Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 47

Biomarker is a characteristic that is readily detectable in plasma or cellular molecules (typically gene mutations or proteins) objectively measured and evaluated as an indicator of normal biological processes pathogenic processes or pharmacologic responses to a therapeutic interventionDesensitization: agonist‐induced loss of receptor responsiveness triggered by a persistent exposure of receptors to an agonist by any mechanism – receptor phosphorylation, uncoupling, antagonistic metabolites, or negative physiological feedback that occurs over a relatively short period, receptor downregulation, or receptor internalization or sequestrationEfficacy:A drug’s ability to bind a receptor and elicit a functional response.Enterohepatic recirculation (EHR):refers to the circulation of bile components secreted from the liver, into the small intestine, from where it can be reabsorbed again. EHR contributes to an increased half‐life of a drug. Some phase II conjugates are also secreted into bile and converted back to parent in the distal small intestine and reabsorbed as parent.Glomerular filtration rate (GFR):is the rate at which water is filtered out of the plasma through the glomerular capillary walls into Bowman's capsules, usually measured by the rate of clearance of creatinine.Internalization: is the sequestration of agonist–receptor complexes into endosomal compartments within cells. This is important since removal of receptors from the plasma membrane prevents further stimulation by intercellular signals.Irreversible inhibitor or antagonist (as opposed to reversible):covalently modifies and inactivates the target protein by forming irreversible complex and having bound to the receptor, dissociates from it very slowly or not at all. Example: alkylating agents. Irreversible inhibitors are characterized by low turnover of effect or a long response half‐life and are long acting by virtue of receptor occupancy rather than PK half‐life. Duration of effect is determined only by turnover of target protein.Lead optimization: is a stage of the drug discovery phase, when a preclinical drug candidate is identified from one or more lead series through iterative cycles of compound synthesis, testing, and design. The identified lead should satisfy a predefined criteria with respect to novelty, potency, selectivity, physicochemical characteristics, pharmacokinetics, and toxicity.Polymorphism, polymorphic enzymes: Polymorphism is a discontinuous genetic variation in proteins/enzymes that occurs in at least 1% of a population, leading to different types of individuals in a single species.Predictive biomarker (also called stratification biomarker):is a pretreatment marker (genotype or phenotype that predicts who will/will not benefit from a therapy). This is the basis for a companion diagnostic.Rebound:Occurs when the body tries to return to homeostasis following a sudden discontinuation of a drug. Receptors which are suddenly deprived of their agonists/blockers become hypersensitive to an agent that targets it, causing a further exacerbation of the symptoms/conditions that triggered the use of the drug in the first place. This rebound effect can be minimized by a gradual rather than a sudden discontinuation of the drug.Second messengers: Relay molecules that target other molecules in cytosol and/or nucleus in response to receptors that are activated at the cell surface by hormones, growth factors etc. They can greatly amplify the strength of a signal by causing large changes in the biochemical activities within the cell. Examples of second messengers include cyclic nucleotides like cAMP and cGMP, inositol trisphosphate (IP3), diacylglycerol (DAG), and calcium ions.Sensitization: is defined as an increased effect of drug following repeated doses. Drug‐induced sensitization is the opposite of tolerance. Sensitization can result from accumulation of parent or active metabolites, positive feedback, upregulation of receptors, or enhanced sensitivity of receptors to a ligand.Steric hindrance: is the reduction in metabolic activity of a molecule due to bulky chemical groups close to the site of metabolism in a new chemical entity.Surrogate biomarker or endpoint:is a biomarker intended to substitute for a clinical endpoint. In a clinical trial, it is a laboratory measurement, or a physical sign used as a substitute for a clinically meaningful endpoint.Target engagement: describes how robustly a drug interacts with the mechanism of action.Tolerance: is loss of receptor‐activated function, following prolonged exposure to a drug, usually due to receptor downregulation. Tolerance is reserved for reduced responsiveness developing over longer period while desensitization over shorter period.