Optimizing Druggability through Liposomal Formulations: New Approaches to an Old Concept

Developing innovative delivery strategies remains an ongoing task to improve both efficacy and safety of drug-based therapy. Nanomedicine is now a promising field of investigation, rising high expectancies for treating various diseases such as malignancies. Putting drugs into liposome is an old story that started in the late 1960s. Because of the near-total biocompatibility of their lipidic bilayer, liposomes are less concerned with the safety issue related to the possible long-term accumulation in the body of most nanoobjects currently developed in nanomedicine. Additionally, novel techniques and recent efforts to achieve better stability (e.g., through sheddable coating), combined with a higher selectivity towards target cells (e.g., by anchoring monoclonal antibodies or incorporating phage fusion protein), make new liposomal drugs an attractive and challenging opportunity to improve clinical outcome in a variety of disease. This review covers the physicochemistry of liposomes and the recent technical improvements in the preparation of liposome-encapsulated drugs in regard to the scientific and medical stakes

Planification adaptative des essais de phase I en cancérologie

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Modélisation pharmacocinétique du 5FU et de son métabolite le 5FDHU chez des patients atteints de cancers colorectaux (Apports méthodologiques en analyse de population)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Description de la variabilité en pharmacocinétique de population par l'approche nin paramétrique des noyaux (adaptation de posologie à l'aide des nomogrammes cinétiques)

La mise en oeuvre des approches de population en PK devient systématique aussi bien en milieu industriel qu'en milieu clinique. Ces approches visent à décrire et à quantifier la variabilité interindividuelle en termes de statistiques. L'information obtenue est un élément essentiel car, utilisée dans un critère Bayésien permet l'estimation des paramètres pharmacocinétiques d'un nouvel individu, conduisant dans un contexte clinique à une adaptation rigoureuse de la posologie. L'implémentation des approches non-paramétriques des noyaux et le développement d'une nouvelle procédure d'individualisation de posologie sont les deux contributions principales de ce travail. La description de la variabilité a été abordée par la méthode en deux étapes. Dans le contexte multidimensionnel avec erreurs normales et hétéroscédastiques, nous avons mis en oeuvre différents estimateurs à noyaux "naïfs" et de déconvolution. Le lissage optimal des noyaux a été calculé à l'aide de la validation croisée des moindres carrés. Par ailleurs,nous avons développé les nomogrammes cinétiques en tant que nouvel outil d'individualisation posologique. Etant donné une concentration cible à l'état stationnaire, ces nomogrammes sont construits comme une collection de profils pharmacocinétiques "spécifiques" obtenus après administrations répétées d'un "protocole d'identification". Les graphes obtenus divisent l'espace "temps-concentration" en plusieurs domaines dont chacun correspond à une dose ajustée. Les différents calculs et développements ont été réalisés en utilisant le logiciel Matlab®. Le sélecteur de lissage fournit de bonnes performances et l'implémentation des estimateurs à noyaux précités s'est faite avec succès. Par ailleurs, l'évaluation des performances en termes d'ajustement des doses de Sirolimus® par les nomogrammes cinétiques, que ce soit dans l'étude de simulation ou en clinique, a montré la simplicité et la fiabilité de la procédure. Elle semble efficace même chez les patients dont les caractéristiques pharmacocinétiques varient temporellement. Les estimateurs non-paramétriques à noyaux mis en oeuvre permettent de décrire fidèlement des formes atypiques de la distribution des paramètres pharmacocinétiques, objectif difficilement atteignable avec les approches paramétriques en une seule étape. En clinique, les nomogrammes cinétiques proposés en tant qu'outil d'individualisation de posologie directement disponible au chevet du patient représentent une alternative intéressante aux procédures Bayésiennes traditionnelles.Population pharmacokinetic approaches become nowadays systematic in both industry and clinical settings. The purpose of these studies is to describe and quantify statistically the interindividual variability.The reliability of the obtained information is fundamental because when used in a Bayesian criterion allows the estimation of individual pharmacokinetic parameters, which could lead to appropriate individual dosage regimens. The implementation of nonparametric kernel density estimators and the development of a new toolassisting individualization of dosage regimens are the main contributions in this thesis. A two-stage method was used in the multivariate context with normal heteroscedastic erors. To describe the variability of pharmacokinetic parameters, we implemented nonparmetric "naive" and deconvolution kernel density estimators. Least-squares cross valdation was used to calculate the optimal smoothing parameter for kernel estimators. Moreover, to assist individualization of drug regimens, we developed the kinetic nomograms. They involve collection of concentration-time following repeated administrations of a fixed "identification protocol" and targeting a given steady-state concentration. The profiles divide the concentration-time space into several areas, each of them corresponding to a given adjusted drug dose. All calculations were performed by use ofMatlab® software. The selector of least-squares cross validation provides good performances and implementation of the above kernel estimators was sucessful. Otherwise, performance evaluation in terms of dose adjustement of Sirolimus® by kinetic nomograms, in both simulation and clinical study, showed simplicity and reliability of the new procedure. It provides adequate dosage adjustement even for drugs that exhibit large intra-individual variability. Implemented nonparametric kernel estimators accurately described the interindividual pharmacokinetic variability, which is difficult to achieve when classical single-stage parametric approaches are used. In the clinical context, kinetic nomograms rendered the individual adjustement of dosage regimen a simplified bedside application. They are interesting alternatives to the cumbersome Bayesian procedure.AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics: homogeneous and heterogeneous approaches

The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this new second edition book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with epirical, compartmental, and stochastic pharmacokinetic models, with two new chapters, one on fractional pharmacokinetics and one on bioequivalence; and the fourth mainly with classical and nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. This second edition has new information on reaction limited models of dissolution, non binary biopharmaceutic classification system, time varying models, and interface models. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This book will appeal to graduate students and researchers in pharmacology, pharmaceutical sciences, bioengineering, and physiology. Reviews of the first edition: "This book presents a novel modelling approach to biopharmaceutics, pharmacokinetics and pharmacodynamic phenomena. This state-of-the-art volume will be helpful to students and researchers in pharmacology, bioengineering, and physiology. This book is a must for pharmaceutical researchers to keep up with recent developments in this field." (P. R. Parthasarathy, Zentralblatt MATH, Vol. 1103 (5), 2007) "These authors are the unique (or sole) contributors in this area that are working on these questions and bring a special expertise to the field that is now being recognized as essential to understanding biological system and kinetic/dynamic characteristics in drug development...This text is an essential primer for those who would envision the incorporation of heterogeneous approaches to systems where homogeneous approaches are not sufficient to describe the system." (Robert R. Bies, Journal of Clinical Pharmacology, Vol. 46, 2006)

Apport de l'analyse de population en phase préclinique de développement d'un médicament

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Modélisation de l'évolution de la taille des tumeurs dans le cancer du sein métastatique traité par deux médicaments anticancéreux (le docetaxel et la capecitabine)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Application de l'approche de population en préclinique (comparaison des logiciels Nonmem et Phoenix NLME )

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics: homogeneous and heterogeneous approaches

The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with empirical, compartmental, and stochastic pharmacokinetic models, and the fourth mainly with nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This timely and useful book will appeal to graduate students and researchers in pharmacology, pharmaceutical sciences, bioengineering, and physiology

Toxicités chimio-induites liées à un polymorphisme génétique

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF