The “standard” dose of a drug is based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate the drug (see Clinical Trials: The IND & NDA
Drug in tissues of distribution
FIGURE 3–1 The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are input, distribution, and elimination.
in Chapter 1). This dose will not be suitable for every patient. Several physiologic processes (eg, body size, maturation of organ function in infants) and pathologic processes (eg, heart failure, renal failure) dictate dosage adjustment in individual patients. These processes modify specific pharmacokinetic parameters. The two basic parameters are clearance, the measure of the ability of the body to eliminate the drug; and volume of distribution, the measure of the apparent space in the body available to contain the drug. These parameters are illustrated schematically in Figure 3–2 where the volume of the beakers into which the drugs diffuse represents the volume of distribution, and the size of the outflow “drain” in Figures 3–2B and 3–2D represents the clearance.
Volume of Distribution
Volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma:
The volume of distribution may be defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in equation (1) (C = Cb, Cp, or Cu).
That the V calculated from equation (1) is an apparent volume may be appreciated by comparing the volumes of distribution of drugs such as digoxin or chloroquine (Table 3–1) with some of the physical volumes of the body (Table 3–2). Volume of distribution can vastly exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, would have a minimum possible volume of distribution equal to the blood component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg (Table 3–2) for a drug that is restricted to the plasma compartment.
Drug clearance principles are similar to the clearance concepts of renal physiology. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration (C):
Clearance, like volume of distribution, may be defined with respect to blood (CLb), plasma (CLp), or unbound in water (CLu), depending on where and how the concentration is measured.
It is important to note the additive character of clearance. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ.
CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action
TABLE 3–1 Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.)