Pharmacokinetic optimization in drug research: physico-chemical and in vitro ADME properties
Learning outcomes of the course unit
At the end of the course, the student should have acquired knowledge and skills related to the experimental determination and the role of physico-chemical and ADME properties in the optimization of newly synthesized chemical entities. In particular, the student should be able to: 1. Knowledge and understanding: know the main analytical techniques employed in the experimental determination of the chemical-physical properties covered in the course. Know the fundamental in vitro pharmacokinetic properties considered in the preclinical evaluations of new chemical entities undergoing drug discovery. Being able to use the specific language of the discipline. 2. Ability to apply knowledge and understanding: to be able to recognize the role of the different chemical-physical properties and ADME in the potential developability of a new chemical entity. 3. communication skills: being able to expose the results of studies to an expert audience. 4. Independent judgment: being able to propose a strategy for selecting a compound within a series of analogues based on the physico-chemical and ADME data in possession. 5. Learning skills: connect the different topics covered. Search the literature for suitable sources for solving the problems encountered.
Knowledge of instrumental analytical chemistry.
Course contents summary
The new chemical entities (NCE) selected as candidates for development must have an advantageous pharmacodynamic profile, associated with adequate pharmacokinetics (PK) and minimal toxicity. Normally only a fraction of the biologically active compounds able to bind to the therapeutic target has ADME properties (absorption, distribution, metabolism, excretion) that are acceptable for a passage to the subsequent phases of clinical development. The course aims to provide the student with the theoretical and applicative knowledge to understand the role of physico-chemical and ADME properties in the development of new candidates. The instrumental approaches for the experimental determination of some key chemical-physical properties, such as lipophilicity, ionization constant, solubility, will be considered, inserting these approaches in the in vitro evaluation of the drug-likeness of a drug. The main in vitro ADME properties will be presented such as metabolic stability, both hydrolytic and oxidative, and permeability and their impact on the pharmacokinetic and toxicity profile of a drug, considering the main experimental models available for both screening and more in-depth analyzes. Some case studies will be provided and discussed in which the optimization of properties was effectively conducted and guided the subsequent structural optimization of the candidates.
Introduction: the role of iterative optimization of physico-chemical, ADME and pharmacodynamic properties in drug discovery. Physico-chemical and biochemical factors capable of influencing in vivo exposure to a drug. Biochemical barriers to the absorption and distribution of a drug. Physico-chemical properties: lipophilicity. Definitions. Main parameters employed and their experimental determination. Effect of structural changes on lipophilicity. Constant of ionization (pKa). Experimental screening and in-depth approaches. Role of pKa in drug discovery settings in influencing pharmacokinetics. Solubility: definitions and meaning in drug discovery. Solubility improvement with structural modifications. Examples. Dependence of solubility on experimental conditions. Permeability: notes on the different mechanisms of permeability and on the in vitro experimental approaches for such evaluations. Role of transporters and permeability of the blood-brain barrier. ADME properties: metabolic stability. Hydrolytic stability in plasma. Analytical methods for analysis of single samples or in high-throughput mode. Role of liquid chromatography coupled to mass spectrometry. Stability to phase I and phase II metabolism. Subcellular and cellular systems for the evaluation of metabolism: limits and advantages. Practical examples. Structural elucidation of metabolites. Inhibition and metabolic induction. Experimental models and analytical methods. Prodrugs. Effect of properties on biological assays. Notes on the role of formulations in optimizing the pharmacokinetic profile of a new candidate.
Testa, B., van de Waterbeemd, H., Folkers, G., & Guy, R. (Eds.). (2002). Pharmacokinetic optimization in drug research, biological, physicochemical and computational strategies. Postfach, Switzerland: Verlag Helvetica Chimica Acta.
Testa, B., Krämer, S. D., Wunderli-Allenspach, H., & Folkers, G. (Eds.). (2006). Pharmacokinetic profiling in drug research. Zurich, Switzerland: Verlag Helvetica Chimica Acta.
Kerns, E., Di, L. (2016). Drug-like properties: concepts, structure design, and methods: from ADME to toxicity optimization. Elsevier. Academic Press. USA.
The didactic activities will use active learning modalities alternated with Socratic heuristic lessons. During the Socratic heuristic lessons, dialogue with the classroom will be privileged, in order to bring out any foreknowledge on the topics in question by the doctoral students. The slides are considered an integral part of the teaching material. The slides used to support the lessons will be uploaded to the Elly platform.
Assessment methods and criteria
The learning assessment will be carried out through a final written exam. The written exam, lasting 1 hour, will consist of 5 open-ended questions, each of which will be associated with a score from 0 to 6 points. The student will have to demonstrate that they have understood, and are able to apply, the fundamental concepts of each topic dealt with.