CLASSICAL AND POPULATION PHARMACOKINETICS OF ANTIMICROBIALS, SEDATIVES AND ANAESTHETICS IN VETERINARY MEDICINE

Pharmacokinetics is defined as the use of mathematical models to quantitate the time course of drug absorption and disposition in man and animals. This discipline is the branch of pharmacology that aims to describe, through mathematics, the interactions and physiological processes (i.e. absorption, distribution, metabolism and excretion – the ADME process) that the drugs undergo after administration. When applied to a clinical situation, pharmacokinetics (PK) provides the clinician with important information on optimal drug dosages for each single patient. In the present thesis, the focus moved to the importance of classical PK and its applications, starting from the theory and use of compartmental analysis and at the end arriving to illustrate the more recent notions of this discipline, popPK and PBPK, which are the most innovative topics in the clinical and translational pharmacology field. The classical PK usually, translated clinically, is represented by quick studies which have a significant relevance in understanding ADME process of drugs with their desired, collateral or adverse effects. The population PK approach aims to investigate the influence of the interindividual variability in a target population of subjects, evaluating the populations characteristics that influence the fate of a drug after administration. The time required for the development of a popPK study applied to the clinical setting is much longer than a classical PK study. Three studies of classical clinical PK and one population PK study were included in this thesis. The first study concerned dexmedetomidine (DEX) and aimed to define the kinetic profile of this sedative following intravenous administration in a group of dairy calves, comparing its pharmacological and clinical effects with those of another a-2 agonist, xylazine, for minor surgical procedures. The second study was related to the simultaneous administration, as preanaesthetics, of a mixture of DEX and methadone, an analgesic with a remarkable sedative efficacy belonging to the class of opioid μ-agonists. The aim was to establish the pharmacokinetic profile of this co-administration in dogs by oral transmucosal route and compare it with the intramuscular kinetic profile of the same drugs combination. The third research addressed the species Panthera tigris. Since the literature concerning the non- domestic animals’ PK is lacking and needy of new information, specifically, the objective was to compare the kinetic profile of a simultaneous administration of DEX and ketamine, an injectable anaesthetic antagonist of NMDA receptors, following IM administration for chemical restraint in two groups of tigers. The population PK study wanted to determine the popPK profile of cefazolin administered in a clinical setting for prophylactic purposes in 78 dogs, of different breed, age, weight, sex, body condition scores and health status, undergoing different surgical procedures. The ultimate goal was the definition of Clinical Breakpoints for this antimicrobial administered to the canine patient according to the guidelines of the Veterinary Committee on Antimicrobial Susceptibility Testing (VetCAST). Finally, during these three years of PhD program, another popPK work has been started. This study is in collaboration with the veterinary anaesthesia Operative Unit of the University of Padua, which requested our laboratory for performing propofol quantification. The aim was the definition of the kinetic population profile of propofol, administered for the induction and maintenance of general anaesthesia with modern TCI technique, in order to determine a popPK model that would be applicable to dog anaesthesiology. Until now, propofol quantification has been accomplished, but the final popPK model is still under investigation (for this reason data are not reported in the thesis). In conclusion, the use of appropriate pharmacokinetic modelling was important to perform different types of studies which helped to provide the veterinary pharmacological literature with innovative data with wide clinical implications.