title: Age-related differences in plasma and intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.affiliation: Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198-6000, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Baheti
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: King
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine