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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 -
Seminars in Perinatology Apr 2020The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood.... (Review)
Review
The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood. The dose-response relationship is affected by pharmacokinetics, or what the body does to a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential effects of the changes of pregnancy on one aspect of the dose-response relationship of a drug can be obtained by studying the pharmacokinetics of the drug in the various stages of pregnancy and the postpartum period. There are several available approaches to studying pharmacokinetic changes in pregnancy. Single trough screening studies can provide qualitative estimates of elimination clearance, which with the dosing rate determines the steady-state drug concentration, throughout pregnancy and into the postpartum period. Population pharmacokinetic studies such as two stage pharmacokinetic studies and studies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize pharmacokinetic changes more rigorously.
Topics: Absorption, Physiological; Dose-Response Relationship, Drug; Drug Elimination Routes; Female; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacological Phenomena; Pregnancy; Tissue Distribution
PubMed: 32093881
DOI: 10.1016/j.semperi.2020.151227 -
CPT: Pharmacometrics & Systems... Oct 2016The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on...
The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate the antibacterial activity of ciprofloxacin treatment.
Topics: Animals; Computer Simulation; Humans; Models, Biological; Pharmacokinetics; Risk Assessment; Tissue Distribution
PubMed: 27653238
DOI: 10.1002/psp4.12134 -
Molecules (Basel, Switzerland) May 2021Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation... (Review)
Review
Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.
Topics: Chemical Phenomena; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacokinetics; Stereoisomerism
PubMed: 34070985
DOI: 10.3390/molecules26113113 -
American Journal of Perinatology Jul 2019Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures... (Review)
Review
Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures to drugs that lack adequate data on safety, efficacy, and appropriate dosing in this population. Key physiologic differences between neonates and older children and adults affect drug absorption, distribution, metabolism, and elimination. Adequate understanding and consideration of these differences is essential to ensure optimal dosing of therapeutic agents in this vulnerable population. Moreover, direct study of neonates through appropriately designed pharmacokinetic and pharmacodynamic studies can ensure the development of safe and effective therapeutics in our youngest populations of patients.
Topics: Absorption, Physiological; Humans; Infant, Newborn; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 31238353
DOI: 10.1055/s-0039-1691772 -
Journal of Pharmaceutical Sciences Jan 2019Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules to prolong their systemic circulation, target... (Review)
Review
Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules to prolong their systemic circulation, target specific tissue, or widen the therapeutic window. The multifunctionality of nanoparticles is frequently presented as an advantage but also results in distinct and complicated in vivo disposition properties compared with a conventional formulation of the same molecules. Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool in characterizing and predicting the systemic disposition, target exposure, and efficacy and toxicity of various types of drugs when coupled with pharmacodynamic modeling. Here we review the unique disposition characteristics of nanoparticles, assess how PBPK modeling takes into account the unique disposition properties of nanoparticles, and comment on the applications and challenges of PBPK modeling in characterizing and predicting the disposition and biological effects of nanoparticles.
Topics: Animals; Humans; Models, Biological; Nanoparticles; Pharmacokinetics; Tissue Distribution
PubMed: 30385282
DOI: 10.1016/j.xphs.2018.10.037 -
International Journal of Molecular... Jan 2023RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique... (Review)
Review
RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique targets and prolonged pharmacological effects. Their absorption, distribution, metabolism, and excretion (ADME) have important clinical im-plications, but their pharmacokinetic properties have not been fully understood. Most RNA therapeutics have structural modifications to prevent rapid elimination from the plasma and are administered intravenously or subcutaneously, with some exceptions, for effective distribution to target organs. Distribution of drugs into tissues depends on the addition of a moiety that can be transported to the target and RNA therapeutics show a low volume of distribution because of their molecular size and negatively-charged backbone. Nucleases metabolize RNA therapeutics to a shortened chain, but their metabolic ratio is relatively low. Therefore, most RNA therapeutics are excreted in their intact form. This review covers not only ADME features but also clinical pharmacology data of the RNA therapeutics such as drug-drug interaction or population pharmacokinetic analyses. As the market of RNA therapeutics is expected to rapidly expand, comprehensive knowledge will contribute to interpreting and evaluating the pharmacological properties.
