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Model-Informed Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
The regulatory application of MIDD can be broadly classified into four categories: supportive evidence for efficacy, clinical trial design, dose optimization and informing policy [1]. In this chapter, the models related to the above applications are introduced (Figure 4.1). For the application of supportive evidence for efficacy, the models for describing exposure-response (ER) relationships are introduced which contains classical Dose-response model, direct response Pharmacokinetic/Pharmacodynamic (PK/PD) model, mechanism based PK/PD model and quantitative systems biology model. For the application in clinical trial design, the quantitative disease-drug-trial models are introduced. For the application in dose optimization, population pharmacokinetic model, Physiologically Based Pharmacokinetic model (PB-PK), and Target-Mediated Drug Disposition Model (TMDD) are introduced. For regulatory application, two guidances published by FDA involving MIDD are introduced. In this chapter, some innovative thinking and modeling involving the above applications are introduced. (i) The application of quantitative systems biology models in drug development; (ii) The combined use of disease progression model and traditional trial design methods.
Adherence and the Elderly
Published in Lynn B. Myers, Kenny Midence, Adherence to Treatment in Medical Conditions, 2020
James C. McElnay, C. Rosaleen McCallion
It is necessary to understand how the effect of ageing alters drug handling and drug action in elderly people in order to appreciate how these changes may influence adherence in this subgroup of the population. The pharmacodynamics of a drug relates to the type, intensity, and duration of effect of a given concentration of a drug at the site of action. There is good evidence that age-related changes occur with this parameter. Such effects relate either to changes in homeostatic reserve or to changes in specific receptors or target sites. Tessier (1993) has summarised the main clinically significant age-related changes in drug pharmacodynamics (Table 1).
Disease Prediction and Drug Development
Published in Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam, Introduction to Computational Health Informatics, 2019
Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam
Orally administered drugs, after being absorbed in the gastrointestinal system, move to the liver where they are mixed with the systemic circulation system because the blood passes through the liver. The increase in concentration of the drug increases the positive effect along with the associated toxicity. The effectiveness of a medication saturates beyond a specific concentration. The dosage for a medication depends on: 1) the pharmacodynamics studies of the drug that decides the drug-efficacy; 2) bioactivity measurement of the protein–protein interaction and 3) reported toxicity.
Individualized precision dosing approaches to optimize antimicrobial therapy in pediatric populations
Published in Expert Review of Clinical Pharmacology, 2021
Quyen Tu, Menino Cotta, Sainath Raman, Nicolette Graham, Luregn Schlapbach, Jason A Roberts
Pharmacodynamics is the study of the relationship between a drug concentration and its pharmacological or toxicological response. It is often referred to as ‘what the drug does to the body’ [16]. Less is known about human ontogenesis on antimicrobial PD. Age-specific drug-receptor, drug-disease, and drug-physiology response may account for some differences that have been observed between children and adults [27]. A well-described example is the effect of the tetracycline antimicrobial class on young children. Following up infants who were given tetracycline during the period of tooth formation has revealed the majority of these infants developed yellow and brown discoloration of teeth later in life [101]. This was confirmed to be permanent staining that occurred at any dose and any duration up to 8 years of age [101]. This PD interaction between tetracyclines and children is attributable to the tetracycline-calcium complex chelation during development of tooth formation in children [101]. In another example, Klugman has observed that children with acute meningitis had acceptable vancomycin concentrations in their cerebrospinal fluid (CSF), as opposed to inadequate concentrations in adults [102]. This phenomenon has been justified by the enhanced permeability to small lipid-insoluble molecules in the developing rather than fully mature brain [103].
Accelerating Alzheimer’s disease drug discovery and development: what’s the way forward?
Published in Expert Opinion on Drug Discovery, 2021
Bruno P. Imbimbo, Stefania Ippati, Mark Watling, Claudia Balducci
This is a fundamental question in the process of drug discovery and leads to optimization to identify new clinical candidates. AD models in mice carrying genes for the human forms of APP, PSEN1, PSEN2, or MAPT have been and are still being used as the main pharmacological tool for evaluating the potential therapeutic efficacy of clinical candidates. Although their utility is still recognized, we have to critically admit some of their translational limitations: (i) AD mouse models more closely reproduce ADAD, with a 7 to 12-fold increase in APP expression, and not the commoner SAD, although they faithfully reproduce the major AD biomarkers relevant to human pathology in both forms [17]. (ii) Most transgenic models are based on mutations which do not occur in over 90% of AD patients. (iii) Efficacy investigation is generally carried out only at one selected age rather than at multiple stages of the disease. (iv) In the majority of cases, apparent drug efficacy is not accompanied by pharmacokinetic and pharmacodynamic analyses to provide a rationale for dose selection, or even confirmation that the drug under test reaches the target organ at an appropriate concentration. (v) There is a lack of mouse standardization in terms of genetic background among research groups. (vi) Mouse groups are often underpowered. (vii) Inappropriate end points are often used.
Potential Psychotropic Drug Interactions among Drug-dependent People
Published in Journal of Psychoactive Drugs, 2021
Diego Zapelini do Nascimento, Gabriela Moreno Marques, Fabiana Schuelter-Trevisol
As for the mechanism of action, they were classified into pharmacokinetic and pharmacodynamic interactions. When alterations occur because of the interference with drug absorption, distribution, metabolism, and/or excretion, it is said to be a pharmacokinetic interaction. When changes occur in the drug effect because of increased activity (synergism) or decreased activity and/or activity cancellation (antagonism), it is said to be a pharmacodynamic interaction (Cedraz and Junior 2014). If there was more than one drug interaction with different mechanisms of action in the same medical record of the participant, this, as a whole, was determined by the mechanism of action that was most frequent among all interactions found in the most recent prescribed drugs. If there were only two interactions, it was considered the interaction action mechanism that had the highest clinical risk for the patient. Thus, clinical risks and mechanisms of action were analyzed for each psychotropic drug by reviewing the patient’s medical record to identify drug interactions. All study procedures were approved by the Research Ethics Committee of the University of Southern Santa Catarina on October 24, 2018 (Opinion No. 2 979 024).