Tamara van Donge

Introduction 13 1 Quantitative clinical pharmacology “What is the first dose I should give to this patient?” “How should I adjust the dosing regimen in this patient?” “Is therapeutic drug monitoring needed in this patient?” Quantitative clinical pharmacology is the discipline that is able to provide answers to these questions’ clinicians have to deal with on a daily basis. The successful use of a drug depends on the availability of an appropriate drug dosing regimen that results in maximal therapeutic efficacy while minimizing undesired drug effects. To determine the right dose for every individual patient we need to characterize and understand two distinct main pharmacology processes, namely (i) pharmacokinetics (PK), defined as the movement of the drug throughout the body, and (ii) pharmacodynamics (PD) defined as the body’s response to the drug (Figure 1). 1,2 The PK of a drug, presented as the serum or plasma concentration-time profile, is characterized by the absorption, distribution, metabolism and excretion (ADME) of that particular drug as a function of time. The PD describes the effect of the drug in terms of biochemical interactions. These can be expressed by stimulation, where the drug binds to the receptor and produces a response (agonist) or by inhibition, where the response is prohibited by binding to the receptor (antagonist). Understanding the relationship between PK and PD, i.e. the exposure-response relationship, is essential to get the right dose for every individual patient. 2 Individualization of the dose, which is often called precision medicine, requires an understanding of the underlying reasons for the variability in drug disposition and response. Some patients might not respond to the population dose at all, whereas others might develop adverse drug effects and lower doses are wanted, another group of patients only shows a minor response and higher doses are preferred to elicit the desirable response. 3 When a drug is administered to the body, it undergoes chemical and biochemical processes throughout the body. After oral administration, the drug must be solubilized before it is transported across membranes of the epithelial cells in the gastrointestinal tract. Most of the absorption occurs in the small intestine as it has the largest surface area and permeable membranes. Many factors can have a (positive or negative) impact on the absorption of a drug, such as the solubility and permeability of a drug, the gastric emptying time and its chemical stability at low pH. After absorption, the drug enters the systemic circulation where it is transported to its effector site and distributes into organs and muscles. Relevant aspects are regional blood flow rates, the binding of the drug to proteins such as albumin, and molecular size. The biotransformation of a drug into its metabolites is called metabolism. For the majority of the small molecules