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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10990/636

Autori: Cojutti, Pier Giorgio
Supervisore afferente all'Università: BARALDO, MASSIMO
Centro di ricerca: DIPARTIMENTO SCIENZE MEDICHE E BIOLOGICHE - DSMB
Titolo: Pharmacokinetic/pharmacodynamic relationship and simulation analysis for the evaluation of isoniazid hepatotoxicity risk development in patients with tuberculosis
Abstract (in inglese): INTRODUCTION: Isoniazid represents a pivotal drug in the treatment of tuberculosis. Its peculiar hepatic clearance leads to drug accumulation with consequent development of hepatotoxicity in subjects with the slow acetylator phenotypic profile. The aim of this study was to investigate the concentration-toxicity relationship in order to establish the most reliable isoniazid exposure threshold associated with the likelihood of developing hepatotoxicity. METHODS: A retrospective observational study conducted on 185 patients whose hepatic function along with isoniazid plasma area under the curve (AUC0-24h) has been conducted. RESULTS: The ROC analysis identified an isoniazid AUC0-24h value of 55 mgh/L as the threshold that best discriminate between subjects who will and will not develop hepatotoxicity. The logistic regression model estimated a 50% and 90% likelihood of developing hepatotoxicity when in presence of an isoniazid AUC0-24h of 53.7 mgh/L and 70.0 mgh/L respectively. Monte Carlo Simulation analysis showed that isoniazid dose of 2.5, 5 and 7.5 mg/kg daily are associated with 8.9, 45.7 and 72.5% likelihood of developing hepatotoxicity in slow acetylators respectively, whereas the same probabilities in rapid acetylators are 0.03, 3.46 and 18.6%, respectively. CONCLUSIONS: the results of this study are expected to guide clinicians in tailoring isoniazid drug regimen with respect to each patient specific acetylator status, with the intent of minimizing the development of hepatotoxicity
Parole chiave: Isoniazid; Hepatotoxicity; PK/PD relationship; Tuberculosis; Simulation
MIUR : Settore BIO/14 - Farmacologia
Lingua: eng
Data: 6-mag-2015
Corso di dottorato: Dottorato di ricerca in Scienze e tecnologie cliniche
Ciclo di dottorato: 27
Università di conseguimento titolo: Università degli Studi di Udine
Luogo di discussione: Udine
Altre informazioni: Istituto presso il quale è stata svolta la ricerca: SOC Istituto di Farmacologia Clinica, Azienda Ospedaliero-Universitaria di Udine - Co-supervisori: Miriam Isola, Federico Pea
Citazione: Cojutti, P.G. Pharmacokinetic/pharmacodynamic relationship and simulation analysis for the evaluation of isoniazid hepatotoxicity risk development in patients with tuberculosis. (Doctoral Thesis, Università degli Studi di Udine, 2015).
In01 - Tesi di dottorato

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