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Population pharmacokinetic analysisof lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates.

Methods

Population PK of LMV, STV and ZDV was separately evaluated from plasma concentrations obtained in 54, 39 and 27 HIV1-infected patients, respectively, enrolled in the COPHAR1-ANRS102 trial. The primary objective of this trial was to study the pharmacokinetics of indinavir (IDV) and nelfinavir (NFV) in treated patients with a sustained virological response. Concentrations of nucleoside analogs (NA) were measured in plasma as a secondary objective. A one-compartment model with first-order elimination was used, with zero-order absorption for LMV and first-order absorption for STV and ZDV.

Results

Mean parameters [interpatient variability in coefficient of variation (CV%)] of LMV, STV and ZDV were: oral volume of distribution (V/F) 145 l (52%), 24 l (81%) and 248 l (80%), oral clearance (Cl/F) 32 l/h, 16 l/h (74%) and 124 l/h (51%), respectively. For LMV, absorption duration (T a ) was 1.46 h (64%). For STV and ZDV, k a was 0.46 h−1 and 2.9 h−1, respectively. We found a systematic effect of combination with NFV vs. IDV. We found that intrapatient variability was greater than interpatient variability (except for STV) and greater than 55% for the three drugs.

Conclusion

This trial enabled the estimation of the population PK parameters of three NA in patients with a sustained virological response, and the median curves could be used as references for concentration-controlled strategies. We observed, as for the protease inhibitors, a great variability of PK parameters.

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Acknowledgements

This study was financially supported by the Agence Nationale de la Recherche sur le SIDA (ANRS), Paris, France.

We gratefully acknowledge all members of the scientific committee of the COPHAR1-ANRS102 trial: Prof V. Calvez (Hôpital Pitié-Salpétrière, Paris), Prof G. Chêne (INSERM U330, Bordeaux), Prof B. Diquet (Hôpital Pitié-Salpétrière, Paris), Prof C. Katlama (Hôpital Pitié-Salpétrière, Paris), Prof C. Leport (Hôpital Bichat, Paris), Mrs A. Metro (ANRS, Paris), Dr G. Peytavin (Hôpital Bichat, Paris), Prof F. Raffi (Hôpital Hôtel Dieu, Nantes), Dr A. Roux (Hôpital Ambroise Paré, Boulogne), and Prof D. Salmon-Ceron (Hôpital Cochin, Paris). We would like to thank the investigators in the clinical centres for including patients: J.M. Estavoyer, R. Laurent (Besançon), X. Bazin (Caen), C. Perrone (Garches), J.F. Delfraissy (Kremlin Bicêtre), F. Raffi (Nantes), E. Bouvet, F. Bricaire, S. Herson, W. Rozenbaum, D. Séréni, D. Sicard, A. Simon, J.L. Vildé (Paris), X. Lang (Strasbourg), and the pharmacological laboratories for performing drug assays: B. Royer, P. Muret (Besançon), M. Tod (Bobigny), A.M. Taburet (Kremlin Bicêtre), C. Solas (Marseille), D. Hillaire (Montpellier), E. Dailly (Nantes), B. Diquet, G. Peytavin, J.M. Poirier, E. Rey, H. Sauvageon (Paris), J.C. Alvarez (Versailles). We also thank the patients for their participation.

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Authors and Affiliations

  1. INSERM U738, 16 rue Henri Huchard, 75018, Paris, France

    Xavière Panhard & France Mentré

  2. INSERM U738; UF de Biostatistiques, AP-HP, Hôpital Bichat, Paris, France

    Xavière Panhard & France Mentré

  3. UFR de Médecine, Université Paris 7 Denis Diderot, Paris, France

    Xavière Panhard & France Mentré

  4. Département de Pharmacologie Clinique, AP-HP, Hôpital La Pitié-Salpétrière, Paris, France

    Mayeule Legrand

  5. Service de Pharmacie Clinique, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    Anne-Marie Taburet

  6. Service de Pharmacologie Clinique et Toxicologie, CHU ANGERS, Angers, France

    Bertrand Diquet

  7. Service de Médecine Interne, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    Cécile Goujard

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  1. Xavière Panhard
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  2. Mayeule Legrand
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  3. Anne-Marie Taburet
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  4. Bertrand Diquet
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  5. Cécile Goujard
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  6. France Mentré
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the Cophar 1 - ANRS 102 Study Group

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Correspondence to Xavière Panhard.

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Panhard, X., Legrand, M., Taburet, AM. et al. Population pharmacokinetic analysisof lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART. Eur J Clin Pharmacol 63, 1019–1029 (2007). https://doi.org/10.1007/s00228-007-0337-x

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  • DOI: https://doi.org/10.1007/s00228-007-0337-x

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