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Furlan, Antonio (2011) Pharmacokinetics, safety and inducible cytokine responses during a Phase 1 trial of the histone deacetylase inhibitor ITF2357 (GIVINOSTAT). [Tesi di dottorato]

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Abstract (inglese)

Inhibitors of histone deacetylases (HDAC) are used widely in medicine. ITF2357 is a hydroxamic acid-containing, orally active HDAC inhibitor with anti-inflammatory properties. In endotoxin-stimulated human PBMC, ITF2357 at 50 to 125 nM inhibited the release of TNFalpha and IL-1β by more than 70%, respectively. The induction of IFNgamma by the combination of IL 18 plus IL 12 was also reduced by ITF2357. We report here a Phase I safety and pharmacokinetic trial. After an oral dose of 50 mg, the maximal plasma concentration was 104 nM at 2 hours post dosing with a half-life of 6.9 hours. For the 100 mg dose, the Cmax was 199 nM at 2.1 hours and a half life of 6.0 hours. For a dose of 200 mg, the Cmax was 470 nM after 2.1 hours and a half-life of 6.0 hours. Repeat daily doses of ITF2357 for 7 consecutive days of 50, 100 or 200 mg resulted in nearly the same Cmax and half-life each day as was observed following a single dose. Side effects were limited to reductions in platelets (10-25% of baseline) within the first week after 7 days of treatment, reached a nadir point after 2 to 3 weeks and resolved fully within 2 to 3 weeks. Whole blood was cultured with endotoxin (10 ng/mL). Production of TNFα progressively decreased reaching a nadir 4 hours after oral dosing (45 and 52% of the pre-drug level for 50 and 100 mg, respectively). Similar decreases were observed after 4 hours for IL 1 beta, IL 6 and interferon gamma but not for IL 8. The IL 1 receptor antagonist did not decrease in the same samples. After 24 hours, the levels had returned to base line measurements. In a one week-long multiple dosing schedule, the fall in cytokine production in blood cultures observed on day 7 was nearly the same as that of the first day. We conclude that ITF2357 is a safe and effective therapy for reducing cytokine production following oral dosing.

Abstract (italiano)

Gli inibitori delle istone deacetilasi (HDAC) sono stati recentemente introdotti nella terapia medica oncologica. ITF2357 (Givinostat) è un inibitore delle HDAC, attivo per via orale e con proprietà anti-infiammatorie. In colture di PBMC umani stimolati con LPS, ITF2357 alle concentrazioni da 50 a 125 nM ha dimostrato efficacia nell’inibire il rilascio di TNFα ed IL-1β. Anche l'induzione di IFNγ mediante la combinazione di IL-18 ed IL-12 è ridotta in vitro. Il seguente rappresenta uno studio di Fase I relativo alla sicurezza e alla farmacocinetica di ITF2357 in volontari sani. Dopo una dose orale di 50 mg, la concentrazione plasmatica massima è stata di 104 nM a 2 ore dalla somministrazione, con una emivita di 6,9 ore. Per la dose di 100 mg, la Cmax è stata di 199 nM a 2,1 ore e con un’emivita di 6,0 ore. Per la dose di 200 mg, la Cmax è stata di 470 nM dopo 2,1 ore e una t1/2 di 6,0 ore. Ripetute dosi giornaliere di ITF2357 per 7 giorni consecutivi (50, 100 o 200 mg) hanno generato la stessa Cmax ed emivita osservate dopo una singola dose. Gli effetti collaterali si sono limitati ad una riduzione delle piastrine (10-25% del basale) entro la prima settimana di assunzione con un nadir al settimo giorno ed un ripristino completo dopo 3 settimane. Il sangue intero dei soggetti in studio è stato incubato con lipolisaccaride (10 ng/mL). La produzione di TNFα è risultata ridotta raggiungendo un nadir a 4 ore dall’assunzione orale (-45 e -52% comparati con i livelli pre-assunzione per i dosaggi di 50 e 100 mg, rispettivamente). diminuzioni simili sono state osservate dopo 4 ore per IL-1beta, IL-6 ed IFNgamma ma non per IL-8 ed IL-1Ra. Nei campioni di sangue prelevati a 24 ore dall’assunzione, i livelli citochinici sono tornati comparabili al basale. Nello studio con dosi multiple, l’effetto anti-citochinico osservato al settimo giorno è stato sovrapponibile a quello del primo. In conclusione ITF2357 è una terapia sicura ed efficace nel ridurre la produzione di citochine in un modello ex-vivo.

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Tipo di EPrint:Tesi di dottorato
Relatore:Punzi, Leonardo
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE REUMATOLOGICHE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:24 Gennaio 2011
Parole chiave (italiano / inglese):GIVINOSTAT, CYTOKINES, HDAC
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/16 Reumatologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Medicina Clinica e Sperimentale
Codice ID:3367
Depositato il:21 Lug 2011 08:49
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