DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1894 To be accurate, clearances must be determined
after intravenous drug administration. When only nonparenteral
data are available, the ratio of CL/F is given;
values offset by the fractional availability (F) are indicated
in a footnote. When a drug, or its active isomer for
racemic compounds, is a substrate for a cytochrome
P450 (CYP) or drug transporter, this information is provided
in a footnote. This information is important for
understanding pharmacokinetic variability due to
genetic polymorphisms and for predicting metabolically
based drug-drug interactions.
Volume of Distribution. The total body volume of distribution
at steady state (V ss
) is given in Table AII–1 and
is expressed in units of L/kg or in units of L/m 2 for
some anticancer drugs. Again, when unit conversion
was necessary, we used individual or mean body
weights or body surface area (when appropriate) from
the cited study, or if such data were not available, we
assumed a body mass of 70 kg or a body surface area of
1.73 m 2 for healthy adults.
When estimates of V ss
were not available, values
for V area
were provided; V area
represents the volume at
equilibrated distribution during the terminal elimination
phase (see Equation 2–12). Unlike V ss
, V area
varies
when drug elimination changes, even though there is
no change in the distribution space. Because we may
wish to know whether a particular disease state influences
either the clearance or the tissue distribution of
the drug, it is preferable to define volume in terms of
V ss
, a parameter that is less likely to depend on changes
in the rate of elimination. Occasionally, the condition
under which the distribution volume was obtained was
not specified in the primary reference; this is denoted
by the absence of a subscript.
As with clearance, V ss
usually is defined in the
table in terms of concentration in plasma rather than
blood. Further, if data were not obtained after intravenous
administration of the drug, a footnote will make
clear that the apparent volume estimate, V ss
/F, is offset
by the fractional availability.
Half-Life. Half-life (t 1/2
) is the time required for the
plasma concentration to decline by one-half when elimination
is first order. It also governs the rate of approach
to steady state and the degree of drug accumulation during
multiple dosing or continuous infusion. For example,
at a fixed dosing interval, the patient will be at 50%
of steady state after one t 1/2
, 75% of steady state after
two half-lives, 93.75% of steady state after four halflives,
etc. Determination of t 1/2
is straightforward when
drug elimination follows a monoexponential pattern
(i.e., one-compartment model). However, for a number
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
of drugs, plasma concentration follows a multiexponential
pattern of decline over time. The mean value listed
in Table AII–1 corresponds to an effective rate of elimination
that covers the clearance of a major fraction of
the absorbed dose from the body. In many cases, this
t 1/2
refers to the rate of elimination in the terminal exponential
phase. For a number of drugs, however, the t 1/2
of an earlier phase is presented, even though a prolonged
t 1/2
may be observed at very low plasma concentrations
when extremely sensitive analytical techniques
are used. If the latter component accounts for ≤10% of
the AUC, predictions of drug accumulation in plasma
during continuous or repetitive dosing will be in error
by no more than 10% if this longer t 1/2
is ignored. The
clinician should know the t 1/2
that will best predict drug
accumulation in the patient, which will be the appropriate
t 1/2
to use for estimating the rate constant in
Equations 1–19 through 1–21 (see Chapter 1) to predict
time to steady state. It is this t 1/2
of accumulation
during multiple dosing that is given in Table AII–1.
Half-life usually is independent of body size
because it is a function of the ratio of two parameters,
clearance and volume of distribution, each of which is
proportional to body size. It also should be noted that
the t 1/2
is preferably obtained from intravenous studies,
if feasible, because the t 1/2
of decline in plasma
drug concentration after oral dosing can be influenced
by prolonged absorption, such as when slow release
formulations are given. If the t 1/2
is derived from an
oral dose, this will be indicated in a footnote of Table
AII–1.
Time to Peak Concentration. Because clearance concepts
are used most often in the design of multiple dosage
regimens, the extent rather than the rate of availability
is more critical to estimate the average steady-state concentration
of drug in the body. In some circumstances,
the degree of fluctuation in plasma drug concentration
(i.e., peak and trough concentrations), which govern
drug efficacy and side effects, can be greatly influenced
by modulation of drug absorption rate through
the use of sustained- or extended-release formulations.
Controlled-release formulations often permit a reduction
in dosing frequency from three or four times daily
to once or twice daily. There also are drugs that are
given on an acute basis (e.g., for the relief of breakthrough
pain or to induce sleep), for which the rate of
drug absorption is a critical determinant of onset of
effect. Thus, information about the expected average
time to achieve maximal plasma or blood concentration
and the degree of interindividual variability in that
parameter have been included in Table AII–1.