in the steady state, the average drug concentration in
the individual patient is directly proportional to the
drug bioavailable fraction and inversely proportional
to the clearance rate. Clearly, variability in drug
clearance rate and bioavailable fraction are of
paramount clinical importance in choosing the
maintenance drug dose. Variability in initial drug
volume of distribution is important in selecting the
loading dose, if one is used.
Designing the initial dosing regimen
The formulas used to calculate the doses for a
drug depend upon a number of kinetic parameters.
It is much more likely that the target plasma drug
concentrations will be achieved if an individual
patient’s actual kinetic parameter values are used in
these formulas rather than the average parameters
values of the clinical population. Although the
parameter values for a patient cannot be known with
absolute accuracy prior to instituting drug therapy,
estimates of the values can be made based upon the
clinical diagnosis and routine clinical and laboratory
measurements. Dose calculations based upon these
estimates, as rough as they sometimes seem, do
increase therapeutic efficacy and, perhaps even more
so, therapeutic safety. As an example of the safety
benefit that can result from individualizing drug
dosing, consider the findings of a study of asthma
patients who had plasma theophylline concentrations
in excess of the therapeutic range (Greenberger
et
al.
1991). Fully 80 percent of the patients had
elevated concentrations as a result of the failure on
the part of the patients’ physicians to prescribe
reduced doses of theophylline despite the presence in
the patients of well recognized causes of decreased
theophylline clearance rate such as congestive heart
failure, and liver disease.
Calculation of an individualized maintenance
dose.
Modification of the maintenance dose is the
primary method by which multiple dosing regimens
are individualized. As discussed earlier,
C
ss
,
avg
=
D
m
$
F
Cl
For the general clinical population, the formula can
be rewritten as
C
ss
,
avg
=
usual D
m
$
F
avg
Cl
avg
where
F
avg
and
Cl
avg
are the average drug bio-
availability and drug clearance rate in the
population, respectively. Now consider the formula
as it applies to an individual patient,
C
ss
,
avg
=
individualized D
m
$
F
indiv
Cl
indiv
where
F
indiv
and
Cl
indiv
are, respectively, the individ-
ual’s drug bioavailable fraction and drug clearance
rate. In order to attain the same value for C
ss,avg
in
the individual patient as in the population,
usual D
m
$
F
avg
Cl
avg
=
individualized D
m
$
F
indiv
Cl
indiv
Rearrangement yields,
individualized D
m
=
usual D
m
F
avg
F
indiv
Cl
indiv
Cl
avg
which is the maintenance dose individualization
formula. The formula requires estimates of the
bioavailable fraction and clearance rate of the drug
in the individual and knowledge of the average
values in the population. Means to obtain these
numbers, or to estimate their ratio, are discussed in
a subsequent section.
Calculation of an individualized dosing inter-
val.
Altering the maintenance dose so as to maintain
a constant average plasma drug concentration leads
to changes in the maximum and minimum drug
concentrations. By individualizing the dosing inter-
val, and not the maintenance dose, one can maintain
the average plasma drug concentration while causing
only slight changes in the maximum and minimum
concentrations. Using logic similar to that employed
for the derivation of the formula for maintenance
dose individualization, the dosing interval individu-
alization formula can be derived,
individualized
$
=
usual
$
F
indiv
F
avg
Cl
avg
Cl
indiv
Calculation of an individualized loading dose.
Loading doses are calculated based on the initial
volume of distribution or on the beta volume of
distribution. If the drug has a single disposition
phase, the initial volume of distribution is used,
D
l
=
C
ss
,
avg
V
o
F
Manipulation of this equation yields the following
formula for individualization of loading doses,
individualized D
l
=
usual D
l
V
o
,
indiv
V
o
,
avg
F
avg
F
indiv
where
V
o,indiv
and
V
o,avg
are individual and population
average initial volumes of distribution, respectively.
Drug Therapy
12-7
