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

The time required to achieve a maximal concentration
(T max
) depends on the rate of drug absorption
into blood from the site of administration and the rate
of elimination. From mass balance principles, T max
occurs when the rate of absorption equals the rate of
elimination from the reference compartment. Prior to
this time, absorption rate exceeds elimination rate, and
the plasma concentration of drug increases. After the
peak is reached, elimination rate exceeds the absorption
rate and, at some point, defines the terminal elimination
phase of the concentration-time profile.
The rate of drug absorption following oral administration
will depend on the formulation and physicochemical
properties of the drug, its permeability across
the mucosal barrier, and the intestinal villous blood flow.
For an oral dose, some absorption may occur very rapidly
within the buccal cavity, esophagus, and stomach,
or absorption may be delayed until the drug reaches the
small intestine or until the local pH in the intestine permits
drug release from the dosage formulation. In the
most extreme case, the rate of absorption can be sufficiently
controlled by the drug formulation to permit sustained
or extended delivery as the dosage form traverses
the entire length of the gastrointestinal tract. In some
instances, the terminal elimination of drug from the body
following a peak concentration reflects the slower rate
of absorption and not elimination.
When more than one type of drug formulation is
available commercially, we have provided absorption
information for both the immediate- and sustainedrelease
formulations. Not surprisingly, the presence of
food in the gastrointestinal tract can alter both the rate
and extent of drug availability. We have indicated with
footnotes when the consumption of food near the time
of drug ingestion may have a significant effect on the
drug bioavailability.
Peak Concentration. There is no general agreement about
the best way to describe the relationship between the
concentration of drug in plasma and its effect. Many
different kinds of data are present in the literature, and
use of a single-effect parameter or effective concentration
is difficult. This is particularly true for antimicrobial
agents because the effective concentration depends
on the identity of the microorganism causing the infection.
It also is important to recognize that concentration-effect
relationships are most easily obtained at
steady state or during the terminal log-linear phase of
the concentration-time curve, when the drug concentration(s)
at the site(s) of action are expected to parallel
those in plasma. Thus, when attempting to correlate a
blood or plasma level to effect, the temporal aspect of
distribution of drug to its site of action must be taken
into account.
Despite these limitations, it is possible to define
the minimum effective or toxic concentrations for some
of the drugs currently in clinical use. However, in
reviewing the list of drugs approved within the past
5 years, it is rare to find a declaration of an effective
concentration range, even in the manufacturer’s package
labeling. Thus, it is necessary to infer therapeutic
concentrations from concentrations observed following
effective dosage regimens. For a given dosage regimen,
a time-averaged steady-state blood or plasma concentration
(i.e., C − as estimated by dividing the mean AUC
ss
by the duration of the dosing interval) and the associated
interindividual variability might be one appropriate
parameter to report; however, such data often are
not available. Also, C − does not take into account the
ss
onset and offset of effect during fluctuation of plasma
drug concentration over a dosing interval. In some
instances, drug efficacy may be more closely linked
with peak concentration than with the average or trough
concentration, and differences in peak concentration for
special populations (e.g., elderly) sometimes are associated
with increased incidence of drug toxicity.
For practical reasons, the most commonly
reported parameter, C max
(peak concentration), rather
than effective or toxic concentrations, is presented in
Table AII–1. This provides a more consistent body of
information about drug exposure from which one can
infer, if appropriate, efficacious or toxic blood levels.
Although the value reported is the highest that would be
encountered in a given dose interval, C max
can be related
to the trough concentration (C min
) through appropriate
mathematical predictions (see Equation 1–21). Because
peak levels will vary with dose, we have attempted to
present concentrations observed with a customary dose
regimen that is recognized to be effective in the majority
of patients. When a higher or lower dose rate is used,
the expected peak level can be adjusted by assuming
dose proportionality, unless nonlinear kinetics are indicated.
In some instances, only limited data pertaining to
multiple dosing are available, so single-dose peak concentrations
are presented. When specific information is
available about an effective therapeutic range of concentrations
or about concentrations at which toxicity occurs,
it has been incorporated in a footnote. For individual
drugs, the reader also is referred to the index to locate
pages where more detailed information is provided.
It is important to recognize that significant differences
in C max
will occur when comparing similar
daily-dose regimens for an immediate-release and
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APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA