CHAPTER 1
Clinical Pharmacology of Antidiabetic Drugs

Andrea Llano, Gerry McKay and Ken Paterson

KEY POINTS

• Clinical pharmacology studies the relationship between drugs and the body and has a crucial role in the development of new therapies.
• Pharmacodynamics describes how a drug exerts its actions and pharmacokinetics is the processes a drug undergoes (absorption, distribution, metabolism and excretion).
• The drug development and regulatory process is lengthy and new medicines need to demonstrate safety, efficacy and quality. In addition, drugs intended to be used in diabetes require demonstration of cardiovascular safety.
• Pharmacoeconomics allows the provision of cost-effective therapies to those who need them and is an important tool when there is an increasing demand for healthcare and limited resource.

Introduction

Clinical pharmacology describes all aspects of the relationship between drugs and humans. An understanding not only allows for the discovery and development of new drugs that influence the course of disease, but also a better understanding of how drugs work can aid the prescriber in partnership with the patient to ensure that the most appropriate drug is chosen. This is relevant for prescribing in diabetes given the increase in antidiabetic drugs that are now available for glucose lowering, many with additional benefits. Choosing the correct antidiabetic drug ('antihyperglycaemic' and 'oral hypoglycaemic' are other terms used) is complicated in many cases by the need for wider cardiovascular risk management and the polypharmacy that can result from managing established complications and other co-morbidities. Before getting to the individual with diabetes, antidiabetic drugs have to go through a lengthy development process underpinned by the requirement to show safety, efficacy and quality.

A serendipitous approach to drug discovery and development based on observations and careful measurement of response has been replaced by a deeper understanding of biochemical and pathophysiological processes that influence disease. This has led to the synthesis of specific agents (chemical or biological) with specific actions. Measurement of drug concentrations in plasma and correlation with effect have aided drug development. The development of genomics and proteomics has added further sophistication such that individualisation of drug choice is a much more realistic prospect.

Clinical Pharmacology

Introduction

The dose-response relationship within an individual is a measure of sensitivity to a drug. This has two components: pharmacokinetics and pharmacodynamics. Pharmacokinetics describes the dose-concentration relationship, and pharmacodynamics describes the concentration-effect relationship. Understanding pharmacodynamics and pharmacokinetics is fundamental to the process of drug development, e.g. selecting the appropriate dose to ensure that the concentration of drug at the site of action is likely to have a therapeutic effect. Understanding pharmacokinetics and pharmacodynamics is relevant to clinical practice as it allows optimisation of therapeutic interventions for the individual being treated [1].

Pharmacodynamics

The effect that a drug has on the body can often be explained through a specific mechanism of action. This can be through action on specific receptors, enzymes or membrane ionic channels or by a direct cytotoxic action.

Action on a Receptor A receptor is normally a protein situated on the cell membrane or within the cell. Drugs bind to the receptors and can act in three ways:

• An agonist stimulates the receptor to produce an effect.
• An antagonist blocks the receptor from being activated by an agonist.
• A partial agonist stimulates the receptor to a limited extent but blocks it from being stimulated by naturally occurring agonists.

For antidiabetic drugs the main type of effect seen at receptors is an agonist effect. This can be seen for sulfonylureas, which bind to SU receptors on beta cells, and PPAR gamma agonists, which act on nuclear receptors to increase transcription of insulin-sensitive genes.

Action on an Enzyme Enzymes are proteins that, through interaction with substrates, result in activation or inhibition. Although the mechanism of action of metformin is poorly understood, part of its effect in diabetes is through activated AMP kinase. Another diabetes class acting through an effect on enzymes is DPP-4 inhibitors. These drugs inhibit the action of dipeptidyl peptidase-4, allowing for the prolongation of the action of endogenous incretins GLP-1 and GIP.

Membrane Channels Some drugs exert their action through an effect on membrane channels. SGLT 2 inhibitors work by blocking the sodium glucose co-transporter 2, resulting in the loss of glucose and sodium in urine.

Cytotoxic This mechanism of action is more relevant to drugs used to treat cancer.

Dose-Response Relationship When thinking about drugs an understanding of dose response is important. Dose-response relationships can be steep or flat (Figure 1.1). In the treatment of diabetes with insulin, a flat dose-response curve is desirable for background insulin, but a steep dose-response curve is desirable for prandial insulin. In clinical practice the maximum therapeutic effect might not be achieved because of the emergence of undesirable effects. In drug development, if too high a dose is chosen it may be that the success of the drug is hampered by the side effects, e.g. in the case of the DPP-4 inhibitor vildagliptin, at a higher dose liver function tests need to be monitored, which is not the case for other drugs in the class. It is very important to consider this in drug development both for the desired effect and for adverse effects. This leads to the concept of therapeutic range. The difference between the concentration causing a desired effect and the concentration causing an adverse effect is termed the therapeutic index, a measure of a drug's safety.

FIGURE 1.1 Dose-response relationships for drugs. Schematic examples of a drug (a) with a steep dose- (or concentration-) response relationship in the therapeutic range, and (b) a flat dose- (or concentration-) response relationship within the therapeutic range.

Dose-response curves can be influenced by genetics, environment and disease, and have two components: dose-plasma concentration and plasma concentration-effect. The ability to develop assays to measure drug concentration has allowed a better understanding of the variability in response between individuals but also for some drugs with a narrow therapeutic index the ability to perform therapeutic drug monitoring.

Pharmacokinetics

Absorption After drugs have been given orally, they can be considered to have an absorption rate and bioavailability. By slowing absorption, the dose-concentration relationship can be smoothed out, giving a more sustained effect and minimising side effects, e.g. Glucophage SR® (slow-release metformin). Subcutaneous absorption of insulin can also be manipulated to provide the desired effect, both to make absorption quicker, which is desirable for prandial insulin, and to make it slower, which is desirable for basal insulin. Bioavailability is a term used to describe the fraction of drug that gets into the systemic circulation. GLP-1 receptor agonists like most peptide-based drugs generally cannot be given orally owing to them being digested, so they need to be given parenterally to get sufficient quantities into the systemic circulation. However, one oral preparation of GLP-1 receptor agonist is now available that relies on a sophisticated delivery method and at a much higher dose than the parenteral preparation to achieve sufficient systemic exposure for the desired clinical effect (see Chapter 6). Other orally administered drugs can undergo extensive first-pass metabolism in the liver, resulting in a significant reduction in systemic exposure and clinical effect.

Distribution/Plasma Protein Binding When a drug gets into the systemic circulation it is then distributed to the tissues. This process will be dependent on the properties of the drug, in particular protein binding and lipid solubility factors. In practice protein binding has little in the way of clinical relevance, but if a drug has low protein binding and is highly lipid soluble, it will have only a small amount in the circulation and thus will be considered to have a high volume of distribution. In real terms this has more of an impact on drug development.

Clearance Clearance is the sum of all of the drug eliminated from the body and mostly depends on hepatic metabolism and renal excretion. If a drug is given by intravenous infusion or repeated doses orally, there will come a point at which a balance is reached between the drug entering and the drug leaving the body. This results in a steady-state concentration in the plasma or serum (Css). A constant-rate intravenous infusion will yield a constant Css, while a drug administered orally at regular intervals will result in fluctuation between peak and trough concentrations (Figure 1.2). Clearance depends on the liver and/or kidneys eliminating a drug and will be affected by diseases that affect these organs either directly or via blood flow to these organs. In stable clinical conditions...