physiologically based pharmacokinetic pbpk modeling

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Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations
Author : Sheila Annie Peters
Publisher : John Wiley & Sons
Release Date : 2012-02-17
ISBN 10 : 1118140303
Pages : 450 pages

The only book dedicated to physiologically-based pharmacokineticmodeling in pharmaceutical science Physiologically-based pharmacokinetic (PBPK) modeling has becomeincreasingly widespread within the pharmaceutical industry over thelast decade, but without one dedicated book that provides theinformation researchers need to learn these new techniques, itsapplications are severely limited. Describing the principles,methods, and applications of PBPK modeling as used inpharmaceutics, Physiologically-Based Pharmacokinetic (PBPK)Modeling and Simulations fills this void. Connecting theory with practice, the book explores theincredible potential of PBPK modeling for improving drug discoveryand development. Comprised of two parts, the book first provides adetailed and systematic treatment of the principles behindphysiological modeling of pharmacokinetic processes,inter-individual variability, and drug interactions for smallmolecule drugs and biologics. The second part looks in greaterdetail at the powerful applications of PBPK to drug research. Designed for a wide audience encompassing readers looking for abrief overview of the field as well as those who need more detail,the book includes a range of important learning aids. Featuringend-of-chapter keywords for easy reference—a valuable assetfor general or novice readers without a PBPK background—alongwith an extensive bibliography for those looking for furtherinformation, Physiologically- Based Pharmacokinetic (PBPK) Modelingand Simulations is the essential single-volume text on one of thehottest topics in the pharmaceutical sciences today.

Physiologically Based Pharmacokinetic (PBPK) Modeling
Author : Jeffrey W. Fisher,Jeffery M. Gearhart,Zhoumeng Lin
Publisher : Academic Press
Release Date : 2020-05-20
ISBN 10 : 0128196823
Pages : 346 pages

Physiologically Based Pharmacokinetic (PBPK) Modeling: Methods and Applications in Toxicology and Risk Assessment presents foundational principles, advanced techniques and applications of PBPK modeling. Contributions from experts in PBPK modeling cover topics such as pharmacokinetic principles, classical physiological models, the application of physiological models for dose-response and risk assessment, the use of in vitro information, and in silico methods. With end-of-chapter exercises that allow readers to practice and learn the skills associated with PBPK modeling, dose-response, and its applications to safety and risk assessments, this book is a foundational resource that provides practical coverage of PBPK modeling for graduate students, academics, researchers, and more. Provides end-of-chapter exercises to teach hands-on computational tools used in toxicology Supplies computer code and explanations and includes examples of applied models used in regulatory toxicology and research Authored by expert editors and contributors who are among the best PBPK modelers in the world

Physiologically Based Pharmacokinetic Modeling
Author : Micaela Reddy,R. S. Yang,Melvin E. Andersen,Harvey J. Clewell III
Publisher : John Wiley & Sons
Release Date : 2005-06-14
ISBN 10 : 0471478776
Pages : 420 pages

A definitive, single source of information on PBPK modeling Physiologically-based pharmacokinetic (PBPK) modeling is becomingincreasingly important in human health risk assessments and insupporting pharmacodynamic modeling for toxic responses. Organizedby classes of compounds and modeling purposes so users can quicklyaccess information, this is the first comprehensive reference ofits kind. This book presents an overview of the underlying principles of PBPKmodel development. Then it provides a compendium of PBPK modelinginformation, including historical development, specific modelingchallenges, and current practices for: * Halogenated Alkanes * Halogenated Alkenes * Alkene and Aromatic Compounds * Reactive Vapors in the Nasal Cavity * Alkanes, Oxyhydrocarbons, and Related Compounds * Pesticides and Persistent Organic Pollutants * Dioxin and Related Compounds * Metals and Inorganic Compounds * Drugs * Antineoplastic Agents * Perinatal Transfer * Mixtures * Dermal Exposure Models In addition to pinpointing specific information, readers canexplore diverse modeling techniques and applications. Anauthoritative reference for toxicologists, ecotoxicologists, riskassessors, regulators, pharmacologists, pharmacists, and graduatestudents in pharmacokinetics and toxicology, Physiologically-BasedPharmacokinetic Modeling compiles information from leaders in thefield and discusses future directions for PBPK modeling.

Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications, Third Edition
Author : Johan Gabrielsson,Daniel Weiner
Publisher : CRC Press
Release Date : 2001-11-30
ISBN 10 : 9789186274924
Pages : 924 pages

This is a revised and very expanded version of the previous second edition of the book. "Pharmacokinetic and Pharmacodynamic Data Analysis" provides an introduction into pharmacokinetic and pharmacodynamic concepts using simple illustrations and reasoning. It describes ways in which pharmacodynamic and pharmacodynamic theory may be used to give insight into modeling questions and how these questions can in turn lead to new knowledge. This book differentiates itself from other texts in this area in that it bridges the gap between relevant theory and the actual application of the theory to real life situations. The book is divided into two parts; the first introduces fundamental principles of PK and PD concepts, and principles of mathematical modeling, while the second provides case studies obtained from drug industry and academia. Topics included in the first part include a discussion of the statistical principles of model fitting, including how to assess the adequacy of the fit of a model, as well as strategies for selection of time points to be included in the design of a study. The first part also introduces basic pharmacokinetic and pharmacodynamic concepts, including an excellent discussion of effect compartment (link) models as well as indirect response models. The second part of the text includes over 70 modeling case studies. These include a discussion of the selection of the model, derivation of initial parameter estimates and interpretation of the corresponding output. Finally, the authors discuss a number of pharmacodynamic modeling situations including receptor binding models, synergy, and tolerance models (feedback and precursor models). This book will be of interest to researchers, to graduate students and advanced undergraduate students in the PK/PD area who wish to learn how to analyze biological data and build models and to become familiar with new areas of application. In addition, the text will be of interest to toxicologists interested in learning about determinants of exposure and performing toxicokinetic modeling. The inclusion of the numerous exercises and models makes it an excellent primary or adjutant text for traditional PK courses taught in pharmacy and medical schools. A diskette is included with the text that includes all of the exercises and solutions using WinNonlin.

Toxicokinetics and Risk Assessment
Author : John C. Lipscomb,Edward V. Ohanian
Publisher : CRC Press
Release Date : 2016-04-19
ISBN 10 : 1000612139
Pages : 361 pages

Toxicokinetics in Risk Assessment discusses the noncancer risk assessment process and its reliance on uncertainty factors in order to facilitate the continued study and refinement of the scientific basis for health risk assessment. This text clearly demonstrates the application of physiologically-based pharmacokinetic (PBPK) modeling in human healt

New Technologies for Toxicity Testing
Author : Michael Balls,Robert D. Combes,Nirmala Bhogal
Publisher : Springer Science & Business Media
Release Date : 2012-03-22
ISBN 10 : 1461430550
Pages : 258 pages

The central theme running through this volume on New Technologies for Toxicity Testing is the development and application of advanced techniques for cell and tissue culture, as well as new markers and endpoints of toxicity, as alternatives to the traditional paradigm of relying on data from laboratory animal tests to undertake labelling and risk assessment. Of course, many of the techniques and methods described in this volume are in the early stages of development, and much work will be needed to ensure their further improvement, optimisation and validation. However, we are confident that this will be achieved and that, just as with the in vitro assays that were validated and granted regulatory acceptance over the last decade, these, and many other new, advanced methods, will likewise become part of the toxicologist’s improved toolbox for coping with increasingly stringent and numerous regulatory requirements and test chemicals, while placing less reliance on traditional testing paradigms.

Fundamentals of Pediatric Drug Dosing
Author : Iftekhar Mahmood,Gilbert Burckart
Publisher : Springer
Release Date : 2016-10-28
ISBN 10 : 3319437542
Pages : 146 pages

Focused on pediatric physiology, pharmacology, pharmacokinetics and pharmacodynamics, this book illustrates the differences between the pediatric population and adults; knowledge of extreme importance not only during pediatric drug development but also in the clinical practice. Physicians, nurses, clinical pharmacologists, researchers and healthcare professionals will find this an invaluable resource. With the advent of pediatric exclusivity, and requirements to conduct clinical studies in children, an emphasis has been placed on finding a safe and efficacious dose of a drug in children. Children are not ‘small adults’, and drug dosing in this population requires special consideration. There are subtle physiological and biochemical differences among neonates, infants, children, adolescents and adults and dosing in pediatrics requires proper understanding of these factors. Furthermore, dosing in children, as in adults, should be based on pharmacokinetic and pharmacodynamic data. This is an evolving area, as pediatric pharmacokinetic studies are becoming mandatory for getting approval of new drugs in this population.

Physiologically-based pharmacokinetic (PBPK) models integrate system specific anatomy and physiology information with drug specific physicochemical and pharmacokinetic properties to predict drug disposition. Such integration permits items, events, processes, and pathways to communicate and influence each other interactively. By taking advantage of such mechanistic nature of PBPK modeling, drug dispositions under untested scenarios could be predicted by extrapolation from observed data in known conditions. Renal clearance is one of the major pathways governing drug dispositions, which has three main mechanisms: unbound filtration, passive reabsorption, and active secretion. In comparison to intestinal absorption and hepatic metabolism, renal clearance has been relatively underappreciated. Controlled clinical experiments that test renal clearance changes under altered conditions and mechanisms have been primarily focusing on drug-drug interaction on active secretion. However, huge gaps in understanding renal clearance still exist in other areas such as altered urine pH and impaired renal function. Further, passive reabsorption has not been paid significant attention by the pharmaceutical field. Therefore, the overarching goal of this thesis is to leverage mechanistic PBPK modeling technique to understand and predict renal clearance of drugs and metabolites under altered urine pH and impaired renal function, with a special focus on compounds undergoing significant renal passive reabsorption. In Chapter 2, to predict the spatiodynamic process of renal passive reabsorption in human, we developed a dynamic physiologically-based mechanistic kidney model based on human data that can integrate drug permeability, tubular surface area, ionization status, and drug concentration gradient between lumen and system to estimate renal passive reabsorption and predict renal clearance of drugs. Using 46 test compounds with a variety of physicochemical properties, the model successfully predicted the renal clearances of 87% compounds within 2-fold and 98% compounds within 3-fold. Further, by incorporating active secretion, the model also successfully predicted the renal clearances of para-aminohippuric acid (PAH), cimetidine, salicylic acid, and memantine. In Chapter 3, to ensure the simulation output from PBPK models can be meaningfully compared to the arm vein plasma drug concentrations collected in clinical studies, we developed a forearm model that captures the tissue distribution at the peripheral sampling site using human arm physiology data, allowing for a better prediction of plasma drug concentrations that are comparable to observed data. The model was successfully verified using arterial and venous concentrations of nicotine, ketamine, lidocaine, and fentanyl simultaneously. Further, I demonstrated that use of a discrepant sampling site in PBPK modeling than observed clinical studies may lead to biased model evaluation, erroneous model parameterization, and misleading prediction in unstudied clinical scenarios. In Chapter 4, to predict the altered renal excretion and systemic AUC of drug and metabolite when urine pH is changed, the mechanistic kidney model developed and verified from Chapter 2 was integrated with the peripheral arm sampling and full body PBPK model developed from Chapter 3. The model was successfully verified with methamphetamine and amphetamine under varying urine pH statuses, and showed feasibility to predict quantitatively and clinically significant changes in drug and metabolite disposition under comedications and diseases that can alter urine pH. In Chapter 5, to predict renal clearance in patients with impaired renal function such as chronic kidney diseases, physiological changes in tubular flow and urine flow observed in chronic kidney disease patients were incorporated into the mechanistic kidney model developed and verified from Chapter 2. The model accounts for the adaptive renal tubular filtrate flows that decrease disproportionately with glomerular filtration rate, and was successfully verified using three parent-metabolite pairs, six non-permeable drugs, six permeable drugs, and two secreted drugs. In conclusion, in this thesis, I developed and verified a physiologically-based mechanistic kidney model to translate drug properties such as plasma protein binding, transcellular permeability, and active transport into renal clearance of drugs and metabolites. This mechanistic kidney model allows prediction of alterations in renal clearance of drugs and metabolites upon changes in urine pH and renal functions, and can be incorporated into a full-body PBPK model to predict alterations in systemic disposition of drugs and metabolites.

