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CPT: Pharmacometrics & Systems... Oct 2018Reliance on modeling and simulation in drug discovery and development has dramatically increased over the past decade. Two disciplines at the forefront of this activity,... (Review)
Review
Reliance on modeling and simulation in drug discovery and development has dramatically increased over the past decade. Two disciplines at the forefront of this activity, pharmacometrics and systems pharmacology (SP), emerged independently from different fields; consequently, a perception exists that only few examples integrate these approaches. Herein, we review the state of pharmacometrics and SP integration and describe benefits of combining these approaches in a model-informed drug discovery and development framework.
Topics: Pharmacology; Systems Integration
PubMed: 29761892
DOI: 10.1002/psp4.12313 -
The Journal of Pharmacology and... Sep 2019The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug... (Review)
Review
The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug has poor pharmacokinetics/biodistribution (PK/BD) or significant off-site toxicities. Successful translation of DDS into the clinic is dependent on a thorough understanding of the in vivo behavior of the carrier, which has, for the most part, been an elusive goal. This is, at least in part, due to significant differences in the mechanisms controlling pharmacokinetics for classic drugs and DDSs. In this review, we summarize the key physiologic mechanisms controlling the in vivo behavior of DDS, compare and contrast this with classic drugs, and describe engineering strategies designed to improve DDS PK/BD. In addition, we describe quantitative approaches that could be useful for describing PK/BD of DDS, as well as critical steps between tissue uptake and pharmacologic effect.
Topics: Animals; Drug Delivery Systems; Drug Therapy; Humans; Pharmacokinetics; Pharmacology; Tissue Distribution
PubMed: 30837281
DOI: 10.1124/jpet.119.257113 -
Indian Journal of Pharmacology Oct 2016Competency-based medical education (CBME) is gaining momentum across the globe. The Medical Council of India has described the basic competencies required of an Indian... (Review)
Review
Competency-based medical education (CBME) is gaining momentum across the globe. The Medical Council of India has described the basic competencies required of an Indian Medical Graduate and designed a competency-based module on attitudes and communication. Widespread adoption of a competency-based approach would mean a paradigm shift in the current approach to medical education. CBME, hence, needs to be reviewed for its usefulness and limitations in the Indian context. This article describes the rationale of CBME and provides an overview of its components, i.e., competency, entrustable professional activity, and milestones. It elaborates how CBME could be implemented in an institute, in the context of basic sciences in general and pharmacology in particular. The promises and perils of CBME that need to be kept in mind to maximize its gains are described.
Topics: Competency-Based Education; Curriculum; Education, Medical; Humans; Pharmacology
PubMed: 28031599
DOI: 10.4103/0253-7613.193312 -
Clinical Pharmacology and Therapeutics Jul 2015The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and... (Review)
Review
The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and Systems Pharmacology (QSP). This new research direction might significantly advance the discovery, development, and clinical use of therapeutic drugs. Research communities from computational biology, systems biology, and biological engineering--working collaboratively with pharmacologists, geneticists, biochemists, and analytical chemists--are creating and modeling large data on drug effects that is transforming our understanding of how these drugs work at a network level. In this review, we highlight developments in a new and rapidly growing field--pharmacometabolomics--in which large biochemical data-capturing effects of genome, gut microbiome, and environment exposures is revealing information about metabotypes and treatment outcomes, and creating metabolic signatures as new potential biomarkers. Pharmacometabolomics informs and complements pharmacogenomics and together they provide building blocks for QSP.
Topics: Biomarkers; Biomarkers, Pharmacological; Drug Discovery; Humans; Metabolic Networks and Pathways; Metabolome; Pharmacogenetics; Pharmacology; Phenotype; Precision Medicine
PubMed: 25871646
DOI: 10.1002/cpt.134 -
British Journal of Anaesthesia Jul 1979
Topics: Anesthetics; Animals; Humans; Infusions, Parenteral; Kinetics; Models, Biological; Pharmaceutical Preparations; Pharmacology; Protein Binding
PubMed: 550900
DOI: 10.1093/bja/51.7.579 -
Pediatric Research Jun 2018Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses... (Review)
Review
Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.
