title: Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis.
abstract: The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC0-24h) is not reached.
  
  
  
  Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4-18 years, body weight 3.4-60.5 kg); 2061 samples (median 12 per child); daily oral dose 60-300 mg (3.9-17.6 mg kg-1)]. Steady state AUC0-24hwas calculated per individual (adult target 8.9 mg·h l-1).
  
  
  
  A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2 l h-1(4.2%) and 38.9 l (7.0%) for a median individual of 16.6 kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14 kg and <14 kg, respectively, the target AUC0-24hwas reached.
  
  
  
  Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months-18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg-1day-1if the adult target for AUC0-24his aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Esther J H
authors.initials: EJH
authors.lastname: Janssen
authors.affiliation: Department of Pharmacy & Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Diane E T
authors.initials: DET
authors.lastname: Bastiaans
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Pyry A J
authors.initials: PAJ
authors.lastname: Välitalo
authors.affiliation: Division of Pediatric Infectious Diseases and Immunology, Erasmus MC/Sophia, Rotterdam, the Netherlands.
authors.forename: Annemarie M C
authors.initials: AMC
authors.lastname: van Rossum
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Université Paris VII, Paris, France.|Clinical Investigation Center CIC9202, INSERM, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
authors.affiliation: Department of Pediatrics, St Mary's Hospital, London, UK.
authors.forename: Hermione
authors.initials: H
authors.lastname: Lyall
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.|Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Catherijne A J
authors.initials: CAJ
authors.lastname: Knibbe
authors.affiliation: Department of Pharmacy & Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D015233:Models, Statistical; D011153:Population
chemical_list: D019380:Anti-HIV Agents; D019259:Lamivudine
keywords: human immunodeficiency virus/acquired immune deficiency syndrome; modelling and simulation; paediatrics; pharmacotherapy; therapeutic drug monitoring