Ecotoxicology Modeling
Author : James Devillers
Publisher : Springer Science & Business Media
Release Date : 2009-08-07
ISBN 10 : 9781441901972
Pages : 412 pages

Ecotoxicology Modeling is a comprehensive and well-documented text providing a collection of computational methods to the ecotoxicologists primarily interested in the study of the adverse effects of chemicals, their mechanisms of action and/or their environmental fate and behavior. Avoiding mathematical jargon, the book presents numerous case studies to enable the reader to understand the interest but also the limitations of linear and nonlinear models in ecotoxicology. Written by an international team of scientists, Ecotoxicology Modeling is of primary interest to those whose research or professional activity is directly concerned with the development and application of models in ecotoxicology. It is also intended to provide the graduate and post-graduate students with a clear and accessible text covering the main types of modeling approaches used in environmental sciences.

Metabolite Safety in Drug Development
Author : Suzanne L. Iverson
Publisher : John Wiley & Sons
Release Date : 2016-08-01
ISBN 10 : 111894965X
Pages : 352 pages

A reference on drug metabolism and metabolite safety in the development phase, this book reviews the analytical techniques and experimental designs critical for metabolite studies. It features case studies of lessons learned and real world examples, along with regulatory perspectives from the US FDA and EMA. • Reviews the analytical techniques and experimental designs critical for metabolite studies • Covers methods including chirality, species differences, mass spectrometry, radiolabels, and in vitro / in vivo correlation • Discusses target pharmacology, in vitro systems aligned to toxicity tests, and drug-drug interactions • Includes perspectives from authors with firsthand involvement in industry and the study of drug metabolites, including viewpoints that have influenced regulatory guidelines

Quantitative Modeling in Toxicology
Author : Kannan Krishnan,Melvin E. Andersen
Publisher : John Wiley & Sons
Release Date : 2010-04-01
ISBN 10 : 0470686707
Pages : 504 pages

Governments around the world are passing laws requiring industry to assess the toxicity of the chemicals and products they produce, but to do so while reducing, refining, or even replacing testing on animals. To meet these requirements, experimental toxicologists and risk assessors are adopting quantitative approaches and computer simulations to study the biological fate and effects of chemicals and drugs. In Quantitative Modeling in Toxicology leading experts outline the current state of knowledge on the modeling of dose, tissue interactions and tissue responses. Each chapter describes the mathematical foundation, parameter estimation, challenges and perspectives for development, along with the presentation of a modeling template. Additionally, tools and approaches for conducting uncertainty, sensitivity and variability analyses in these models are described. Topics covered include: the quantitative models of pharmacokinetics of individual chemicals and mixtures models for toxicant-target tissue interaction. models for cellular, organ, and organism responses. approaches, tools and challenges for model application and evaluation A website containing computer codes accompanies the book to help the reader reconstruct the models described and discussed in the various chapters. Quantitative Modeling in Toxicology serves as an essential reference source and tool box for risk assessors and researchers and students in toxicology, public health, pharmacology, and human toxicology interested in developing quantitative models for a better understanding of dose-response relationships.

