Nouvelles approches en pharmacocinetique et pharmacodynamie de population: Applications a des medicaments commercialises et en voie de commercialisation (French text).

摘要

The drug research and development process is associated with multiple scientific, regulatory and financial restrictions. We believe that the drug development process can be improved by the integration of population methods in preclinical and clinical studies. The main objective of this thesis was to prove this by performing population analyses with new compartmental models in order to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs in preclinical, phase I and IV studies.; Trans-resveratrol was identified as one of the biologically active compounds in red wine. Informations on its absorption, metabolism and disposition are limited despite the vast amount of research on its capacity to prevent multiple pathophysiological processes. We propose to develop a compartmental model to determine the PK and enterohepatic recirculation of trans-resveratrol in its early development phase in rats and humans for the first time. Population analyses of trans-resveratrol (aglycone and total forms) were performed using an iterative two-stage approach (IT2S). Results of these studies support the working hypothesis that trans-resveratrol in its total form may be responsible for the pharmacological activity of the product and that simulations are essential tools to determine dose-concentration-efficacy and dose-concentration-toxicity relationships for supporting efficient drug development programs.; A novel PK/PD model was developed to improve the bioequivalence assessment between two formulations of albuterol (salbutamol) in a phase I study. It is recognized that albuterol (β₂-agonist) acts topically on specific receptors in the upper airways of the lungs and that systemic absorption data does not necessarily reflect airway absorption and effect. Therefore, the most practical method of showing therapeutic equivalence between two formulations is through the use of pharmacodynamic measures. Population PK/PD modeling was performed using bronchodilation data (FEV₁ and FEF_25–75% ) with a novel E_MAX function. Population analyses (NONMEM) with PD data resulted in 90% confidence intervals within the 80–125% acceptable limit for the first time. We propose to use this population model to assess the bioequivalence of albuterol with robustness when only PD data are available.; Finally, we developed a novel first-pass model to provide new insights on the PK of verapamil and norverapamil enantiomers in young and elderly subjects in a phase IV study. (Abstract shortened by UMI.)