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Giodini, Luciana (2016) Innovative Strategies for the Personalization of the Therapy in Cancer Patients. From Pharmacogenetics to Therapeutic Drug Monitoring: Different Approaches for Optimizing the Chemotherapy Dosing. [Tesi di dottorato]

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Abstract (inglese)

Most of the chemotherapeutic agents are characterized by a low therapeutic index and significant variability in therapeutic and toxic effects.
For this reason, many efforts have been made to optimize the dosage and the administration of antiblastic drugs in order to obtain a maximal anti-tumor effect with acceptable levels of toxicity.
The recent progresses in the cancer field introduced the concept of personalized therapy with the aim of tailoring medical treatment to the individual characteristics and needs of the single patient.
The personalization of the dosage could be obtained with different approaches depending on the molecular peculiarities of each drug and on the genetic characteristics of the patients.
In particular, in this thesis two different strategies were applied to optimize the chemotherapeutic treatment with fluoropirimidines, irinotecan, and sunitinib.
The first strategy concerns a pharmacogenetics approach with the purpose of optimizing the fluoropirimidines and the irinotecan dosage based on genetic biomarkers predictive of severe toxicities.
Regarding the fluoropyrimidines, the aim of the study was to introduce, in the clinical practice, a pre-treatment test for polymorphisms (SNPs) within the DPYD gene, able to predict the development of severe toxicities related to these drugs.
Furthermore, a genotype-driven phase Ib study was designed to optimize the irinotecan dosage: according to UGT1A1*28 genotype, the dosage of irinotecan was chosen for metastatic colorectal cancer (mCRC) patients treated with FOLFIRI (fluorouracil in association with irinotecan) plus cetuximab regimen.
In addition to this, another treatment tailoring strategy was applied, that is the therapeutic drug monitoring (TDM) of sunitinib. This approach aimed to monitor the plasmatic drug concentration in order to maintain it within the therapeutic window.
Aims
-Fluoropyrimidines project: a retrospective study was designed with the aim of validating the speci?city of three DPYD SNPs in predicting the occurrence of severe toxicity events in a large set of oncological patients. The secondary aim of this study was to evaluate whether the additional testing of other investigational DPYD variants could increase the pharmacogenetic test sensitivity.
-Irinotecan project: a phase 1b study was designed with three principal aims: 1) to define the Maximum Tolerated Dose (MTD), administered in the FOLFIRI regimen plus cetuximab in mCRC patients treated as first-line chemotherapy according to UGT1A1*28 genotype; 2) to evaluate the variability of irinotecan pharmacokinetics (PK), in combination with cetuximab, in patients with *1/*1 and *1/*28 genotype and the effect of the PK profile on toxicity and response rate; 3) to evaluate a possible effect of cetuximab on the PK of irinotecan.
-Sunitinib project: the project aimed to develop and validate, according to the FDA guidelines, an analytical method for the quantification of sunitinib and its main metabolite, N-desethyl sunitinib.
Methods
Each project of this thesis considered the application of different methodologies depending on the characteristic of the study.
The methods for SNPs genotyping performed for the pharmacogenetic analysis were set up and developed using three different methodologies: Pyrosequencing, TaqMan® Allelic Discrimination Assay, and automated direct sequencing.
Regarding the PK analyses and the TDM approach, two HPLC-MS/MS methods were applied.
Results
-Fluoropyrimidines project: data from this study demonstrated the clinical validity and specificity of the three DPYD SNPs genotyping test to prevent FL-related Grade =3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.
-Irinotecan project: at the moment, one patient was enrolled in this study. The PK of the enrolled patient was followed during the days 1-3 and the days 15-17. The main PK parameters of CPT-11 and its metabolites of the first patient enrolled were calculated trough a non-compartmental analysis.
-Sunitinib project: the method was setup and validated for the quantification of sunitinib and its main metabolite with a diagnostic perspective. The obtained method resulted easy, rapid and feasible for the clinical routine.
Conclusions
The different approaches described in this PhD thesis shared the same final aim: to translate the research results in the clinical practice and, consequently, to ameliorate cancer patients’ life. In this perspective, the results of this thesis strongly encourage the introduction of the personalized therapy in the cancer field, where the optimization of the chemotherapy dosing is a compelling need

Abstract (italiano)

