Pharmacokinetics

Evaluation of Nevirapine Dosing Recommendations in HIV-infected Children

  1. Frantz Foissac1,2,*,
  2. Naïm Bouazza1,2,
  3. Pierre Frange1,3,
  4. Stéphane Blanche1,3,
  5. Albert Faye4,5,
  6. Eric Lachassinne6,
  7. Catherine Dollfus7,
  8. Déborah Hirt1,2,8,
  9. Sihem Benaboud1,2,
  10. Jean-Marc Treluyer1,2,8,9,†,
  11. Saïk Urien1,2,8,†

DOI: 10.1111/bcp.12069

Additional Information

Author Information

  1. 1

    EA 3620 Université Paris Descartes Sorbonne Paris Cité, France

  2. 2

    Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, France

  3. 3

    Unité d′immunologie, hématologie et rhumatologie pédiatriques, Hôpital Necker, APHP, France

  4. 4

    Service de Pédiatrie générale, Hôpital Robert Debré, AP-HP, France

  5. 5

    Université Paris Diderot Sorbonne Paris Cité, Paris, France

  6. 6

    Service de Pédiatrie, Hôpital Jean Verdier, AP-HP, France

  7. 7

    Service d'Hématologie et d'oncologie pédiatrique, Hôpital Trousseau, APHP, France

  8. 8

    CIC-0901 Inserm & APHP, France

  9. 9

    Laboratoire de Pharmacologie, Hôpital Cochin, Paris, France

  1. †

    # Both last authors contributed equally to this work.

* CORRESPONDENCE:
Frantz FOISSAC
Unité de Recherche Clinique
Hôpital Tarnier
89 rue d'Assas
F75006 Paris
frantz.foissac@cch.aphp.com

  1. †

    # Both last authors contributed equally to this work.

  2. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12069

Publication History

  1. Accepted manuscript online: 28 DEC 2012 02:01AM EST
  2. Manuscript Accepted: 16 DEC 2012

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Keywords:

  • nevirapine;
  • population pharmacokinetics;
  • children

Abstract

Aims

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic HIV 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 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

NVP 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. Apparent clearance and volume of distribution estimates were respectively 3.9 L.h-1 70 kg-1 and 140 L 70 kg-1. Based on simulations of EMA and WHO dosing recommendations, the probability to observe minimal concentrations below the efficacy target of 3 mg/L is higher following the EMA recommendations than the WHO recommendations. However NVP under-dosing persists for the 3-6 kg and 6-10 kg weight ranges following the WHO recommendations.

Conclusions

It is suggested to increase doses to 75 mg BID and 100 mg BID for the 3-6 kg and 6-10 kg weight ranges respectively in order to obtain more than 95% of children with concentrations above 3 mg/L.

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