“Quantitative Pharmacology: An introduction to integrative pharmacokinetic-pharmacodynamic analysis”

Reviewed by PJ Lowe1 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 log e(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 trade off 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 timedependent changes such as induction of metabolism. Not forgetting, of course, that plasma protein binding can also be nonlinear and non-time constant. In “Rapid concentrationresponse equilibria,” pharmacological concentration–effect relationships are introduced, including linear, logarithmic, exponential, and sigmoid E max. Also explained are experiments to generate appropriate data and how to decide between candidate models. Examples are given of how species differing concentrationresponses 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 1Modelling & Simulation, Novartis Pharma AG, Basel, Switzerland. Correspondence: PJ Lowe ([email protected])