High Exposure to Zidovudine During the First 2 Weeks of Life and ConcentrationToxicity Relationships

Hirt, Déborah PharmD, PhD*,†,‡; Warszawski, Josiane MD, PhD§,‖,¶; Firtion, Ghislaine MD, PhD#; Giraud, Carole PharmD, PhD*,†,‡,**; Chappuy, Hélène MD, PhD*,**,††,‡‡; Lechenadec, Jérôme PhD§; Benaboud, Sihem PharmD*,**; Urien, Saïk MD, PhD*,†,**; Blanche, Stéphane MD, PhD**,§§; Tréluyer, Jean-Marc MD, PhD*,†,‡,**

JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3182908c00
Basic and Translational Science
Abstract

Objectives: 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.

Author Information

*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.

Correspondence to: Déborah Hirt, PharmD, PhD, Service de Pharmacologie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France (e-mail: deborah.hirt@parisdescartes.fr).

The authors have no funding or conflicts of interest to disclose.

Received October 29, 2013

Accepted March 04, 2013

© 2013 by Lippincott Williams & Wilkins