Drug efficacy is a direct consequence of the control of its concentration in the blood and in the organs. Accordingly, a detailed knowledge of drug course in the body is a necessary prerequisite for an effective drugs and therapies development. Pharmacokinetics is concerned with the study of drugs concentration time course in blood and in the various organs and tissues of the body. The research discussed in this thesis focuses on the use of mathematical models to determine and predict drugs pharmacokinetic properties, with a specific emphasis on cancer treatment. Computer simulations are a potential tool to reduce the complexities, limitations, and costs of the standard experimental pharmacokinetic studies. Goal of this work is the formulation of a complete model to simulate the entire course of drugs at various detail levels. Three sequential models describe drugs pharmacokinetics at the body, organ, and cellular level. The result is a multiscale pharmacokinetic model. At the macroscale, a physiologically based model is applied with focus on the personalization of the simulation. At the mesoscale, nanoparticles distribution in a tumor mass is predicted via the definition of a finite element model and the solution of partial differential equations. Finally, at the microscale the model describes the siRNA molecules intracellular trafficking. The entire model structure and the methodology are highly innovative, and the simulations showed to be in agreement with the experimental data.
L’efficacia di un trattamento farmacologico dipende della concentrazione del farmaco nel sangue e negli organi. Di conseguenza la conoscenza dettagliata del percorso del farmaco nel corpo è un prerequisito necessario per lo sviluppo di nuove terapie farmacologiche. La farmacocinetica riguarda lo studio del profilo temporale della concentrazione dei farmaci nel sangue e nei vari organi e tessuti del corpo. La ricerca discussa in questa tesi si focalizza sull’uso di modelli matematici per determinare e predire le proprietà farmacocinetiche dei farmaci, con un’enfasi specifica sul trattamento dei tumori. Le simulazioni al computer sono uno strumento per ridurre la difficoltà, le limitazioni, e il costo della pratica sperimentale. Lo scopo di questo lavoro è la formulazione di un modello completo per la simulazione del percorso dei farmaci a vari livelli di dettaglio. Tre modelli farmacocinetici sequenziali descrivono i profili di concentrazione dei farmaci a livello del corpo, degli organi, e delle cellule. Il risultato complessivo è un modello farmacocinetico multi-scala. Alla macro-scala, si applica un modello fisiologico volto alla personalizzazione della simulazione farmacocinetica. Alla meso-scala viene modellata la distribuzione di nano-particelle in una massa tumorale attraverso la definizione di un modello ad elementi finiti ed alla soluzione di equazioni alle derivate parziali. Infine, alla micro-scala il modello descrive i processi di trasporto intracellulari delle molecole di siRNA. L’intera struttura del modello e la metodologia sono fortemente innovative e le simulazioni mostrano di essere in accordo con i dati sperimentali.
An integrated multiscale physiologically-based pharmacokinetic model to assist drug development and individualized therapies
ABBIATI, ROBERTO ANDREA
Abstract
Drug efficacy is a direct consequence of the control of its concentration in the blood and in the organs. Accordingly, a detailed knowledge of drug course in the body is a necessary prerequisite for an effective drugs and therapies development. Pharmacokinetics is concerned with the study of drugs concentration time course in blood and in the various organs and tissues of the body. The research discussed in this thesis focuses on the use of mathematical models to determine and predict drugs pharmacokinetic properties, with a specific emphasis on cancer treatment. Computer simulations are a potential tool to reduce the complexities, limitations, and costs of the standard experimental pharmacokinetic studies. Goal of this work is the formulation of a complete model to simulate the entire course of drugs at various detail levels. Three sequential models describe drugs pharmacokinetics at the body, organ, and cellular level. The result is a multiscale pharmacokinetic model. At the macroscale, a physiologically based model is applied with focus on the personalization of the simulation. At the mesoscale, nanoparticles distribution in a tumor mass is predicted via the definition of a finite element model and the solution of partial differential equations. Finally, at the microscale the model describes the siRNA molecules intracellular trafficking. The entire model structure and the methodology are highly innovative, and the simulations showed to be in agreement with the experimental data.File | Dimensione | Formato | |
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Thesis RA_Final.pdf
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https://hdl.handle.net/10589/132116