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Journal of Clinical Pharmacology Oct 2018Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In... (Review)
Review
Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug-response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.
Topics: Aging; Child; Child Development; Humans; Intestinal Absorption; Kidney; Pharmaceutical Preparations; Pharmacokinetics; Pharmacological Phenomena; Tissue Distribution
PubMed: 30248190
DOI: 10.1002/jcph.1284 -
Marine Drugs Nov 2020Marine organisms represent an excellent source of innovative compounds that have the potential for the development of new drugs. The pharmacokinetics of marine drugs has... (Review)
Review
Marine organisms represent an excellent source of innovative compounds that have the potential for the development of new drugs. The pharmacokinetics of marine drugs has attracted increasing interest in recent decades due to its effective and potential contribution to the selection of rational dosage recommendations and the optimal use of the therapeutic arsenal. In general, pharmacokinetics studies how drugs change after administration via the processes of absorption, distribution, metabolism, and excretion (ADME). This review provides a summary of the pharmacokinetics studies of marine-derived active compounds, with a particular focus on their ADME. The pharmacokinetics of compounds derived from algae, crustaceans, sea cucumber, fungus, sea urchins, sponges, mollusks, tunicate, and bryozoan is discussed, and the pharmacokinetics data in human experiments are analyzed. In-depth characterization using pharmacokinetics is useful for obtaining information for understanding the molecular basis of pharmacological activity, for correct doses and treatment schemes selection, and for more effective drug application. Thus, an increase in pharmacokinetic research on marine-derived compounds is expected in the near future.
Topics: Animals; Aquatic Organisms; Biological Availability; Biological Products; Drug Dosage Calculations; Half-Life; Humans; Metabolic Clearance Rate; Tissue Distribution
PubMed: 33182407
DOI: 10.3390/md18110557 -
Science China. Life Sciences Oct 2018Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology, the computer-aided drug design techniques... (Review)
Review
Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology, the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical trials. Owing to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence (AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening, activity scoring, quantitative structure-activity relationship (QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability, deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules, which will further promote the application of AI technologies in the field of drug design.
Topics: Artificial Intelligence; Computational Biology; Computer Simulation; Computer-Aided Design; Drug Design; Drug Discovery; Humans; Pharmaceutical Preparations; Pharmacokinetics; Structure-Activity Relationship
PubMed: 30054833
DOI: 10.1007/s11427-018-9342-2 -
Biochemical Pharmacology Aug 2020Dosing time accounts for a large variability in efficacy and/or toxicity for many drugs. Therefore, chronotherapy has been shown to effectively improve drug efficacy and... (Review)
Review
Dosing time accounts for a large variability in efficacy and/or toxicity for many drugs. Therefore, chronotherapy has been shown to effectively improve drug efficacy and to reduce drug toxicity. Circadian changes in pharmacokinetics and pharmacodynamics (drug target) are two essential sources of time-varying drug effects. Pharmacokinetics determines the drug and metabolite concentrations (exposure) in target tissues/organs, thereby impacting drug efficacy and toxicity. Pharmacokinetic processes are generally divided into drug absorption, distribution, metabolism and excretion (so-called "ADME"). Recent years of studies have revealed circadian (~24 h) rhythms in ADME processes, and clarified the underlying mechanisms related to circadian clock regulation. Furthermore, there is accumulating evidence that circadian pharmacokinetics can be translated to chronotoxicity and chronoefficacy. In this article, we review circadian rhythms in pharmacokinetic behaviors along with the underlying mechanisms. We also discuss the correlations of circadian pharmacokinetics with chronotoxicity and chronoefficacy.
Topics: Animals; Chronotherapy; Circadian Clocks; Circadian Rhythm; Humans; Pharmaceutical Preparations; Tissue Distribution
PubMed: 32446886
DOI: 10.1016/j.bcp.2020.114045 -
British Journal of Clinical Pharmacology Mar 2015A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with... (Review)
Review
A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials.
Topics: Child; Clinical Trials as Topic; Humans; Inactivation, Metabolic; Intestinal Absorption; Models, Biological; Pediatrics; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 25855821
DOI: 10.1111/bcp.12267 -
European Journal of Pharmaceutical... Jun 2019The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the... (Review)
Review
The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.
