Quantitative Pharmacology: An Introduction to Integrative Pharmacokinetic-Pharmacodynamic Analysis

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ISBN 9781466560314
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Summary

PKPD awareness is vital if we are to attempt to relate preclinical results to the acute and long term consequences in humans. The debate on whether preclinical findings can be translated to the human usage is still engaging scientists across industry, academia and regulatory bodies. Pharmacokinetics (PK) and pharmacodynamics (PD) comprise traditionally distinct disciplines within pharmacology, the study of the interaction of drugs with the body. It is our intention to show that by deliberately, intimately and systematically integrate these disciplines our understanding of drugs and the efficiency and effectiveness of drug discovery and development may be greatly enhanced. The book is therefore written with a broad audience in mind and focuses on concepts. Pharmacologists of all sorts, safety scientists, pharmacokineticists, medicinal chemists, clinicians, statisticians, veterinarians, animal science professionals, project leaders and students of medical, pharmaceutical and veterinary sciences are the primary targets.

This textbook

  • Introduces the basics of PK and PD concepts
  • Outlines the implications of integrating PK and PD analysis
  • Introduces the principles behind different biomarkers and inter-species scaling
  • Discusses experimental design of PK, PD and safety studies in non-human species
  • Covers numerous real life Case Studies from the drug discovery arena

Table of Contents

Introduction - What is PK/PD and Quantitative Pharmacology
The scope of pharmacokinetics and pharmacodynamics
The basic tools of pharmacokinetics and pharmacodynamics
Quantitative pharmacology
Drug discovery and development

Principles of kinetics from a pharmacodynamic point of view
What is this chapter about?
Essential pharmacokinetic concepts and relationships
Basic principles of compartmental modelling
One-Compartment Models
Constant rate infusion
Integration of clearance and volume
Extravascular administration
Extent of absorption - bioavailability
Accumulation and time to steady-state
Dose-rate and unbound clearance determines free concentration
Multi-Compartment Models
Active metabolites
How is PK and PD integrated?

Principles of plasma protein binding
What is this chapter about?
Plasma protein binding - General implications
In vitro (closed) versus in vivo (open) systems
Impact of free fraction on PK and PD properties
How is information about PPB integrated with PD?

Principles of dose, time and flow dependencies
What is this chapter about?
Capacity-dependent kinetics
Time-dependent kinetics
Combining Capacity, Flow and Time-dependent kinetics
Target mediated drug disposition (TMDD)
How is nonlinear drug disposition integrated with PD?

Principles of rapid concentration-response equilibria
What is this chapter about?
Why concentration-response instead of dose-response?
Multiple dose pharmacodynamics
Linear concentration-response relationship - case example
Exponential concentration-response relationship
Hill versus log-linear models
Michaelis-Menten type of binding model
Case Study example: Analysis of brain occupancy and exposure data of several species
Summary and discussion of concentration response relationships

Time delays between plasma concentration and response
What is this chapter about?
Time delays observed as hysteresis
Delays caused by distributional processes
Delays caused by turnover
Delays caused by slow receptor on/offset
Comparisons of the link-, turnover and receptor on/off models

Principles of inter-species scaling
When and why do we extrapolate data across species?
What is allometry and allometric equations?
The elementary Dedrick plot
Examples of allometric plots
Time scales differ between different species
Physiological variables of 11 animal species and man
Allometric scaling of turnover parameters
General conclusions
Dose nomogram and scaling of pharmacodynamic parameters
Principles of candidate drug selection for a first time in man study: Allometry, dose-nomogram and safety margin

Bibliography
Symbols and their definitions
Index

Author Bio(s)

Johan Gabrielsson has been Senior Principal Scientist at AstraZeneca R&D Mölndal. His responsibilities included kinetic/dynamic related project tasks in the CV & GI & CNS & Cancer & Biologics areas. He is author of the textbook ‘Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications’ 4th ed. (2006). He is professor of Integrative Pharmacology at the Swedish Agricultural University in Uppsala, Sweden. He is also academically affiliated with Dept. of Pharmaceutics, Univ. Tennessee and University of Manchester. He has published extensively in the field of pharmacokinetic-pharmacodynamic modeling and reasoning, and has run numerous courses internally and externally in the area of biological data analysis since 1985 in Europe, the US and Asia (>4000 participants) at both the undergraduate and graduate level. His research focuses on modelling different aspects of endogenous turnover, such as functional tolerance and rebound phenomena, physiological limits and target-mediated drug disposition in collaboration with Professor LA Peletier, Leiden University. He has been external examiner on several PhD Theses abroad.

Stephan Hjorth is Principal Scientist at the Bioscience Dept., AstraZeneca R&D, Mölndal. His main responsibilities includes pharmacodynamic-related project tasks in the CV&GI, metabolism, area. Before joining AstraZeneca R&D he spent ~25 years in various positions at the Dept. of Pharmacology, Gothenburg Univ., and latterly as appointed professor at the Dept. of Pharmacology & Clinical Neurosciences, Umeå Univ., doing research and teaching at the undergraduate as well as the graduate level. He has published extensively, mainly in the field of preclinical neuro- and psychopharmacology, and also acted as editor for the Journal of Neural Transmission. He is a member of several national and international scientific societies, has reviewed grant applications to the EU Framework programme and other foreign grant agencies, and been external examiner at several PhD dissertations in Sweden and abroad. His current research primarily focuses on discovery and development of drugs for obesity and appetite control, including efforts towards animal models useful in translational modelling of PK-PD relationships.

Editorial Reviews

"… provides very attractive and comprehensive reading for a broad audience—inside as well as outside Pharma—with interest in integrating PK and PD observations for greater understanding of how to connect drug fate and treatment consequences in vivo."
—Professor Arvid Carlsson, Nobel Laureate, Gothenburg University

"I consider the book by Gabrielsson and Hjorth to be very useful for in depth studies by scientists working with drug development and experimentalists in clinical pharmacology. It combines the analysis of effects versus time patterns with kinetic corollaries in a most comprehensive way. Moreover, it is a book of great graphical beauty exceptionally styled with a cover painted by one of the authors."
--Gunnar Alvan MD PhD, Emeritus professor and former Director General of the Swedish Medical Products Agency