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PBPK Modeling

Last updated:
5 December 2017
Physiologically-Based Pharmacokinetic (PBPK) Modeling Modeling and simulation approaches have become an integral part of drug discovery and development. Physiologically-based pharmacokinetic (PBPK) models have the capability to predict the PK of a drug prior to conduct of any clinical studies in a target population which may have varying physiology and biology compared to healthy individuals. These models, when used in combination with PK-pharmacodynamic (PD) models, can also predict the effect profile and required dosage regimen to attain the desired exposure in vivo. Application of PBPK modeling used in conjunction with “in vitro - in vivo extrapolation” (IVIVE) of ADME data can provide a useful starting point to understand and extrapolate PK and dose across different species, populations, and disease states (read the Tutorial “Basic Concepts in Physiologically Based Pharmacokinetic Modeling in Drug Discovery and Development”). With the emergence of this new wave of combined IVIVE-PBPK models, it is not surprising to see a shift from classical applications of PBPK, largely in the environmental toxicology, to applications in modern drug development and clinical pharmacology.


The enthusiasm for understanding and expanding on PBPK modeling capabilities within the pharmacometrics and systems pharmacology community has given further boost by several recent regulatory approvals for incorporating IVIVE-PBPK modeling and simulations outcome into drug labeling in lieu of clinical studies . The collection of articles presented here in the special Themed Virtual Issue of CPT:PSP provides the state-of-the-art applications of PBPK models. It would serve to give an up-to-date overview on the subject for researchers in the field of Pharmacometrics and Systems Pharmacology who wish to familiarize themselves with this fast moving specialty within the modeling and simulation community.


Pediatrics

Last updated:
5 December 2017
Children experience rapid changes in growth and development over the course of their childhood. The large differences in pharmacokinetics (PK) and pharmacodynamics (PD) as observed for many drugs used in neonates, infants and children are the result of developmental changes in drug metabolism, drug transport and drug target ontogeny, most which have not been explored to any extent. The objective of this series of CPT:PSP articles is to provide a current, and evolving overview of how physiologically-based PKPD modeling, pharmacometrics and systems pharmacology principles are being applied to quantify the effects of growth and maturation on drug disposition and effects to facilitate the development of age-appropriate medication and dosing algorithms.


Tutorials

Last updated:
5 December 2017
Tutorials are educational articles providing practical tutorial on tools, methodologies, and approaches in pharmacometrics and systems pharmacology. Tutorials aim to increase the awareness and potential of pharmacometrics and systems pharmacology outside the disciplines, introduce methodology to newcomers interested in model-based approaches, and provide further training and specialized guides to those already working in the field.


Hematology

Last updated:
5 December 2017
Hematology is the branch of medicine concerned with disorders of blood and bone marrow, for example anemia, coagulation disorders, and cancers such as leukemia. Pharmacometrics and quantitative systems pharmacology (QSP) are increasingly being used in model-informed drug discovery and development (MID3) of novel hematological drugs, but also as clinical tools to optimise the use of existing therapies. The links between quantitative pharmacology and hematology were established more than a century ago when A.V. Hill published a mathematical model for the sigmoidal binding of oxygen to haemoglobin, which (known as the “Hill equation”) became one of the central equations in pharmacometrics and QSP.


This virtual issue of CPT:PSP provides an up-to-date overview of the breadth and depth of state-of-the-art application of advanced pharmacometrics and QSP in hematology in drug discovery, development, and clinical practise.

Cardiovascular System

Last updated:
5 December 2017
For many decades, pharmacological modulation of the cardiovascular system has been the cornerstone of rational drug design for diseases of the heart and circulation which has resulted in many ground-breaking therapies. At the same time, cardiovascular side effects are one of the most common safety issues in drug development and a significant contributor to compound attrition. Mathematical modeling has made invaluable contributions to the understanding of cardiovascular (patho)physiology, exemplified by the classical work of Frank and Sterling on the mechanical function of the heart and Guyton’s model of the systemic circulation. Such models are now increasingly being extended by “bottom up” models of pharmacological pathway modulation as well as “top down” approaches to include outcome of therapeutic interventions in clinical and real life settings. The Cardiovascular System virtual issue of CPT:PSP illustrates how the resulting integrated pharmacometrics and systems pharmacology models are being applied in current drug discovery and development, pharmacological research, and regulatory sciences.

Cancer

Last updated:
6 November 2017
Nonclinical and patient-level observations on the many pathways comprising cancer are becoming increasingly available, at various levels of biological organization. Quantitative tools to comprehensively interpret such data are also coming of age. Pharmacometrics and systems pharmacology can contribute to further the understanding of this heterogeneous disease and related therapeutic approaches. The intent of this compilation of CPT:PSP articles is to provide a current, evolving overview of how pharmacometric and systems pharmacology principles are being applied to this complex disease.


Infectious Diseases

Last updated:
6 November 2017
Infectious diseases continue to be the leading cause of death globally. Treatment is often inadequate because the pharmacokinetics and pharmacodynamics in different patient subpopulations are not well understood and are affected by complexities such as drug-drug interactions, co-infections, and emerging drug resistance. Pharmacometrics and Systems Pharmacology are efficient approaches for integrating information across studies and populations and can provide quantitative characterizations of the interaction between drugs, germs, and patients. This virtual issue of CPT:PSP covers a wide range of models for virus, bacteria, fungi, and parasites and exemplifies and discusses the value of models for improved treatments and trial designs in this area.


