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

estimated from the concentration of creatinine in serum
(C cr
). In men:
CL cr
[ 140 −age (yr)] ⋅[weight (kg)]
( mL/min)
=
72⋅ [C cr
(mg/dL)]
(Equation A-1)
For women, the estimate of CL cr
by the above
equation should be multiplied by 0.85 to reflect their
smaller muscle mass. The fraction of normal renal function
(rfx pt
) is estimated from the following:
rfx
pt
CLcr,pt
=
100 mL/min
(Equation A-2)
A more accurate measure of rfx pt
seldom is necessary
because, given the considerable degree of
interindividual variation in nonrenal clearance, the
adjustment of clearance is an approximation. The following
equation for adjustment of clearance uses the
quantities discussed:
rf = 1 − [ fe
⋅( 1 − rfx )]
pt nl pt
(Equation A-3)
where fe nl
is the fraction of systemic drug excreted
unchanged in normal individuals (see Table AII–1). The
renal factor (rf pt
) is the value that, when multiplied by
normal total clearance (CL nl
) from the table, gives the
total clearance of the drug adjusted for the impairment
in renal function.
Example. The clearance of vancomycin in a patient with
reduced renal function (creatinine clearance = 25 mL/
min/70 kg) may be estimated as follows:
25 mL/min
rfx = = 025 .
pt
100 mL/min
fe = 079 . (see listing for vancomycin)
nl
rf pt
= 1−[ 0. 79⋅( 1−0.25)] = 0.
41
CL pt
= (1.3 mL/min/kg) ⋅0.41
= 0.53 mL/min/kg
Importantly, such a clearance adjustment should
be regarded only as an initial step in optimizing the
dosage regimen; depending on the patient’s response to
the drug, further individualization may be necessary.
Conventionally, clearance is adjusted for the size
of the patient to reflect a difference in the mass of the
eliminating organ. For orally administered drugs, the
applicability of such an adjustment may be limited by
the available dosage strengths of commercial formulations.
In some cases, scored tablets can be split, or commercial
tablet splitters are used to increase the range of
available dosage strengths. However, this practice
should be followed only with the recommendation of
the drug manufacturer because splitting a tablet sometimes
can compromise the bioavailability of a product.
With the exception of certain oncolytic agents, the
data presented in the table are normalized to weight.
Thus, interindividual variability in the weight-normalized
clearance reflects a variation in the intrinsic metabolic
or transport clearance and not the size of the
organ. Further, these differences can be attributed to
variable expression/function of metabolic enzymes or
transporters. However, it is important to recognize that
liver mass and total enzyme/transporter content may not
increase or decrease in proportion to weight in obese
or malnourished individuals. Alternative approaches
such as normalization by body surface area or other
measures of body mass may be more appropriate. For
example, many of the drugs used to treat cancer are
dosed according to body surface area (see Chapter 51).
In the tabulation, if the literature reported dose per body
surface area, we presented the data in the same unit. If
the cited clearance data were not normalized, but the
preponderance of the literature utilized body surface
area, we followed the practice of using values of body
surface area from the literature source or a standard of
1.73 m 2 for a healthy adult.
Volume of Distribution. Volume of distribution should be
adjusted for the modifying factors indicated in Table
AII–1 as well as for body size. Again, the data in the
table most often are normalized to weight. Unlike clearance,
volume of distribution in an individual most often
is proportional to weight itself. Whether this applies to
a specific drug depends on the actual sites of distribution
of drug; no absolute rule applies.
Whether or not to adjust volume of distribution
for changes in binding to plasma proteins cannot be
decided in general; the decision depends critically on
whether or not the factors that alter binding to plasma
proteins also alter binding to tissue proteins. Qualitative
changes in volume of distribution, when they occur, are
indicated in the table.
Half-Life. Half-life may be estimated from the adjusted
values of clearance (CL pt
) and volume of distribution
(V pt
) for the patient:
t
1/2
0.
693⋅V
=
CL
pt
pt
(Equation A-4)
1897
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA