Treatment response and disease progression

This tutorial defines the concepts of disease progression in the context of clinical pharmacology. Disease progression describes the natural history of disease, such as pain, or biomarker of drug response, such as blood pressure. The action of a drug, such as inhibiting an enzyme or activating a receptor, leads to a change in disease status over time. Two main types of drug response can be defined based on the pattern of the time course of disease status. The most common is a symptomatic effect equivalent to a shift up or down of the natural history curve. Less common but quite clinically important is a disease-modifying effect equivalent to a change in the rate of disease progression.

Pharmacodynamic principles and target concentration intervention

This tutorial reviews the principles of dose individualisation with an emphasis on target concentration intervention (TCI). Once a target effect is chosen then pharmacodynamics can predict the target concentration and pharmacokinetics can predict the target dose to achieve the required response. Dose individualisation can be considered at three levels: population, group and individual. Population dosing, also known as fixed dosing or “one size fits all” is often used but is poor clinical pharmacology; group dosing uses patient features such as weight, organ function and co-medication to adjust the dose for a typical patient; individual dosing uses observations of patient response to inform about pharmacokinetic and pharmacodynamics in the individual and use these individual differences to individualise dose.

Pharmacodynamic principles and the time course of delayed and cumulative drug effects

This tutorial reviews the principles of the concentration — effect relationship for the usual case when drug effects are delayed relative to changes in circulating concentrations. The key processes determining delay are distribution from the circulation to the receptor, binding to the receptor to produce a stimulus and translation of the receptor stimulus into an effect through turnover of physiological mediators. Some clinical outcomes are dependent on the accumulation of drug action which is predictable in terms of basic pharmacokinetic and pharmacodynamic concepts.

Pharmacokinetic variability due to environmental differences

This tutorial describes sources of pharmacokinetic variability that are not obviously linked to genetic differences. The sources of variability are therefore described as environmental. The major quantitative sources of environmental variability are body size (including body composition), maturation and organ function. Size should be considered in all patients. Maturation is mainly relevant to neonates and infants less than 2 years of age. Renal function is the most important predictable source of variability due to differences in organ function.

Pharmacodynamic principles and the time course of immediate drug effects

This tutorial defines the principles of the concentration - effect relationship which are the basis of pharmacodynamics. The two key parameters of pharmacodynamics are the maximum response (Emax) and the concentration producing 50% of Emax (C₅₀). The time course of effect is illustrated under the assumption that drug effects are immediately related to concentration in the central compartment e.g. plasma. The related idea of duration of drug action and its relationship to dose is shown to have a simple relationship with drug half-life.

Volume of Distribution

This tutorial deals with basic concepts of volume of distribution, the second most important parameter in pharmacokinetics but often challenging for students in clinical pharmacology. Its relationships with dose, concentration and amount in the body are discussed using a physical model and examples of commonly used drugs, as well as its physiological aspects pertaining to the physical volume of differing organs. Finally, application of volume of distribution to the calculation of loading dose and half-life is used to show how it is essential in pharmacotherapy and clinical pharmacology.

Absorption and Half-Life

This tutorial deals with basic concepts of absorption processes and links previous tutorials on clearance and volume of distribution to introduce the concept of half-life. The time course of both absorption and elimination are commonly described using a half-life. Half-life can also be used to describe drug accumulation. Understanding the principles underlying the time course of absorption and elimination are essential in pharmacotherapy and clinical pharmacology.

Erratum: Clearance

The third equation on page 44 should be corrected.

Clearance

This tutorial deals with basic concepts of clearance, the most important parameter in pharmacokinetics but often challenging for students in clinical pharmacology. Its relationships with dose, concentration and elimination rate are discussed using a physical model and examples of commonly used drugs, as well as its physiological aspects pertaining to the blood flow to differing organs. Finally, application of clearance to the calculation of maintenance dose rate and half-life is used to show how it is essential in pharmacotherapy and clinical pharmacology.