Floris Fauchet (1) (2), Elodie Valade (1) (2), Jean-Marc Tréluyer (1) (2) (3), Saïk Urien (1) (2) , Déborah Hirt (1) (2) (3)
(1) Université Paris Descartes, Sorbonne Paris Cité, EA 3620, (2) Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France, (3) Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, France
Objectives: The aims of this study were to describe the maternal and fetal zidovudine (ZDV) pharmacokinetics resulting from the maternal administration during pregnancy (orally) and labor (infusions), to estimate the placental transfer during pregnancy and to simulate different ZDV protocols during labor in order to get the lowest percentage of fetuses with high-risk toxicity (ZDV exposure higher than 8.4 mg.h/L)[1]
Methods: In a large HIV-infected population, 74 women in active labor, 56 pregnant (PW) and 89 non-pregnant women (NPW) were included. A total of 273 maternal and 79 cord blood ZDV concentrations were collected. Women (PW+NPW) received ZDV orally twice daily. At start of labor, 2 mg/kg/h was infused during the first hour then the rate was decreased to 1mg/kg/h until delivery. The data were analyzed using the nonlinear mixed-effect modeling software NONMEM.
Results:Women plasma ZDV concentration-time courses were best described by a one-compartment model with first-order absorption and elimination. An effect compartment with two exchange rate constants represented satisfactorily the cord blood concentrations. Residual variabilities were best described by proportional error models and BSVs were estimated for CL and V. No covariates (pregnancy, maternal bodyweight, maternal age, gestational age) had significant effect on CL or V. The mean population parameter estimates (between-subject variability) were: 56 % for bioavailability, 131 liters.h-1 (0.358) for clearance; 188 liters (0.363) for volume of distribution, and the two exchange rate constants, 1.21 and 0.943 h-1, respectively.
The placental transfer defined as fetal-to-maternal exposure ratio during pregnancy was estimated at 128 %. The median fetal exposure and the percentage of children with high-risk toxicity were 3.20 mg.h/L and 0 % after maternal oral administration; 9.71 mg.h/L and 51 % after maternal infusion during labor. Two options were considered to reduce fetal exposure during labor: (i) maternal infusion rates could be 1 mg/h/kg during 1 hour followed by 0.5 mg/h/kg, (ii) mother could only take oral ZDV every 5 hours from start of labor until delivery with her neonate having his first ZDV dose as soon as possible after birth.
Conclusions: Zidovudine exposures are very important during labor and during the first days of neonate’s life[2]. Maternal ZDV dose should be decreased in labor in order to protect the fetus against risk of ZDV toxicity.
References:
[1] Capparelli EV, Englund JA, Connor JD, Spector SA, McKinney RE, Palumbo P, Baker CJ. 2003. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. J. Clin. Pharmacol. 43:133–140
[2] Hirt D, Warszawski J, Firtion G, Giraud C, Chappuy H, Lechenadec J, Benaboud S, Urien S, Blanche S, Tréluyer J-M. 2013. High exposure to zidovudine during the two first weeks of life and concentration – toxicity relationships. J. Acquir. Immune Defic. Syndr.
Reference: PAGE 23 (2014) Abstr 3082 [www.page-meeting.org/?abstract=3082]
Poster: Drug/Disease modeling - Infection