title: Population pharmacokinetic analysis of lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART.
abstract: OBJECTIVE
  This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates.
  
  
  METHODS
  Population PK of LMV, STV and ZDV was separately evaluated from plasma concentrations obtained in 54, 39 and 27 HIV1-infected patients, respectively, enrolled in the COPHAR1-ANRS102 trial. The primary objective of this trial was to study the pharmacokinetics of indinavir (IDV) and nelfinavir (NFV) in treated patients with a sustained virological response. Concentrations of nucleoside analogs (NA) were measured in plasma as a secondary objective. A one-compartment model with first-order elimination was used, with zero-order absorption for LMV and first-order absorption for STV and ZDV.
  
  
  RESULTS
  Mean parameters [interpatient variability in coefficient of variation (CV%)] of LMV, STV and ZDV were: oral volume of distribution (V/F) 145 l (52%), 24 l (81%) and 248 l (80%), oral clearance (Cl/F) 32 l/h, 16 l/h (74%) and 124 l/h (51%), respectively. For LMV, absorption duration (Ta) was 1.46 h (64%). For STV and ZDV, ka was 0.46 h(-1) and 2.9 h(-1), respectively. We found a systematic effect of combination with NFV vs. IDV. We found that intrapatient variability was greater than interpatient variability (except for STV) and greater than 55% for the three drugs.
  
  
  CONCLUSIONS
  This trial enabled the estimation of the population PK parameters of three NA in patients with a sustained virological response, and the median curves could be used as references for concentration-controlled strategies. We observed, as for the protease inhibitors, a great variability of PK parameters.
authors: INSERM U738, 16 rue Henri Huchard, 75018, Paris, France. xaviere.panhard@bichat.inserm.fr
authors: Xavière
authors: X
authors: Panhard
authors: Mayeule
authors: M
authors: Legrand
authors: Anne-Marie
authors: AM
authors: Taburet
authors: Bertrand
authors: B
authors: Diquet
authors: Cécile
authors: C
authors: Goujard
authors: France
authors: F
authors: Mentré
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D019259:Lamivudine / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D019888:Nelfinavir / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*; D018119:Stavudine / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015215:Zidovudine / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir; D018119:Stavudine; D019888:Nelfinavir
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