La maggior parte degli agenti chemioterapici è caratterizzata da un basso indice terapeutico e da una elevata variabilità interpaziente sia nella risposta alla terapia che nello sviluppo di tossicità.
Per questo motivo, la comunità scientifica ha investito molto nell’ottimizzazione del dosaggio dei chemioterapici con il fine ultimo di ottenerne la massima efficacia con accettabili livelli di tossicità. A tal proposito, i recenti progressi nel campo della medicina oncologica hanno portato all’introduzione del concetto di terapia personalizzata. Tale approccio propone di individuare il giusto trattamento per ogni singolo individuo, basandosi sulle sue caratteristiche e necessità.
La personalizzazione della terapia chemioterapica può essere ottenuta tramite diversi approcci che dipendono sia dalle proprietà e caratteristiche molecolari del farmaco sia dalle peculiarità del singolo paziente. Questo lavoro di tesi si inserisce in questo filone di ricerca. In particolar modo, sono stati perseguiti due diversi approcci al fine di ottimizzare il trattamento con fluoropirimidine, irinotecano e sunitinib.
Il primo approccio selezionato si basa sull’applicazione delle conoscenze ottenute dalla farmacogenetica, disciplina che ha lo scopo di identificare il ruolo di varianti genetiche, polimorfismi (SNP), nella risposta al trattamento in termini sia di efficacia che di rischio di sviluppo di tossicità. In tale fase, la potenzialità dell’utilizzo di SNP predittivi di tossicità grave è stata studiata per migliorare il dosaggio di fluoropirimidine ed irinotecano.
Nel caso delle fluoropirimidine è stato disegnato uno studio retrospettico con lo scopo di definire la validità clinica di un test genetico pre-trattamento per alcuni SNP nel gene della DPYD al fine di valutare la capacità di questo test di predire lo sviluppo di tossicità gravi correlate a tale tipo di trattamento. Lo scopo di questo studio è di introdurre nella pratica clinica tale test al fine di migliorare la qualità di vita dei pazienti cui vengono somministrati questi farmaci.
Un’ altra applicazione delle conoscenze della farmacogenetica analizzata in questa tesi è rappresentata dagli studi di fase Ib basati sul genotipo, strategia che è stata perseguita per ottimizzare il dosaggio dell’irinotecano. Più in dettaglio, la massima dose tollerata (MTD) di tale farmaco è stata valutata in base al polimorfismo UGT1A1*28 in pazienti con cancro metastatico al colon retto trattati con il regime FOLFIRI (5-fluorouracile associato con irinotecano) e cetuximab.
Infine, un’altra strategia che riguarda la personalizzazione della terapia è rappresentata dal monitoraggio terapeutico del farmaco (TDM). Questo approccio è stato applicato per il sunitinib in modo da monitorarne le concentrazioni plasmatiche e mantenerle all’interno di una finestra terapeutica.
Scopo
-Fluoropirimidine: è stato disegnato uno studio retrospettico con il fine ultimo di validare la specificità di tre SNP della DPYD nel predire l’insorgenza di tossicità grave in un’ampia casistica di pazienti oncologici. Scopo secondario di questo studio è stata quello di valutare se l’analisi di altre varianti del gene della DPYD possano migliorare la sensibilità del test farmacogenetico.
-Irinotecano: è stato disegnato uno studio di fase 1b con i seguenti scopi: 1) definire la MTD, in base al genotipo UGT1A1*28, in pazienti metastatici con tumore al colon retto trattati con regime FOLFIRI associato a cetuximab; 2) valutare la variabilità dei parametri farmacocinetici dell’irinotecano, in combinazione con cetuximab, in pazienti con genotipo UGT1A1*1/*1 e UGT1A1*1/*28 e analizzare il possibile effetto del profilo farmacocinetico sulla tossicità e risposta; 3) stabilire se il cetuximab ha un effetto sulla farmacocinetica dell’irinotecano.
-Sunitinib: lo scopo di questo progetto è lo sviluppo e la validazione, in base alle linee guida rilasciate dalla Food and Drug Administration (FDA), di un metodo bioanalitico per quantificare sia il sunitinib sia il suo metabolita attivo, N-desetil sunitinib.
Materiali e metodi
In base agli scopi e alle peculiarità dei singoli progetti di questa tesi sono state applicate specifiche metodiche.
I metodi messi a punto ed utilizzati per le analisi farmacogenetiche sono i seguenti: pyrosequencing, saggio Taqman per la discriminazione allelica e sequenziamento diretto automatizzato.
Per quanto riguarda invece le analisi di farmacocinetica sono stati utilizzati due metodi in HPLC-MS/MS, uno dei quali, il metodo del sunitinib, è stato messo a punto e validato secondo le linee guida FDA.
Risultati
-Fluoropirimidine: i dati ottenuti da questo studio hanno dimostrato la validità clinica e la specificità del test farmaco genetico pre-trattamento basato sulla DPYD per prevenire l’insorgenza di tossicità gravi di grado =3. Tali risultati incoraggiano l’introduzione di questo test nella pratica clinica.
-Irinotecano: al momento una sola paziente è stata ritenuta eleggibile secondo i criteri dello studio. La farmacocinetica di CPT-11 e dei suoi principali metaboliti è stata descritta grazie a prelievi ripetuti durante la prima (giorni 1-3) e la seconda (giorni 15-17) somministrazione. Sono stati inoltre calcolati i principali parametri farmacocinetici di CPT-11 e dei suoi metaboliti tramite l’applicazione di un’analisi non compartimentale.
-Sunitinib: il metodo per la quantificazione del sunitinib e del suo metabolita attivo è stato messo a punto e validato. Considerata la facilità e la rapidità di tale analisi , si può auspicare che tale metodo possa essere facilmente applicabile nella pratica clinica.
Conclusioni
Gli approcci descritti in questa tesi condividono lo stesso scopo finale: traslare, cioè, i risultati della ricerca nella pratica clinica e, di conseguenza, migliorare la vita dei pazienti oncologici. In questa ottica, i risultati di questo lavoro incoraggiano fortemente l’introduzione di una terapia personalizzata nel campo oncologico, dove urge la necessità di nuovi approcci per ottimizzare il dosaggio dei farmaci

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Tipo di EPrint:Tesi di dottorato
Relatore:Giusti, Pietro
Correlatore:Toffoli, Giuseppe
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE FARMACOLOGICHE > FARMACOLOGIA MOLECOLARE E CELLULARE
Data di deposito della tesi:28 Gennaio 2016
Anno di Pubblicazione:2016
Parole chiave (italiano / inglese):farmacogenetica/pharmacogenetics, cancro/cancer, fase I/phase I, monitoraggio terapeutico del farmaco/therapeutic drug monitoring
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:9305
Depositato il:07 Ott 2016 10:21
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