Topics: Biomarkers; Child; Child, Preschool; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy; Endpoint Determination; Health Policy; Humans; Infant; Infant, Newborn; Patient Compliance; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology; Practice Guidelines as Topic; Reproducibility of Results; Research Design; Risk; United States; United States Food and Drug Administration
PubMed: 29667952
DOI: 10.1038/pr.2018.38 -
Chrono-Pharmaceutical Approaches to Optimize Dosing Regimens Based on the Circadian Clock Machinery.Biological & Pharmaceutical Bulletin 2021Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at... (Review)
Review
Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The "circadian clock" is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables 'chrono-pharmaceutical' applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology
PubMed: 34719634
DOI: 10.1248/bpb.b21-00476 -
Neonatology 2014Drug therapy is a powerful tool for improving neonatal outcome. Despite this, neonatologists still routinely prescribe off-label compounds developed for adults and... (Review)
Review
Drug therapy is a powerful tool for improving neonatal outcome. Despite this, neonatologists still routinely prescribe off-label compounds developed for adults and extrapolate doses from those used for children or adults. Knowledge integration through pharmacokinetic modeling is a method that could improve the current situation. Such predictive models may convert neonatal pharmacotherapy from explorative to confirmatory. This can be illustrated by research projects related to the prediction of neonatal renal clearance and neonatal glucuronidation. This type of model will also improve the current knowledge of neonatal (patho)physiology. In the meanwhile, the fields of clinical pharmacology (e.g. pharmacokinetic/pharmacodynamic modeling and pharmacogenetics) and neonatology (e.g. whole-body cooling and the lower limit of viability) have both matured, resulting in new research topics. However, in order for the modeling and the newly emerging topics to become effective tools, they need to be tailored to the specific characteristics of neonates. Consequently, the field of neonatal pharmacotherapy needs dedicated neonatologists who continue to raise the awareness that off-label practices, eminence-based dosing regimens and the absence of neonatal drug formulations all reflect suboptimal care.
Topics: Age Factors; Body Size; Chemistry, Pharmaceutical; Decision Support Techniques; Drug Dosage Calculations; Humans; Infant, Newborn; Infant, Newborn, Diseases; Models, Biological; Neonatology; Off-Label Use; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics; Quality of Health Care; Risk Assessment; Risk Factors
PubMed: 24931327
DOI: 10.1159/000360648 -
CPT: Pharmacometrics & Systems... Mar 2023Good eyesight belongs to the most-valued attributes of health, and diseases of the eye are a significant healthcare burden. Case numbers are expected to further increase... (Review)
Review
Good eyesight belongs to the most-valued attributes of health, and diseases of the eye are a significant healthcare burden. Case numbers are expected to further increase in the next decades due to an aging society. The development of drugs in ophthalmology, however, is difficult due to limited accessibility of the eye, in terms of drug administration and in terms of sampling of tissues for drug pharmacokinetics (PKs) and pharmacodynamics (PDs). Ocular quantitative systems pharmacology models provide the opportunity to describe the distribution of drugs in the eye as well as the resulting drug-response in specific segments of the eye. In particular, ocular physiologically-based PK (PBPK) models are necessary to describe drug concentration levels in different regions of the eye. Further, ocular effect models using molecular data from specific cellular systems are needed to develop dose-response correlations. We here describe the current status of PK/PBPK as well as PD models for the eyes and discuss cellular systems, data repositories, as well as animal models in ophthalmology. The application of the various concepts is highlighted for the development of new treatments for postoperative fibrosis after glaucoma surgery.
Topics: Animals; Network Pharmacology; Models, Biological; Pharmaceutical Preparations; Pharmacology
PubMed: 36708082
DOI: 10.1002/psp4.12918 -
European Journal of Pediatrics Apr 2013Effective and safe drug administration in young infants should be based on integrated knowledge concerning the evolving physiological characteristics of the infant who... (Review)
Review
Effective and safe drug administration in young infants should be based on integrated knowledge concerning the evolving physiological characteristics of the infant who will receive the drug and the pharmacokinetic and pharmacodynamic characteristics of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we are entitled to take care of. Even more than median estimates, covariates of variability within the population are of clinical relevance. We aim to illustrate the complexity and the need for neonatal clinical pharmacology based on the gap between current and likely best clinical practice for two commonly administered compounds (aminoglycosides for infection and ibuprofen for patent ductus arteriosus) and one new compound (bevacizumab, to treat threshold retinopathy of prematurity). Progression has been made to render pharmacokinetic studies child size, e.g., low volume samples, optimal study design, and population pharmacokinetics. Challenges to further improve clinical pharmacology in neonates include, when appropriate, the validation of off-patent drug dosing regimens and of infant-tailored formulations. Knowledge integration, i.e., the use of available data to improve current drug use and to predict pharmacokinetics/pharmacodynamics for similar compounds is needed. Development of clinical research networks is helpful to achieve these goals.
Topics: Aminoglycosides; Analgesics, Non-Narcotic; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Bevacizumab; Dose-Response Relationship, Drug; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Pharmacology, Clinical; Retinopathy of Prematurity
PubMed: 22588521
DOI: 10.1007/s00431-012-1734-4