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- An Introduction to Integrative Pharmacokinetic-Pharmacodynamic Analysis
Johan Gabrielsson and Stephan Hjorth
Apotekarsocieteten - Swedish Academy of Pharmaceutical Sciences
It is with great excitement that I hold a brand new book on pharmacokinetics
-pharmacodynamics in my hands. This has occurred a number of times before in my
professional life and my question is always: How will these authors explain the
stuff and how will they make the readers interested? Will there be some new
approaches? Even more so when you know the authors as extremely competent in the
area and also with a high reputation as teachers. The new book by Johan
Gabrielsson and Stephan Hjorth has the wise and very timely title Quantitative
Pharmacology, further specified as an Introduction to Integrative
Pharmacokinetic Pharmacodynamic Analysis. The authors explain convincingly why
it is now time to apply the integrative approach in this area which I find
The journey of the drug through the body in its strict sense is known as
pharmacokinetics and the drug effects, are collected under the term
pharmacodynamics . The drug molecules have to reach a site of action where they
interact with some target structures to produce the response. This principle is
epitomized in the introductory graph below showing the integrated 3D plot with
time as an independent variable and its relation to drug concentration and
response as well as the relationship between concentration and response.
Failure to exploit and understand integrated effects of PK and PD is a driver
for the author team and is rooted in their experiences from pharmaceutical drug
development. Insight in experimental design and how to analyze and interpret
results will prove to be also of great economical importance. Mistakes here
could even kill a promising drug candidate of which pharmacokinetic properties
do not seem favorable. Three compounds are stated as examples; felodipine,
omeprazole and quetiapine with quite or rather low bioavailability and short
half lives in man. However, they were all successful in oral dosage forms since
they have long pharmacodynamic half life. - This approach indicates the primary
reader target group for the book, but it can undoubtedly also benefit senior
students and workers in the pharmacological and clinical pharmacological areas.
Hence, it is recommended that readers should have some prior familiarity with PK
and PD before starting the book.
The structure of the content is to present kinetic phenomena from a
"pharmacodynamic point of view" which is a refreshing and useful approach. Other
standard items like the influence and treatment of protein binding are
conventionally explained. I felt stimulated by collecting one set of phenomena
under the subtitle "Principles of Dose, Time and Flow Dependencies.
One highlight is the chapter on "Time delays between plasma concentrations and
response". The authors review how a delay is observed e.g. as hysteresis and a
number of reasons for such a delay. Strategies taken to evaluate the
observations e.g. the introduction of an effect compartment or the application
of mechanism based turnover models that have gained increased popularity in
recent years. This means that accepted mathematical expressions e.g. for enzyme
inhibition or receptor interaction may be used in the context to fit and
interpret observational data to model parameters.
The concept of biomarkers is increasingly stressed in this area of research.
Some quantity has to be measured to make the work meaningful and a discussion
persist about the properties of biomarkers, their relevance, distribution,
precision, etc. A useful 7-step grading of biomarkers reaching from the
fundamental type 0 genetic and phenotypic markers up to type 6 which
characterizes clinical states is presented.
The book is ended by a thoughtful and accurate chapter on why, how and when
interspecies scaling shall be applied.
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
Gunnar Alvan MD PhD
Emeritus professor and former Director General of the Swedish Medical Products
264 pages. Illustrated in colour. ISBN 9789197945233.
Make your order from our webshop at www.lma-books.se or by e-mail to
Project Manager, M Sc Pharm
Swedish Academy of Pharmaceutical Sciences
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