Evaluation of nevirapine dosing recommendations in HIV-infected children

Authors

  • Frantz Foissac,

    Corresponding author
    1. Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France
    • EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
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  • Naïm Bouazza,

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France
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  • Pierre Frange,

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité d'immunologie, hématologie et rhumatologie pédiatriques, Hôpital Necker, AP-HP, Paris, France
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  • Stéphane Blanche,

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité d'immunologie, hématologie et rhumatologie pédiatriques, Hôpital Necker, AP-HP, Paris, France
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  • Albert Faye,

    1. Service de Pédiatrie générale, Hôpital Robert Debré, AP-HP, Paris, France
    2. Université Paris Diderot Sorbonne Paris Cité, Paris, France
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  • Eric Lachassinne,

    1. Service de Pédiatrie, Hôpital Jean Verdier, AP-HP, Paris, France
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  • Catherine Dollfus,

    1. Service d'Hématologie et d'oncologie pédiatrique, Hôpital Trousseau, AP-HP, Paris, France
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  • Déborah Hirt,

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France
    3. CIC-0901 Inserm & AP-HP, Paris, France
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  • Sihem Benaboud,

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France
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  • Jean-Marc Treluyer,

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France
    3. CIC-0901 Inserm & AP-HP, Paris, France
    4. Laboratoire de Pharmacologie, Hôpital Cochin, Paris, France
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    • J.-M.T. and S.U. contributed equally to this work.
  • Saïk Urien

    1. EA 3620 Université Paris Descartes Sorbonne Paris Cité, Paris, France
    2. Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France
    3. CIC-0901 Inserm & AP-HP, Paris, France
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    • J.-M.T. and S.U. contributed equally to this work.

Correspondence

Frantz Foissac, Unité de Recherche Clinique, Hôpital Tarnier, 89 rue d'Assas, F75006 Paris, France.

Tel.: +33 1 5841 3386

Fax: +33 1 5841 1183

E-mail: frantz.foissac@cch.aphp.fr

Abstract

Aims

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations.

Methods

Concentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolix 4.0.

Results

Nevirapine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70 kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9 l h−1 (70 kg)−1 and 140 l (70 kg)−1, respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3 mg l−1 is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3–6 and 6–10 kg weight ranges following the WHO recommendations.

Conclusions

It is suggested to increase doses to 75 and 100 mg twice daily for the 3–6 and 6–10 kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3 mg l−1.

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