Immunology & Inflammation

Last updated:
6 November 2017

Acute inflammation is an essential defense response of the immune system when it receives signals of potentially harmful challenges, such as infections, toxins or injury. However, when the immune system turns against organs in the absence of an obvious harmful external stimulus the resulting chronic inflammation can lead to diseases such as rheumatoid arthritis, Chrohn's disease, psoriasis, lupus, ulcerative colitis and many other auto-immune conditions. In recent years, it has become clear that inflammation and immunology may also play a key role in the pathology of, for example, the cardiovascular and central nervous systems and cancer. 

In the last decade, spectacular progress has been made in unraveling the biological pathways that control immunology and inflammation and as consequence a rich pipeline of novel pharmacological targets and treatments has emerged. This virtual issue of CPT:PSP provides an up-to-date collection of original research articles and reviews of pharmacometrics and systems pharmacology approaches applied to drug discovery and development inflammation and immunology. 

Neuroscience

Last updated:
25 October 2017
In the early 1950's, Alan Hodgkin and Andrew Huxley published a series of papers on the fundamental mechanism by which membrane currents are generated and travel in neurons. Their mathematical model describing these events quantitatively became universally known as the Hodgkin & Huxley model, which formed the basis for the field computational neuroscience and arguably was one of the first examples of a quantitative biological systems model. Despite this head start, the development and application of quantitative pharmacology (QSP) approaches in neuroscience has been lagging behind most other therapeutic areas, which in part can be explained by the complexity of the pathophysiology of diseases of the central nervous system which resulted in a wide-spread belief that the brain may be "too complex to model". However, in recent years there has been a marked increase in the application of model-based approaches in neuroscience drug discovery and development, as illustrated by this virtual issue which contains state-of-the-art research, reviews, and tutorials.  

Diabetes

Last updated:
9 October 2017
Diabetes is a complex multifactorial disease. Mathematical models of glucose homeostasis have been developed for many decades in the field of physiology and are now increasingly being applied in diabetes drug discovery and development. This collection of CPT:PSP articles provides an up-to-date overview of state-of-the-art Pharmacometrics and Systems Pharmacology research in diabetes.


Safety Pharmacology

Last updated:
9 October 2017
In addition to its growing use and impact in predicting and optimizing drug efficacy, pharmacometrics and systems pharmacology is also increasingly being applied to define and maximize the benefit-risk profile of pharmacological interventions through quantitative assessment of safety liabilities. Model-based approaches such as exposure-response analysis, physiologically-based pharmacokinetics (PBPK), quantitative systems toxicology (QST) and bio-informatics are now being applied across the R&D spectrum and should contribute to the development of safer medicines. The rapid expansion of the drugable target space into novel areas of biology and pathophysiology requires a parallel development of innovative predictive quantitative frameworks for safety and toxicology. The aim of this virtual issue of CPT:PSP is to publish cutting edge development and application of such methods in drug discovery and development and clinical usage, as well as providing readers with state-of-the-art overviews and tutorials.

Precision Medicine

Last updated:
29 August 2017
The theme of the ASCPT 2017 Annual Meeting is "Advancing Patient Care Through Precision and Translational Medicine". In the spirit of avowing the shared vision of ASCPT's Journal Family around these vital issues relevant to the future of the field, each journal has devoted a portion of its March issue to the subject of Precision Medicine. These articles have been compiled to form the following shared "Virtual Issue," which provides an overview of relevant issues and challenges facing this area of research, as well as opportunities available for pushing forward in order to more effectively identify and treat disease using tools and methodology at the cutting edge of pharmacology, systems biology, and translational medicine.



The Precision Medicine theme is shared between the ASCPT Journal Family. Access the Precision Medicine content from: 

Reviews

Last updated:
29 August 2017
CPT:PSP Reviews provide comprehensive, state-of-the-art overviews of pharmacometrics and systems pharmacology approaches and in-depth systematic reviews of applications in disease areas.

Immuno-oncology

Last updated:
10 July 2017
Although the critical role of the immune system in cancer has long been recognized, the development of novel oncological pharmacotherapies through specifically targeting the immune system is a relatively new area of research. Key challenges for the effective translation of emerging science into efficient drug development include:

  • Identification of novel targets and optimal dosing regiments for combination therapies
  • Individualized dosing and prediction and management of the therapeutic window in special patient populations
  • Identification of subgroups of patients most likely to benefit through use of biomarkers, diagnostic and precision medicine
Model-informed drug discovery and development (MID3) is increasingly being used to tackle such challenges and provides a quantitative framework for rational development of immune-oncology therapies.



This immuno-oncology virtual issue of CPT-PSP contains original research articles, case studies, reviews and tutorials of cutting-edge pharmacometric and systems pharmacology approaches spanning the R&D continuum from drug discovery to development as well as regulatory approval and clinical use.





Liver

Last updated:
10 July 2017

The liver is the most important organ for drug metabolism and determines pharmacokinetics for most medicines. It is also a target for therapeutics for the treatment of a variety of diseases, such as hepatitis, non-alcoholic fatty liver disease, cirrhosis and hemochromatosis. In addition, hepatotoxicity remains a significant safety issue during drug discovery and development. Quantitative, model-based approaches have contributed to scientific advancement in all these areas, ranging from better understanding of liver (patho)physiology as a determinant of inter- and intra-individual pharmacokinetics (PBPK) to identification and validation of novel targets for drug treatment using quantitative systems pharmacology (QSP). The Liver Virtual Issue CPT:PSP is a resource of state-of-the-art original research, reviews, and tutorials of pharmacometrics and systems pharmacology science and applications in the field of hepatology.