title: High exposure to zidovudine during the first 2 weeks of life and concentration-toxicity relationships.
abstract: OBJECTIVE
  The aims of the study were in a large group of neonates to identify the relative effect of bodyweight, postnatal age, and gestational age on zidovudine (ZDV) pharmacokinetics; to link concentrations with lactate and hemoglobin levels; and to find the more appropriate neonatal ZDV dose.
  
  
  METHODS
  In 484 neonates aged 3-30 days, born to HIV-infected mothers, 767 ZDV and 417 ZDV glucuronide concentrations were collected.
  
  
  RESULTS
  Using a population approach, ZDV clearance per kilogram increased with postnatal age but not with gestational age. High neonatal exposures were found as follows: 14,025 ng/mL·h the first week and 6528 ng/mL·h the second week in comparison to 3000 ng/mL·h in adults. At month 1, median lactate level was 2.8 mmol/L (60%, ≥2.5 mmol/L) and median hemoglobin was 10.1 g/dL (90%, <12 g/dL). ZDV trough concentrations at first sampling (days 3-7) or at last sampling (day 20 ± 10) were significantly negatively correlated to hemoglobin at months 1, 3, and 6 (P < 0.02). ZDV maximal or trough concentrations at days 3-7 and at day 20 ± 10 were significantly positively correlated to lactate levels at months 3 and 6, respectively.
  
  
  CONCLUSIONS
  To obtain an exposure comparable to adults, which should reduce neonatal toxicity, doses should to be decreased during the first 2 weeks of life.
authors.affiliation: *AP-HP, Unité de Recherche clinique, Hôpital Tarnier, Paris, France; †CIC-0901 Inserm, Cochin-Necker, Paris, France; ‡AP-HP, Service de Pharmacologie Clinique, Hôpital Cochin, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France; §INSERM CESP U1018 Equipe VIH et IST, Le Kremlin-Bicêtre, France; ‖University of Paris-Sud, Le Kremlin-Bicêtre, France; ¶AP-HP, Service d'Epidémiologie et Santé Publique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; #AP-HP, Service de Néonatologie, Hôpital Cochin/Port Royal, Paris, France; **Université Paris Descartes EA 3620, Sorbonne Paris Cité, Paris, France; ††Laboratoire d'Ethique Médicale, Université Paris Descartes, Paris, France; ‡‡Service d'Urgences Pédiatriques, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; and §§AP-HP, Unité d'Immunologie, Hématologie et Rhumatologie Pédiatriques, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Hirt
authors.forename: Josiane
authors.initials: J
authors.lastname: Warszawski
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Firtion
authors.forename: Carole
authors.initials: C
authors.lastname: Giraud
authors.forename: Hélène
authors.initials: H
authors.lastname: Chappuy
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lechenadec
authors.forename: Sihem
authors.initials: S
authors.lastname: Benaboud
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tréluyer
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control* / Q000635:transmission; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007231:Infant, Newborn; D007773:Lactates / Q000097:blood; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D006454:Hemoglobins; D007773:Lactates; D015215:Zidovudine