Clinical Pharmacology and Therapeutics

CHAPTER 3
PHARMACOKINETICS
● Introduction 11
● Constant-rate infusion 11
● Single-bolus dose 12
● Repeated (multiple) dosing 13
● Deviations from the one-compartment model
with first-order elimination 14
● Non-linear (‘dose-dependent’) pharmacokinetics 15
INTRODUCTION
Pharmacokinetics is the study of drug absorption, distribution,
metabolism and excretion (ADME) – ‘what the body does
to the drug’. Understanding pharmacokinetic principles, combined
with specific information regarding an individual drug
and patient, underlies the individualized optimal use of the
drug (e.g. choice of drug, route of administration, dose and
dosing interval).
Pharmacokinetic modelling is based on drastically simplifying
assumptions; but even so, it can be mathematically cumbersome,
sadly rendering this important area unintelligible to
many clinicians. In this chapter, we introduce the basic concepts
by considering three clinical dosing situations:
• constant-rate intravenous infusion;
• bolus-dose injection;
• repeated dosing.
Bulk flow in the bloodstream is rapid, as is diffusion over
short distances after drugs have penetrated phospholipid membranes,
so the rate-limiting step in drug distribution is usually
penetration of these membrane barriers. Permeability is determined
mainly by the lipid solubility of the drug, polar watersoluble
drugs being transferred slowly, whereas lipid-soluble,
non-polar drugs diffuse rapidly across lipid-rich membranes.
In addition, some drugs are actively transported by specific
carriers.
The simplest pharmacokinetic model treats the body as a
well-stirred single compartment in which an administered
drug distributes instantaneously, and from which it is eliminated.
Many drugs are eliminated at a rate proportional to
their concentration – ‘first-order’ elimination. A single (one)-
compartment model with first-order elimination often approximates
the clinical situation surprisingly well once absorption
and distribution have occurred. We start by considering this,
and then describe some important deviations from it.
CONSTANT-RATE INFUSION
If a drug is administered intravenously via a constant-rate
pump, and blood sampled from a distant vein for measurement
of drug concentration, a plot of plasma concentration
versus time can be constructed (Figure 3.1). The concentration
rises from zero, rapidly at first and then more slowly until a
plateau (representing steady state) is approached. At steady
state, the rate of input of drug to the body equals the rate of
elimination. The concentration at plateau is the steady-state
concentration (C SS ). This depends on the rate of drug infusion
and on its ‘clearance’. The clearance is defined as the volume
of fluid (usually plasma) from which the drug is totally eliminated
(i.e. ‘cleared’) per unit time. At steady state,
so
administration rate elimination rate
elimination rate C SS clearance
clearance administration rate/C SS
[Drug] in plasma
Constant infusion of drug
Time →
Figure 3.1: Plasma concentration of a drug during and after a
constant intravenous infusion as indicated by the bar.