Population pharmacokinetics of Zidovudine and its metabolite in HIV-1 infected children: Evaluation doses recommended

Floris Fauchet (1) (2), Jean-Marc Tréluyer (1) (2) (3) (4), Saïk Urien (1) (2) (4), Déborah Hirt (1) (2) (3) (4)

(1) EA 3620 Université Paris Descartes, Sorbonne Paris Cité, France, (2) Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France, (3) Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, France, (4) CIC-0901 Inserm, Cochin-Necker, Paris, France

Objectives: To describe Zidovudine (ZDV) pharmacokinetics (PK) and its biotransformation to its metabolite (G-ZDV) in HIV-infected children, to identify factors that influence the ZDV pharmacokinetics, to compare and evaluate doses recommended by the World Health Organization (WHO)[1] and by the Food and Drug Administration (FDA)[2]

Methods: In 247 children aged from 6 months to 18 years, ZDV and G-ZDV concentrations were collected. A total of 782 and 554 samples for the ZDV and G-ZDV were retrospectively measured on a routine basis. The data were analyzed using the nonlinear mixed-effect modeling software NONMEM (version 6.2) [3]

Results: A one-compartment model, with first-order absorption and elimination, was used to describe plasma ZDV concentrations. An additional compartment for G-ZDV was added, which was linked to the ZDV compartment with a first order rate constant. A combined variability and a proportional variability models were used to describe accurately the residual errors. The effect of bodyweight was significant on the apparent elimination clearance and on the apparent volume of distribution. The mean population parameter estimates (between-subject variability) were as follows: the apparent elimination clearance, 89.7 liters h^-1 (0.701);  the apparent volume of distribution, 229 liters (0.807); the apparent metabolic clearance, 12.6 h^-1.liters^-1 (0.352)  and the elimination rate constant of G-ZDV, 2.27 h^-1. Based on simulations of FDA and WHO dosing recommendations, the probabilities of observing exposure described as efficient (around 3 to 5 mg.L.h^-1)[4-6] with lower adverse event (below 8.4 mg.L.h^-1)[7] are higher following the FDA recommendations than the WHO recommendations. But, risks of toxicity are more important in children weighing from 20 to 40 kg, 20 % of their exposures were higher than the safety target.

Conclusions: Modelling and simulation of ZDV PK suggest that the FDA recommendations are more appropriate but lower doses should be considered for the weight band 20-40 kg. These results seem according to another study [8] which has suggested that the neonatal doses recommended by the WHO produced very high exposure of ZDV.

References:
[1] World Health Organization. 2010. Antiretroviral therapy for HIV infection in infants and children; towards universal access: recommendations for a public health approach. World Health Organization, Geneva.
[2] FOOD DRUG ADMINISTRATION. 2009. Office of clinical pharmacology review for Retrovir.
[3] Beal SL, Sheiner LB. 1998. NONMEM User Guides (I-VIII).
[4] Crémieux AC, Katlama C, Gillotin C, Demarles D, Yuen GJ, Raffi F. 2001. A comparison of the steady-state pharmacokinetics and safety of abacavir, lamivudine, and zidovudine taken as a triple combination tablet and as abacavir plus a lamivudine-zidovudine double combination tablet by HIV-1-infected adults. Pharmacotherapy 21:424-430.
[5] Vanhove GF, Kastrissios H, Gries JM, Verotta D, Park K, Collier AC, Squires K, Sheiner LB, Blaschke TF. 1997. Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy. Antimicrob. Agents Chemother. 41:2428-2432.
[6] Bergshoeff AS, Fraaij PLA, Verweij C, Van Rossum AMC, Verweel G, Hartwig NG, De Groot R, Burger DM. 2004. Plasma levels of zidovudine twice daily compared with three times daily in six HIV-1-infected children. J. Antimicrob. Chemother. 54:1152-1154.
[7] 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.
[8] 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 22 () Abstr 2783 [www.page-meeting.org/?abstract=2783]

Poster: Paediatrics

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