Publishing year: 2012
Author: Johan Gabrielsson, Stephan Hjorth
File size: 23 MB
Gunnar Alvan MD PhD
– July 5, 2012
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 Hjort 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 refreshing.
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 Hjort 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
Professor Arvid Carlsson, Nobel Laureate Gothenburg University
– July 5, 2012
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 development perspective.
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.
P J Lowe, Novartis Pharma AG, Basel, Switzerland
– December 19, 2012
What is “Quantitative Pharmacology”? Surely, pharmacologists have long quantitated responses through parameters such as ED50 or EC50, the dose or concentration for half-maximum effect, seeking to understand the influence of many factors, whether they be drug structure or patient-disease related. In “Quantitative Pharmacology,” Gabrielsson and Hjorth explain that it is the integration of key time-dependent processes in vivo: pharmacokinetics (PK; absorption; distribution to target and other sites; binding to target and nonspecific entities; elimination) and pharmacodynamics (PD; target binding driving system–related responses, whether in parallel or a causal series). These fit together in the context of how, after a lead candidate is discovered, a drug should be optimized by taking account of all aspects to be successfully developed as a marketable product.
Beyond the introduction, there are six further chapters. In “Kinetics from a PD point of view,” the essentials of clearance (CL) and multicompartmental behaviors are covered, including a diagram well illustrating the filling and emptying of compartments in the initial and terminal phases of plasma drug concentration–time profiles. From a PD point of view, the concept of the “effective half-life” of a compound is important, i.e., that which covers the majority of the exposure (aka area under the curve). Perhaps, there should be a renaissance of the mean residence time, the effective half-life being this multiplied by loge(2).
In “Plasma protein binding,” the hypothesis for the unbound drug being the driver of PD responses is presented. From a discovery point of view, compounds should not only be optimized for target binding potency but also for low unbound CL to maximize tissue equilibrating unbound drug concentrations. In the end, it is the tradeoff between potency (e.g., Ki), the fraction unbound (fu), and CL which must be optimized.
In “Dose, time and flow dependencies,” potential nonlinear and non-time constant properties are explored. This includes forms of target-mediated drug disposition (including Michaelis–Menten saturable elimination), saturable transfer processes (e.g., absorption), and time-dependent changes such as induction of metabolism. Not forgetting, of course, that plasma protein binding can also be nonlinear and non-time constant. In “Rapid concentration-response equilibria,” pharmacological concentration–effect relationships are introduced, including linear, logarithmic, exponential, and sigmoid Emax. Also explained are experiments to generate appropriate data and how to decide between candidate models. Examples are given of how species differing concentration-responses can become similar once unbound drug concentrations are used. Slightly perplexing is the example with brain receptor binding, with the unexplained appearance of a kon parameter to enable the estimation of the half-life of receptor dissociation from koff. All previous presentations used an equilibrium KD. Perhaps, this is from the next chapter.
In “Time delays between plasma concentration and response,” three classes of PD model are described: distributional delay, turnover delay (aka indirect response), and receptor on/off. These are well illustrated with clear graphics. The example in which PKPD modeling was used rather than direct summarization of washout data was interesting as it changed conclusions regarding safety margins. Of note was the example in which a “hit-and-run” single time point dose–response study design caused a 100% bias in the potency estimate of a candidate. Clearly, the authors advocate complete, integrative, time series PKPD analyses, i.e., “Quantitative Pharmacology” approaches.
Finally, in “Inter-species scaling,” information is integrated to scale preclinical PKPD models to man. The core steps are (i) scale PK (only CL if steady-state concentrations required), (ii) translate pharmacology between species through unbound concentrations; if PD turnover required, scale by bodyweight to ¾ power; (iii) combine scaled PK and PD to produce a human dose prediction. However, importantly for human safety, there is step (iv) which allows for uncertainty, the potential to be wrong, by giving ranges (e.g., half and double) of possible predicted CLs and effective unbound plasma concentrations.
Overall, this book is an easy introduction to “Quantitative Pharmacology.” I read cover to cover in two sessions plus a day’s travelling, without my eyes drooping. If you are a nonkinetically minded research pharmacologist, medicinal chemist, physician, veterinarian, or statistician, and are curious about what PKPD experts and modelers are up to and what they can deliver, it is well worth reading.
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