01 AI074340/AI/NIAID NIH HHS; P01 AI074340/AI/NIAID NIH HHS; U01 AI068632/AI/NIAID NIH HHS; U01 AI068632/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Anti-HIV Agents; 0/Organophosphonates; 0/Reverse Transcriptase Inhibitors; 0/tenofovir disoproxil; JAC85A2161/Adenine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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