Topics: Drug Interactions; Chemical Phenomena; Biological Transport; Pharmacokinetics
PubMed: 36614189
DOI: 10.3390/ijms24010746 -
Journal of Pharmacokinetics and... Dec 2010Malcolm Rowland has greatly facilitated an understanding of drug structure-pharmacokinetic relationships using a physiological perspective. His view points, covering a... (Review)
Review
Malcolm Rowland has greatly facilitated an understanding of drug structure-pharmacokinetic relationships using a physiological perspective. His view points, covering a wide range of activities, have impacted on my own work and on my appreciation and understanding of our science. This overview summarises some of our parallel activities, beginning with Malcolm's work on the pH control of amphetamine excretion, his work on the disposition of aspirin and on the application of clearance concepts in describing the disposition of lidocaine. Malcolm also spent a considerable amount of time developing principles that define solute structure and transport/pharmacokinetic relationships using in situ organ studies, which he then extended to involve the whole body. Together, we developed a physiological approach to studying hepatic clearance, introducing the convection-dispersion model in which there was a spread in blood transit times through the liver accompanied by permeation into hepatocytes and removal by metabolism or excretion into the bile. With a range of colleagues, we then further developed the model and applied it to various organs in the body. One of Malcolm's special interests was in being able to apply this knowledge, together with an understanding of physiological differences in scaling up pharmacokinetics from animals to man. The description of his many other activities, such as the development of clearance concepts, application of pharmacokinetics to the clinical situation and using pharmacokinetics to develop new compounds and delivery systems, has been left to others.
Topics: Absorption; Animals; Biological Transport; Humans; Liver; Metabolic Clearance Rate; Permeability; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology, Clinical; Technology Transfer; Tissue Distribution
PubMed: 21107662
DOI: 10.1007/s10928-010-9174-0 -
Anti-cancer Agents in Medicinal... Dec 2012Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More... (Review)
Review
Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches.
Topics: Absorption; Administration, Oral; Animals; Anticarcinogenic Agents; Biological Availability; Genistein; Humans; Injections, Intraperitoneal; Injections, Intravenous; Metabolic Clearance Rate; Models, Biological; Molecular Structure; Tissue Distribution
PubMed: 22583407
DOI: 10.2174/187152012803833107 -
European Journal of Pharmaceutical... Sep 2022The infinite time of oral drug absorption was conceived from the first day of the birth of pharmacokinetics when H. Dost introduced the term pharmacokinetics in his book... (Review)
Review
The infinite time of oral drug absorption was conceived from the first day of the birth of pharmacokinetics when H. Dost introduced the term pharmacokinetics in his book published in 1953. He adopted the function developed by H. Bateman back in 1908 for the decay of the nuclei isotopes to describe oral drug absorption as a first-order process. We unveiled this false hypothesis relying on common wisdom i.e. drugs are absorbed in finite time. This false assumption had dramatic effects on the evolution of oral pharmacokinetics but most importantly on the bioavailability and bioequivalence concepts and metrics. This work focuses on the finite absorption time (FAT) concept, the relevant Physiologically Based Finite Time (PBFTPK) models developed and their applications in oral pharmacokinetics, bioavailability and bioequivalence. The crux of the matter is that drug absorption from the gastrointestinal tract takes place under sink conditions because of the high blood flow rate in the vena cava. The termination of oral, pulmonary and intranasal drug absorption at a specific time point, calls for regulatory changes in bioavailability and bioequivalence studies in terms of the study design and metrics used for the bioequivalence assessment.
Topics: Administration, Oral; Biological Availability; Gastrointestinal Tract; Humans; Male; Pharmacokinetics; Therapeutic Equivalency
PubMed: 35863551
DOI: 10.1016/j.ejps.2022.106265