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Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

Csajka, Chantal ; Décosterd, Laurent ; Buclin, Thierry ; Pagani, Jean-Luc ; Fattinger, Karin ; Bille, Jacques ; Biollaz, Jérôme

In: European Journal of Clinical Pharmacology, 2001, vol. 57, no. 10, p. 723-727

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    Title
    • Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients
    Author
    • Csajka, Chantal. Division of Clinical Pharmacology, University Hospital, CHUV, Lausanne, Switzerland, Switzerland
    • Décosterd, Laurent. Division of Clinical Pharmacology, University Hospital, CHUV, Lausanne, Switzerland, Switzerland
    • Buclin, Thierry. Division of Clinical Pharmacology, University Hospital, CHUV, Lausanne, Switzerland, Switzerland
    • Pagani, Jean-Luc. Division of Infectious Diseases, University Hospital CHUV, Lausanne, Switzerland, Switzerland
    • Fattinger, Karin. Division of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland, Switzerland
    • Bille, Jacques. Division of Infectious Diseases, University Hospital CHUV, Lausanne, Switzerland, Switzerland
    • Biollaz, Jérôme. Division of Clinical Pharmacology, University Hospital, CHUV, Lausanne, Switzerland, Switzerland
    Document Type
    • Postprint
    Language
    • English
    Published in
    • European Journal of Clinical Pharmacology, 2001, vol. 57, no. 10, p. 723-727. Springer-Verlag
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:309869
    Summary
    Abstract.: Objectives: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. Methods: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37months in 132 HIV+ patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. Results: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorption from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79l/h, the volume of distribution 57l and the absorption constant (ka) 0.93h-1. Inter-occasion variability in clearance (45%) was large relative to inter-subject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. Conclusion: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary prevention