Topics: Administration, Oral; Biological Availability; Drug Liberation; Europe; Food-Drug Interactions; Gastrointestinal Absorption; Gastrointestinal Tract; Humans; Intestinal Absorption; Pharmacokinetics
PubMed: 30974173
DOI: 10.1016/j.ejps.2019.04.003 -
Journal of Clinical Pharmacology Jan 2024Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously "undruggable" diseases. After nearly 2 decades of... (Review)
Review
Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously "undruggable" diseases. After nearly 2 decades of efforts in addressing the problems of the poor drug profile of naked unmodified siRNAs, this new modality has finally come to fruition, with 5 agents (patisiran, givosiran, lumasiran, inclisiran, and vutrisiran) being approved since 2018, and with many others in the different phases of clinical development. Unlike small-molecule drugs and protein therapeutics, siRNAs have different sizes, distinct mechanisms of action, differing physicochemical and pharmacological properties, and, accordingly, a unique pharmacokinetic/pharmacodynamic (PK/PD) relationship. To support the continuous development of siRNAs, it is important to have a thorough and deep understanding of the PK/PD and clinical pharmacology related features of siRNAs. As most of the current siRNA products are conjugated by N-acetylgalactosamine (GalNAc), this review focuses on the PK/PD relationships and clinical pharmacology of GalNAc-conjugated siRNAs, including their absorption, distribution, metabolism, excretion (ADME) properties, PK/PD models, drug-drug interactions, clinical pharmacology in special populations, and safety evaluation. In addition, necessary background information related to the development of siRNAs as a therapeutic modality, including the mechanisms of action, the advantages of siRNAs, the problems of naked siRNAs, as well as the strategies used to enhance the clinical utility of siRNAs, have also been covered. The goal of this review is to serve as a "primer" on siRNA PK/PD, and I hope the readers, especially those who have a limited background on siRNA therapeutics, will have a fundamental understanding of siRNA PK/PD and clinical pharmacology after reading this review.
Topics: Humans; RNA, Small Interfering; Drug Interactions; Pharmacology, Clinical; Pharmacokinetics
PubMed: 37589246
DOI: 10.1002/jcph.2337 -
Future Medicinal Chemistry Jan 2022
Topics: Administration, Oral; Biological Availability; Cell Membrane; Enzyme Inhibitors; Humans; Ligands; Molecular Structure; Permeability; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 34583518
DOI: 10.4155/fmc-2021-0208 -
Journal of Clinical Pharmacology Feb 2020Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high-affinity binding of a compound to its... (Review)
Review
Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high-affinity binding of a compound to its pharmacologic targets. As the interaction between a drug and its pharmacologic target belongs to the process of pharmacodynamics (PD), TMDD can be viewed as a consequence of "PD affecting PK." Although there are numerous TMDD-related articles in the literature, most of them focus on characterizing TMDD using various mathematical models, which may not be suitable for those readers who have little interest in mathematical modeling and only want to have an understanding of the basic concept. The goal of this review is to serve as a "primer" on TMDD. This review explains (1) how TMDD happens; (2) why large-molecule and small-molecule compounds exhibiting TMDD demonstrate substantially different nonlinear PK behaviors; (3) what nonlinear PK profiles look like in large-molecule and small-molecule compounds exhibiting TMDD, using pegfilgrastim, erythropoietin, ABT-384, and linagliptin as case examples; and (4) how to identify whether the nonlinear PK of a compound is because of TMDD.
Topics: Animals; Drug Delivery Systems; Humans; Nonlinear Dynamics; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 31793004
DOI: 10.1002/jcph.1545 -
European Journal of Drug Metabolism and... Jul 2021Short bowel syndrome is a clinical condition defined by malabsorption of nutrients and micronutrients, most commonly following extensive intestinal resection. Due to a...
BACKGROUND AND OBJECTIVES
Short bowel syndrome is a clinical condition defined by malabsorption of nutrients and micronutrients, most commonly following extensive intestinal resection. Due to a loss of absorptive surfaces, the absorption of orally administered drugs is also often affected. The purpose of this study was to systematically review the published literature and examine the effects of short bowel syndrome on drug pharmacokinetics and clinical outcomes.
METHODS
Studies were identified through searches of databases MEDLINE, EMBASE, Web of Science, and SCOPUS, in addition to hand searches of studies' reference lists. Two reviewers independently assessed studies for inclusion, yielding 50 studies involving 37 different drugs in patients with short bowel syndrome.
RESULTS
Evidence of decreased drug absorption was observed in 29 out of 37 drugs, 6 of which lost therapeutic effect, and 14 of which continued to demonstrate clinical benefit through drug monitoring.
CONCLUSIONS
The influence of short bowel syndrome on drug absorption appears to be drug-specific and dependent on the location and extent of resection. The presence of a colon in continuity may also influence drug bioavailability as it can contribute significantly to the absorption of drugs (e.g., metoprolol); likewise, drugs that have a wide absorption window or are known to be absorbed in the colon are least likely to be malabsorbed. Individualized dosing may be necessary to achieve therapeutic efficacy, and therapeutic drug monitoring, where available, should be considered in short bowel syndrome patients, especially for drugs with narrow therapeutic indices.
Topics: Administration, Oral; Biological Availability; Humans; Intestinal Absorption; Pharmaceutical Preparations; Pharmacokinetics; Short Bowel Syndrome
PubMed: 34196913
DOI: 10.1007/s13318-021-00696-y