Déborah Hirt1, Josiane Warszawski, Ghislaine Firtion, Carole Giraud, Hélène Chappuy, Jérôme Lechenadec, Sihem Benaboud, Saïk Urien, Stéphane Blanche, Jean-Marc Tréluyer. 1. *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.
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.
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 ZDVglucuronide 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: Frantz Foissac; Jörn Blume; Jean-Marc Tréluyer; Thorkild Tylleskär; Chipepo Kankasa; Nicolas Meda; James K Tumwine; Mandisa Singata-Madliki; Kim Harper; Silvia M Illamola; Naïm Bouazza; Nicolas Nagot; Philippe Van de Perre; Stéphane Blanche; Déborah Hirt Journal: Antimicrob Agents Chemother Date: 2017-01-24 Impact factor: 5.191