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

1896 sustained-release product. Indeed, the sustainedrelease
product sometimes is administered to reduce
peak-trough fluctuations during the dosing interval
and to minimize swings between potentially toxic or
ineffective drug concentrations. Again, we report C max
for both immediate- and extended-release formulations,
when available. In addition to parent drug concentrations,
we have included information on any
active metabolite that circulates at a concentration that
may contribute to the overall pharmacological effect,
particularly those active metabolites that accumulate
with multiple dosing. Likewise, for chiral drugs whose
stereoisomers differ in their pharmacological activity
and clearance characteristics, we present information
on the levels of the individual enantiomers or the
active enantiomer that contributes most to the drug’s
efficacy.
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
ALTERATIONS OF PARAMETERS
IN THE INDIVIDUAL PATIENT
Dose adjustments for an individual patient should be
made according to the manufacturer’s recommendation
in the package labeling when available. This information
generally is available when disease, age, or race
has a significant impact on drug disposition, particularly
for drugs that have been introduced within the past
10 years. In some cases, a significant difference in drug
disposition from the “average” adult can be expected
but may not require dose adjustment because of a sufficiently
broad therapeutic index. In other cases, dose
adjustment may be necessary, but no specific information
is available. Under these circumstances, an estimate
of the appropriate dosing regimen can be obtained
based on pharmacokinetic principles described in
Chapter 1.
Unless otherwise specified, the values in Table
AII–1 represent mean values for populations of normal
adults; it may be necessary to modify them for calculation
of dosage regimens for individual patients. The
fraction available (F) and clearance (CL) also must be
estimated to compute a maintenance dose necessary to
achieve a desired average steady-state concentration.
To calculate the loading dose, knowledge of the volume
of distribution is needed. The estimated t 1/2
is used in
deciding a dosing interval that provides an acceptable
peak-trough fluctuation; note that this may be the
apparent t 1/2
following dosing of a slowly absorbed formulation.
The values reported in the table and the
adjustments apply only to adults; exceptions are footnoted.
Although the values at times may be applied to
children who weigh more than ~30 kg (after proper
adjustment for size; see “Clearance” and “Volume of
Distribution” later), it is best to consult pediatrics textbooks
or other sources for definitive advice.
For each drug, changes in the parameters caused
by certain disease states are noted within the eight segments
of the table. In all cases, the qualitative direction
of changes is noted, such as “b LD,” which indicates a
significant decrease in the parameter in a patient with
chronic liver disease. The relevant literature and the
package label should be consulted for more definitive,
quantitative information for dosage adjustment recommendations.
Plasma-Protein Binding. Most acidic drugs that are
extensively bound to plasma proteins are bound to albumin.
Basic lipophilic drugs, such as propranolol, often
bind to other plasma proteins (e.g., α 1
-acid glycoprotein
and lipoproteins). The degree of drug binding to proteins
will differ in pathophysiological states that cause
changes in plasma-protein concentrations. Significant
pharmacokinetic effects from a change in plasma-protein
binding will be denoted under clearance or volume
of distribution.
Although pharmacokinetic parameters based on
total drug or metabolite concentrations often are
reported, it is important to recognize that in many cases
it is the concentration of unbound drug that drives
access to the site of action and the degree of pharmacological
effect. Remarkable changes in the total plasma
concentration may accompany disease-induced alteration
in protein binding; however, the clinical outcome
is not always affected because an increase in free fraction
also will increase the apparent clearance of an
orally administered drug and of a low-extraction drug
dosed intravenously. Under such a scenario, the mean
unbound plasma concentration at steady state will not
change with reduced or elevated plasma-protein binding,
despite a significant change in mean total drug concentration.
If so, no adjustment of daily maintenance
dose is needed.
Clearance. For drugs that are partly or predominantly
eliminated by renal excretion, plasma clearance
changes in accordance with the renal function of an
individual patient. This necessitates dosage adjustment
that is dependent on the fraction of normal renal function
remaining and the fraction of drug normally
excreted unchanged in the urine. The latter quantity
appears in the table; the former can be estimated as the
ratio of the patient’s creatinine clearance (CL cr
) to a normal
value (100 mL/min/70 kg body weight). If urinary
creatinine clearance has not been measured, it may be