Pharmacokinetic-Pharmacodynamic Modeling and Simulation
Author : Peter L. Bonate
Publisher : Springer Science & Business Media
Release Date : 2006-05-14
ISBN 10 : 0387271996
Pages : 388 pages

A natural hierarchy exists in pharmacokinetic-pharmacodynamic modeling culminating in population pharmacokinetic models, which are a specific type of nonlinear mixed effects model. The purpose of this book is to present through theory and example how to develop pharmacokinetic models, both at an individual and population level. In order to do so, however, one must first understand linear models and then build to nonlinear models followed by linear mixed effects models and then ultimately nonlinear mixed effects models. This book develops in that manner – each chapter builds upon previous chapters by first presenting the theory and then illustrating the theory using published data sets and actual data sets that were used in the development of new chemical entities collected by the author during his years in industry. A key feature of the book is the process of modeling. Most books and manuscripts often present the final model never showing how the model evolved. In this book all examples are presented in an evolutionary manner.

Human Biomonitoring for Environmental Chemicals
Author : National Research Council,Division on Earth and Life Studies,Board on Environmental Studies and Toxicology,Committee on Human Biomonitoring for Environmental Toxicants
Publisher : National Academies Press
Release Date : 2006-10-30
ISBN 10 : 9780309133906
Pages : 316 pages

Biomonitoring—a method for measuring amounts of toxic chemicals in human tissues—is a valuable tool for studying potentially harmful environmental chemicals. Biomonitoring data have been used to confirm exposures to chemicals and validate public health policies. For example, population biomonitoring data showing high blood lead concentrations resulted in the U.S. Environmental Protection Agency's (EPA's) regulatory reduction of lead in gasoline; biomonitoring data confirmed a resultant drop in blood lead concentrations. Despite recent advances, the science needed to understand the implications of the biomonitoring data for human health is still in its nascent stages. Use of the data also raises communication and ethical challenges. In response to a congressional request, EPA asked the National Research Council to address those challenges in an independent study. Human Biomonitoring for Environmental Chemicals provides a framework for improving the use of biomonitoring data including developing and using biomarkers (measures of exposure), research to improve the interpretation of data, ways to communicate findings to the public, and a review of ethical issues.

Drug Transporters
Author : Martin F. Fromm,Richard B. Kim
Publisher : Springer Science & Business Media
Release Date : 2010-11-19
ISBN 10 : 9783642145414
Pages : 454 pages

It is increasingly recognized that various transporter proteins are expressed throughout the body and determine absorption, tissue distribution, biliary and renal elimination of endogenous compounds and drugs and drug effects. This book will give an overview on the transporter families which are most important for drug therapy. Most chapters will focus on one transporter family highlighting tissue expression, substrates, inhibitors, knock-out mouse models and clinical studies.

Author : National Research Council,Division on Earth and Life Studies,Board on Environmental Studies and Toxicology,Committee on Toxicology,Subcommittee on Iodotrifluoromethane
Publisher : National Academies Press
Release Date : 2004-12-23
ISBN 10 : 0309093074
Pages : 112 pages

The U.S. military is considering using a compound called iodotrifluoromethane (CF3I) for fire suppression to replace previously-used compounds (halons) that are being phased out because they deplete the ozone layer. This report reviews available toxicological data on CF3I and evaluates the scientific basis of the U.S. Army's proposed exposure limit of 2,000 parts per million (ppm). The report recommends that CF3I be used for fire suppression in normally unoccupied spaces because of its potential to cause cardiac sensitization in test animals. The report also recommends that further genotoxicity testing be conducted (testing for changes in genetic material), and that CF3I be assessed for its potential to cause cancer. Should the Army decide to use CF3I, information should be collected and evaluated on how much of the chemical or any of its degradation products might be released and how often.

