Évaluation et contrôle de l'irrégularité de la prise médicamenteuse : proposition et développement de stratégies rationnelles fondées sur une démarche de modélisations pharmacocinétiques et pharmacodynamiques

The heterogeneity of PK and/or PD profiles in patients undergoing the same treatment regimen should be avoided during treatment or clinical trials. Two traditional approaches are continually used to achieve this purpose. One builds on the interactive synergy between the health caregiver and the patient to exert the patients to become a whole part of his own compliance.  Another attempt is to develop drugs or drug dosing regimens  that forgive the poor compliance. The main objective of this thesis was to develop new methodologies for assessing and monitoring the impact of irregular drug intake on the therapeutic outcome.     Specifically, the first phase of this research was to develop algorithms for evaluation of the efficacy of a treatment by improving classical breakpoint estimation methods to the situation of variable drug disposition. This method introduces the ``efficiency'' of a PK profile by using  the efficacy function as a weight in the  area under curve ($AUC$) formula. It gives a more powerful PK/PD link and reveales, through some examples, interesting issues about uniqueness of therapeutic outcome indices and antibiotic resistance problems.    The second part of this thesis was to determine the optimal sampling times by accounting for the intervariability in drug disposition in collectively treated pigs. For this, we have developed an advanced mathematical model  able to generate different PK profiles for various feed strategies. Three algorithms have been performed to identify the optimal sampling times with the criteria of minimizing the PK intervariability .  The median-based method yielded suitable sampling periods in terms of convenience for farm staff and animal welfare.   The last part of our research was to establish a rational way to delineate drugs in terms of their ``forgiveness'', based on drugs PK/PD properties. For this, a global sensitivity analysis (GSA) has been performed to identify the most sensitive parameters to dose omissions. Then we have proposed a comparative drug forgiveness index to rank the drugs in terms of their tolerability to non compliance with application to four calcium channel blockers. The classification of these molecules in terms of drug forgiveness is in concordance to what has been reported in experimental studies.  The strategies developed in this Ph.D. project and essentially based on the analysis of complex relationships between drug intake history,  pharmacokinetic and pharmacodynamic properties are able to assess and regulate noncompliance impact with an acceptable uncertainly.  In general, the algorithms that imply these approaches will be undoubtedly efficient tools in patient monitoring during dosing regimen. Moreover, they will contribute to control the harmful impact of non-compliance by developing new drugs able to tolerate sporadic dose omission.

Keyphrases: Irregular drug intake, Breakpoint, Collective feeding behaviour, Collective feedind behaviour-pharmacokinetic model, Global sensitivity analysis, Comparative drug forgiveness index, Monte-Carlo approach