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A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES

CONTENTS

1. 1.1 Introduction
2. 1.2 Pharmacokinetic Principles
   1. 1.2.1 Routes of Drug Administration
   2. 1.2.2 Intravenous Bolus
   3. 1.2.3 Plasma Protein Binding and Blood-Plasma Ratio
   4. 1.2.4 Hepatic, Renal, and Biliary Clearances
   5. 1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption
   6. 1.2.6 Absorption from Solid Dosage Forms
   7. 1.2.7 Role of Transporters in ADME
   8. 1.2.8 Linear and Non-Linear Pharmacokinetics
   9. 1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics, and Accumulation
   10. 1.2.10 Active Metabolite and Prodrug Kinetics
3. 1.3 Pharmacokinetic Variability
4. 1.4 Pharmacokinetics Optimization in Drug Discovery
5. 1.5 Pharmacodynamic Principles
   1. 1.5.1 Pharmacological Targets and Drug Action
   2. 1.5.2 Functional Adaptation Processes
   3. 1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints
   4. Keywords
   5. References

1.1 INTRODUCTION

The dose and dosing frequency of a drug (dosage regimen), needed to maintain an efficacious concentration at the site of its pharmacological action, for a duration that is long enough to achieve the therapeutic objective, should be safe and convenient to the patient. To achieve this optimal exposure at the target site of pharmacological action in humans, the rate and extent of multiple processes like drug absorption from the site of administration into systemic circulation, tissue distribution, metabolism, and elimination (ADME) are optimized during lead optimization in drug discovery. Pharmacokinetics (PK) is the study of the fate of drug in the body, that determines its exposure/concentration at the target effect site, driven by ADME processes. The relationship of the exposure/concentration at the target effect site to the onset, intensity, and duration of drug action is determined by pharmacodynamics (PD). A well-defined, quantitative relationship between drug concentrations in biological fluids and pharmacodynamic effect can support the selection of dose and dosing regimen for early clinical trials. This chapter is intended to provide a brief overview of PK and PD principles. The forthcoming chapters will draw heavily upon the concepts laid out in this chapter.

1.2 PHARMACOKINETIC PRINCIPLES

1.2.1 Routes of Drug Administration

Common routes of drug administration include per oral (PO), intramuscular (IM), subcutaneous (SC) intravenous (IV) bolus and infusion, and intrathecal (around the spinal cord). Other less common routes include buccal, sublingual, rectal, transdermal, inhalational, and topical. The oral route is the most preferred route, but it is not suitable for drugs that are not stable in the gut, like for example peptide and protein drugs.

1.2.2 Intravenous Bolus

Intravenous (IV) administration ensures rapid, complete drug availability for drugs that are not in the form of suspensions or oils, by bypassing absorption barriers. Drugs having poor oral bioavailability or causing unacceptable pain when administered intramuscularly or subcutaneously may be administered by this route. However, it is potentially hazardous, as the initial high drug concentration may elicit toxic effects. Therefore, the use of IV route is restricted to situations demanding a rapid onset of action as in anesthesia, emergency medicine etc. or, when the patient is persistently vomiting, is unconscious or is too young to safely swallow solid forms of medication. Controlled drug administration through IV infusions offers one way to mitigate the risk of toxicity, as the infusion may be halted in the unexpected event of adverse effects during administration. Apart from causing severe pain, intra-arterial administration is associated with the risk of dangerous pressure buildup in the muscles leading to decreased blood flow and consequently to nerve and muscle damage. Intra-arterial injections are therefore reserved to situations in which localizations to specific tissues are desired.

1.2.2.1 Zero- and First-Order Kinetics

Drug elimination from the body may follow zero or first-order kinetics (Figure 1.1). In zero-order kinetics, a constant amount of the drug is eliminated in a certain time (e.g., 20?mg per hour). In first-order processes, a constant proportion of the drug is eliminated in a certain time (e.g., 20% per hour). Though relatively rare, zero-order kinetics may be encountered in intravenous infusions as well as in elimination of some drugs (e.g. ethanol) but will not be further elaborated here.

The temporal changes in the drug concentrations following an IV bolus injection of 50?mg of a drug with first-order kinetics are depicted in Figure 1.2. The slope and area under the curve (AUC) are the two parameters that can be extracted from the concentration-time profile as shown in the semilogarithmic and linear plots respectively. Other useful pharmacokinetic parameters may be derived from these two parameters, as will become evident from the mathematical derivations below.

1.2.2.2 Clearance, Volume of Distribution, Half-life, and AUC

The first-order rate equation depicting the rate of change of drug concentrations in the blood (C) is given by

Figure 1.1. Temporal changes in drug concentrations for (a) zero-order and (b) first-order kinetics.

Figure 1.2. Linear (a) and semilogarithmic (b) plots of drug concentrations vs. time. Area under the curve (AUC) and slope are the two parameters that can be obtained from the plot. C2 and C1 are drug concentrations at times t2 and t1 respectively. kel, first-order elimination rate constant; CL, is the total drug clearance; and V, volume of distribution.

where A is the amount of drug in the body at any time, t, kel is the first-order elimination rate constant, and V is the volume of distribution of the drug. The product of kel and V is defined as the total clearance, CL, of the drug from blood.

Integrating Equation 1.1 (-dC/dt = kel × C),

Taking natural logarithms on both sides,

Thus, kel may be obtained by measuring the slope of a semilogarithmic plot of drug concentration vs time (Figure 1.2).

Similarly, integrating Equation 1.2 (-dA/dt = kel × A) yields

where A0 is the initial amount of drug in the body, the dose administered as IV bolus. Bringing A0 to the left-hand side, Equation 1.5 becomes,

Taking the natural logarithms on both sides of the resulting equation leads to the following:

The half-life (t1/2) of a drug, defined as the time taken for half of the administered drug to get eliminated from the body (time taken for drug amount in body to go from A0, to A0/2, or time taken for the drug concentration to be halved), is given by:

Using Equation 1.8, the half-life of a drug can be calculated from the elimination rate constant kel which is obtained from the semilogarithmic plot of concentration vs. time (Figure 1.2).

Integrating the Equation 1.2 (-dA = CL × C dt) yields

where AUC is the area under the drug concentration-time profile (Figure 1.2), which may be estimated from the plot by applying the trapezoidal rule. Recognizing that the integral dA over time 0 to t is the dose, Equation 1.9 becomes,

Knowing the dose administered and the AUC, clearance can be calculated using Equation 1.10. The volume of distribution, V, of the drug can be determined using Equation 1.11, knowing that clearance is the product of kel and V.

Most small molecule drugs bind reversibly to plasma proteins such as albumin and alpha-glycoprotein. Drug binding to plasma proteins is of major interest in pharmacokinetics as it impacts both clearance and volume of distribution. Thus far, the term clearance refers to blood clearance. However, measurements of drug concentrations are often done in plasma, as whole blood contains cellular elements (red and white blood cells, platelets etc.) and proteins (albumin, glycoproteins, globulin, lipoproteins etc.). The clearance of a drug determined using the AUC estimated from plasma drug concentration-time profile is referred to plasma clearance. To convert plasma clearance to blood clearance, the distribution of a drug between blood and plasma should be measured. The ratio of drug concentrations in blood to plasma is known as blood-plasma...