Transporters in Drug Development
Author : Yuichi Sugiyama,Bente Steffansen
Publisher : Springer Science & Business Media
Release Date : 2013-09-16
ISBN 10 : 1461482291
Pages : 317 pages

Transporters in Drug Development examines how membrane transporters can be dealt with in academic–industrial drug discovery and pharmaceutical development as well as from a regulatory perspective. The book describes methods and examples of in vitro characterization of single transporters in the intestines, liver and kidneys as well as characterization of substrate overlap between various transporters. Furthermore, probes and biomarkers are suggested for studies of the transporters’ impact on the pharmacokinetics of drug substrates/candidates interacting on transporters. The challenges of translating in vitro observed interaction of transporters into in vivo relevance are explored, and the book highlights perspectives of applying targeted proteomics and mechanistic modeling in this process.

Author : J. Christopher States
Publisher : John Wiley & Sons
Release Date : 2015-11-02
ISBN 10 : 111851114X
Pages : 576 pages

"This book acts as a compendium of up-to-date knowledge on arsenic as a toxicant, its exposure sources, health risks, and mechanisms"--

Pharmaceutical Nanotechnology
Author : Jean Cornier
Publisher : John Wiley & Sons
Release Date : 2017-02-06
ISBN 10 : 3527340548
Pages : 775 pages

With its focus on concrete methods and recent advances in applying nanotechnology to develop new drug therapies and medical diagnostics, this book provides an overall picture of the field, from the fundamentals of nanopharmacy with the characterisation and manufacturing methods to the role of nanoparticles and substances. Actual examples of utilization include drug development issues, translation to the clinic, market prospects, and industrial commercialization aspects. The applications described are taken from cancer treatment as well as other major therapeutic areas, such as infectious diseases and dermatology. An in-depth discussion on safety, regulatory, and societal aspects rounds off the book. Written by a top team of editors and authors composed of the leading experts in Europe and the USA who have pioneered the field of nanopharmacy!

Anesthetic Pharmacology
Author : Alex S. Evers,Mervyn Maze,Evan D. Kharasch
Publisher : Cambridge University Press
Release Date : 2011-03-10
ISBN 10 : 1139497022
Pages : 329 pages

In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.

Intracellular Delivery III
Author : Aleš Prokop,Volkmar Weissig
Publisher : Springer
Release Date : 2016-10-31
ISBN 10 : 3319435256
Pages : 453 pages

A critical review is attempted to assess the status of nanomedicine entry onto the market. The emergence of new potential therapeutic entities such as DNA and RNA fragments requires that these new “drugs” will need to be delivered in a cell-and organelle-specific manner. Although efforts have been made over the last 50 years or so to develop such delivery technology, no effective and above all clinically approved protocol for cell-specific drug delivery in humans exists as yet. Various particles, macromolecules, liposomes and most recently “nanomaterials” have been said to “show promise” but none of these promises have so far been “reduced” to human clinical practice. The focus of this volume is on cancer indication since the majority of published research relates to this application; within that, we focus on solid tumors (solid malignancies). Our aim is critically to evaluate whether nanomaterials, both non-targeted and targeted to specific cells, could be of therapeutic benefit in clinical practice. The emphasis of this volume will be on pharmacokinetics (PK) and pharmacodynamics (PD) in animal and human studies. Apart from the case of exquisitely specific antibody-based drugs, the development of target-specific drug–carrier delivery systems has not yet been broadly successful at the clinical level. It can be argued that drugs generated using the conventional means of drug development (i.e., relying on facile biodistribution and activity after (preferably) oral administration) are not suitable for a target-specific delivery and would not benefit from such delivery even when a seemingly perfect delivery system is available. Therefore, successful development of site-selective drug delivery systems will need to include not only the development of suitable carriers, but also the development of drug entities that meet the required PK/PD profile.