Pegylation, generally described as the molecular attachment of polyethylene glycols (PEGs) with different molecular weights to active drug molecules or surface treatment of drug-bearing particles with PEGs, is one of the most promising and extensively studied strategies with the goal of improving the pharmacokinetic behavior of the therapeutic drugs. A variety of PEGs, both linear and branched, with different molecular weights have been exploited successfully for use in this procedure in the form of reactive PEG species. Both reversible and irreversible PEG-drug conjugates have been prepared with relative advantages/disadvantages. The main pharmacokinetic outcomes of pegylation are summarized as changes occurring in overall circulation life-span, tissue distribution pattern, and elimination pathway of the parent drug/particle. Based on these favorable pharmacokinetic consequences leading to desired pharmacodynamic outcomes, a variety of proteins/peptides as well as small molecule drugs have been pegylated and evaluated successfully. Also a number of corresponding products have been approved by the U.S. FDA for specific clinical indications and some others are underway. In this article, the chemistry, rationale, strategies, pharmacokinetic outcomes, and therapeutic possibilities of pegylated drugs are reviewed with pharmacokinetic aspects presented with more details.
Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug’s pharmacokinetics related to the conventional formulation. Poly(lactide-
co
-glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs’ long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA–PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel’s pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs.
With the extensive progress in nanotechnology-based drug delivery systems, pharmacokinetic evaluations have gained much attention from researchers as a central part of the study of these systems. Because the fulfillment of any therapeutic goal(s) by a novel drug delivery system requires that the absorption, distribution, metabolism, and excretion (ADME) be considered from the early stages of the system design to the final clinical evaluations, extensive knowledge of the pharmacokinetic aspects related to ADME is a crucial part of research in this field. The main objectives of the nanotechnology-based drug delivery systems from a pharmacokinetic viewpoint are (1) an improved drug-release profile in vivo, (2) enhanced drug absorption, (3) site-directed drug distribution, (4) a modified drug metabolism pattern, (5) prolonged drug residence time in body (e.g., in blood circulation), and (6) delayed and/or decreased renal excretion of the drug. Accordingly, the purpose of the current review is to present an insightful summary of pharmacokinetic analyses of nanotechnology-based drug delivery systems along with a critical review of recent findings.
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