Caractérisation de la pharmacocinétique de formulations sensibles au pH et de formulations destinées au traitement des intoxications médicamenteuses

Drug delivery is the field of pharmaceutical sciences which focuses on altering the immediate environment of drug molecules to improve their efficacy and safety.  Drug delivery systems can potentiate the effect of active principles or alleviate their side effects by modifying their circulation profiles and/or biodistribution. The objective of this research project was to investigate the role of pharmacokinetic (PK) analysis in the development of novel drug delivery systems. PK analysis is generally applied to describe and predict the blood concentration profiles of low molecular weight drugs and their metabolites. Nevertheless, it is herein used to characterize the circulation of 2 liposomal formulations: pH-sensitive liposomes designed to alter the intracellular distribution of drugs and liposomes with transmembrane pH gradient for drug detoxification.   The first series of experiments were designed to study the circulation kinetics of a pH-sensitive polymer prepared with N-isopropylacrylamide (NIPAM) and methacrylic acid (MAA). The copolymer p(NIPAM-co-MAA) is used in our laboratory to prepare serum-stable, PEGylated, pH-sensitive liposomes. The circulation profiles of polymers with different characteristics were characterized. The parameters which impacted the fate of the macromolecules were the length of the polymer chain, its cloud point and the presence of a hydrophobic anchor at one extremity of the molecule. The glomerular filtration cut-off of the polymer was determined to be around 32,000 g/mol. PK analysis allowed to conclude that the complexes prepared by anchoring the polymer on the surface of the liposomes remained stable in the bloodstream. This data established that pH-sensitive vesicular formulations could be produced using a polymer which could be excreted through renal filtration. It also confirmed that the formulation remained intact in the bloodstream.    The second part of this work involved the development of liposomes with a transmembrane pH gradient designed to treat cardiovascular drug intoxications. Liposomes were designed and optimized in vitro to capture a model cardiovascular drug, diltiazem (DTZ). In vitro, the liposome uptake capacity was 40-fold higher than the lipid emulsion used in the clinic. PK analysis was used to verify the stability of the formulation in vivo, and to assess the impact of the liposomes on the plasma concentration of DTZ and its principal active metabolite, deacetyl-diltiazem (DAD). It was shown that the vesicles were able to capture and sequester DTZ and DAD. Injection of liposomes 2 min prior to administration of DTZ significantly increased the area under the plasma-concentration vs. time curve of both DTZ and DAD, while lowering their clearance and volume of distribution. The impact of the changes in PK on the pharmacological effect of the drug was also investigated. Liposomes tempered the hypotensive effect of the drug when the latter was administered via an intravenous bolus or a 1-h perfusion. Throughout this work, PK analysis proved to be an efficient tool to study the ability of transmembrane pH gradient liposomes to alter the blood circulation profiles of a cardiovascular drug, and to reduce its pharmacological effect. This proof of concept establishes firm ground for the further development of this colloidal formulation to treat drug intoxications.    This work pointed out the relevance of PK analysis for the development of multi-purpose, colloidal drug delivery systems. At this stage, the predictive nature of the analysis was not exploited, but its descriptive properties allowed objective comparison of the circulation profiles of distinct systems and pertinent conclusions concerning their fate in vivo.

Keyphrases: liposomes, biodistribution, poly(N-isopropylacrylamide), poly(ethylene glycol), detoxification, lipid emulsion, pH-sensitivity, active loading, pharmacokinetic, biodistribution, poly(N-isopropylacrylamide), liposomes