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"Quantitative Pharmacology: An introduction to Integrative
Reviewed by Professor Arvid Carlsson, Nobel Laureate
Authors: Johan Gabrielsson and Stephan Hjorth
Apotekarsocieteten - Swedish Academy of Pharmaceutical Sciences, 2012
264 pp., hardcover.
Dedicated textbooks in the area of integrative pharmacology are very
scarce, notwithstanding the true need for educational narratives on the
subject. It is therefore very gratifying that Johan Gabrielsson and
Stephan Hjorth, both of whom carry a substantial track record (30yrs+)
of industrial experience and academic research in pharmacokinetics and
pharmacology, have taken the task on to fill this longstanding void.
The book focuses on why integration of pharmacokinetics (PK; what the
body does to the drug) and pharmaco-dynamics (PD; what the drug does to
the body) is so important in drug discovery and development.
Gabrielsson/Hjorth embrace the subject matter both thoroughly and
enthusiastically, with several illustrative real-world examples. Topics
covered demonstrate well how an integrated approach may avoid the
problems and pitfalls related to design of studies, analysis and
interpretation of data. Practice examples for the reader are also,
commendably, included. Divided into seven Chapters, the book
instructively states the holistic approach intended by the authors.
Given their affiliations in the Pharma environment it is logical that
much emphasis is put on biomarkers, translational aspects and scaling
from animal species to man. In my view, Gabrielsson/Hjorth have
successfully achieved their stated purpose with the book.
The first Chapter sets the stage through a general introduction into the
field of quantitative pharmacology and some of the terminology commonly
encountered. A useful framework is described, on how to link drug- vs.
system-specific properties using biomarkers as navigational tools,
through a translational chain of events from geno/phenotype to clinical
response in disease, and from animals to man. The book then goes on to
examine the impact of PK upon our understanding of a pharmacological
response. Chapter 2 sheds light on factors, confounders and challenges
involved in connecting PK and PD for any given drug in vivo and points
to complexities translating in vitro findings to in vivo. Chapter 3
focuses on various aspects of plasma protein binding and when it
matters. A thought-provoking and illuminating example is the notably
changed predictions of drug safety margins based on comparisons of total
instead of free unbound plasma concentrations across animal models
(e.g., Fig 3.10). Throughout Chapters 2-3 the authors emphasize unbound
(free) plasma concentrations for comparisons of results across species,
compound and studies. This theme is echoed also in later Chapters (cf.,
e.g., Fig. 5.28), further stressing the importance of relating PD
responses to drug levels actually encountered by the target biophase.
Non-linearities commonly observed in drug discovery, and which sometimes
confound the interpretation of pharmacological data, are discussed in
Chapter 4, whereas Chapter 5 concisely presents rapid
concentration-response equilibria. In the latter context, Fig. 5.26
illustrates a far from unknown, but often neglected, relation between
receptor occupancy and response magnitude for some targets and drugs. Do
comparisons of IC50/EC50 values between different agents and across
exposures always represent the most relevant measure in a given drug
benefit/risk efficacy comparison?
Chapter 6 addresses the temporal disconnect sometimes found between
plasma concentrations vs. target binding and physiological or disease
biomarkers. In this context, the concept and usefulness of hysteresis
analysis is described by the authors in a very didactic fashion. They
effectively explain the merits of this approach to re-connect two or
more otherwise seemingly separate biomarkers; several Case Studies are
also included - intended as potential practice examples for the
interested reader. In the final Chapter the reader's attention is then
focused upon the prospects of inter-species scaling of PK/PD properties
from animals to humans - a task of utmost importance in the drug
Taken together, the book emphasizes the importance of utilising in vivo
data and thereby distances itself quite a bit from the commonly
reductionistic use of in vitro data as a substitute for whole animal
systems. I find this a very sympathetic approach that does a good job in
uncovering the power of integrating PK and PD findings to optimise drug
discovery and development. Mathematical equations and derivations are
perhaps unavoidable in a book carrying integral PK content. However, the
authors have strived to limit these and to maintain a high transparency
in the understanding of complex and abstract relations using a nicely
graphics-supported style throughout the presentation. Background
acquaintance with PK and PD concepts is useful but not a prerequisite
for the presumptive reader. To summarise, this book by
Gabrielsson/Hjorth should provide 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.
-End of reviewe.
Make your order from our webshop at www.lma-books.se or by e-mail to
Project Manager, M Sc Pharm
Laekemedelsakademin I Stockholm AB
Swedish Academy of Pharmaceutical Sciences
PO Box 1136, SE 111 81 Stockholm, Sweden
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