Flurbiprofen, α-Methyl-α-(2-fluoro-4-biphenylyl)acetic acid, is a nonsteroidal anti-inflammatory drug (NSAID) used in racemic mixture for local oromucosal treatment of painfuland/or inflammatory conditions of the oropharynx. In this work was developed and validated an analytical method to determine pharmacokinetic profile of plasmatic Flurbiprofen in order to study bioequivalence, and in particular non-superiority, between a new generic formulation of tablets (test) compared to a commercial product (reference) in a Phase I clinical trial. The analytical method was developed with HPLC-MS/MS system with an ESI source, operating in negative mode, and a triple quadrupole detector. Validation was conducted in accordance with EMA guidelines ("Guideline on bioanalytical Method Validation", July 21, 2011) and good laboratory practice guidelines (GLP); were performed tests of selectivity and specificity, carry-over, linearity (4000 - 50ng/mL in plasma), limit of quantification (LOQ, 50ng/mL in plasma), accuracy and precision (within and between- analytical run), matrix effect, dilution integrity and various stability tests. The analytical method was in accordance with the guidelines and was employed for the analysis of plasma samples from 24 volunteers who participated in clinical trial. Bioequivalence between the two formulations was demonstrated and has been published a clinical article, based on analytical data obtained, where was studied the alleged influence of the oral dissolution time (i.e. time spent suckling the lozenge from its intake to complete dissolution) on speed and total variability of plasmatic Flurbiprofen during absorption.
Il Flurbiprofene, acidoα-Metil-α-(2-fluoro-4-bifenilil) acetico, è un farmaco antinfiammatorio non steroideo (FANS) utilizzato in miscela racemica nel trattamento locale del dolore della mucosa orale e/o di condizioni infiammatorie del tratto orofaringeo. In questo lavoro è stato sviluppato e validato un metodo analitico per determinare il profilo farmacocinetico di Flurbiprofene plasmatico al fine di studiare la bioequivalenza, e in particolare la non superiorità, tra una nuova formulazione generica di pastiglie (test) rispetto al prodotto commerciale (reference) all'interno di uno studio clinico di Fase I. Il metodo di determinazione utilizzato è stato sviluppato con sistema HPLC-MS/MS dotato di una sorgente ESI, operantein modalità negativa, e rivelatore a triplo quadrupolo. La validazione è stata condotta in accordo con le linee guida EMA (“Guideline on Bioanalytical Method Validation”,21 Luglio 2011) e quelle per la buona pratica di laboratorio (GLP); sono state eseguite prove di selettività e specificità, carry-over, linearità (4000 - 50ng/mL in plasma), limite di quantificazione (LOQ, 50ng/mL in plasma), accuratezza e precisione (intra e inter-corsa analitica), effetto matrice, diluizione di campioni e le varie prove di stabilità. Il metodo analitico è risultato conforme alle linee guida ed è stato impiegato per l’analisi di campioni plasmatici dei 24 volontari che hanno partecipato allo studio clinico. È stata dimostrata la bioequivalenza tra le due formulazioni. Sulla base dei dati analitici ottenuti tramite il metodo, in unostudio clinico è stata consideratala presuntainfluenza del tempo di dissoluzione orale (cioè il tempo trascorso dalla assunzione per completare la dissoluzione della pastiglia) su velocità e variabilità totale di Flurbiprofene plasmatico durante l'assorbimento.
Determinazione di Flurbiprofene plasmatico in uno studio di bioequivalenza (Fase I): metodo UPLC-MS/MS secondo le linee guida EMA
MICHELINI, ROBERTA
2014/2015
Abstract
Flurbiprofen, α-Methyl-α-(2-fluoro-4-biphenylyl)acetic acid, is a nonsteroidal anti-inflammatory drug (NSAID) used in racemic mixture for local oromucosal treatment of painfuland/or inflammatory conditions of the oropharynx. In this work was developed and validated an analytical method to determine pharmacokinetic profile of plasmatic Flurbiprofen in order to study bioequivalence, and in particular non-superiority, between a new generic formulation of tablets (test) compared to a commercial product (reference) in a Phase I clinical trial. The analytical method was developed with HPLC-MS/MS system with an ESI source, operating in negative mode, and a triple quadrupole detector. Validation was conducted in accordance with EMA guidelines ("Guideline on bioanalytical Method Validation", July 21, 2011) and good laboratory practice guidelines (GLP); were performed tests of selectivity and specificity, carry-over, linearity (4000 - 50ng/mL in plasma), limit of quantification (LOQ, 50ng/mL in plasma), accuracy and precision (within and between- analytical run), matrix effect, dilution integrity and various stability tests. The analytical method was in accordance with the guidelines and was employed for the analysis of plasma samples from 24 volunteers who participated in clinical trial. Bioequivalence between the two formulations was demonstrated and has been published a clinical article, based on analytical data obtained, where was studied the alleged influence of the oral dissolution time (i.e. time spent suckling the lozenge from its intake to complete dissolution) on speed and total variability of plasmatic Flurbiprofen during absorption.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/23120