of the individual parameter values. This variability
is due to errors in the timing of drug administration,
to variation introduced by blood specimen collection,
and to variation in the process of assaying the drug
concentration.
MONITORING THERAPY AND ADJUSTING
THE DOSING REGIMEN
The goal of individualizing the dosing regimen is
to provide safe, efficacious drug treatment to the
individual patient by targeting a steady-state plasma
drug concentration within the range that has been
found to be safe and efficacious in the usual patient.
The initial dosing regimen may fail to achieve this
goal because the steady-state drug concentration may
not actually be within the target range. This can be
due to poor or irregular patient compliance, to short-
comings in the dose individualization scheme (most
notably, to the lack of a reliable quantitative measure
of hepatic drug metabolism), or to unpredictable
sources of interindividual pharmacokinetic variabil-
ity. The regimen may also fail to attain its goal of
safe and efficacious therapy even when the dosing
regimen is a success in terms of achieving the target
steady-state drug concentration. This can happen as
a result of interindividual variability in effect site
drug kinetics (Eichler and Müller 1998) or as a
consequence of interindividual differences in the
effect site drug concentration-drug effect relationship
(Levy 1998).
Recognizing that the initial dose regimen may
not yield the desired therapeutic results, drug
therapy is monitored. Clinical observations and
routine laboratory studies usually provide all of the
information that is needed to assess the efficacy and
toxicity of drug therapy, in which case a patient’s
dosing regimen can be incrementally adjusted to give
the greatest therapeutic effect while maintaining
acceptable levels of toxic effects. An example is the
monitoring of the blood glucose concentration by
patients with diabetes who are being treated with
insulin. If the glucose concentration is within the
target range, the insulin dose is not changed. If the
glucose concentration is too high, and there is no
other explanation for the lack of glycemic control,
the insulin dose is increased or the dosing interval is
shortened. The dose decreased or the dosing inter-
val is lengthened if the glucose concentration is too
low. Sometimes there are no clinical or routine lab-
oratory findings that correlate in a timely fashion
with the effects of drug therapy. This is especially
common for drugs with noninstantaneous drug
effects and for drugs that are used to control episodic
phenomena, such as anti-epileptic agents and anti-
arrhythmic agents. For some these drugs, the
relationship between plasma drug concentration and
drug effect is obscured by interindividual variability
in effect site drug kinetics and by interindividual
variability in the effect site relationship between
drug concentration and drug effect. For other drugs
of this sort, however, plasma drug measurements
have proven to be reliable predictors of drug effect
For these drugs therapy can be monitored using drug
concentrations. This is called therapeutic drug mon-
itoring (Brown et al. 1993, Murphy 1995).
Therapeutic drug monitoring
.
The usual scheme for monitoring drug therapy
is: (1) determine the value of the plasma drug
concentration once steady-state conditions prevail,
(2) compare the measured concentration to the thera-
peutic range for the drug, and, if indicated, (3)
adjust the maintenance dose of the drug. After the
attainment of the new steady state, the drug concen-
tration is measured again to ascertain if the dose
adjustment has brought the concentration into the
therapeutic range. The process is repeated until the
therapeutic range is achieved.
Plasma drug concentration.
Most commonly,
therapeutic drug monitoring is based upon the mea-
surement of trough drug concentrations. The trough
concentration is the concentration at the end of the
dosing interval, immediately prior to the administra-
tion of the next maintenance dose. There are practi-
cal considerations that make this an attractive time to
sample, especially fairly reliable timing of specimen
collection. In addition, if the disposition kinetics at
the drug’s site of action are rapid, in the steady
state, the trough plasma drug concentration is
directly proportional to the minimum effect site drug
concentration. The minimum effect site drug
concentration is particularly important because it
represents the proximate kinetic target for drugs
whose effects are instantaneous and, therefore,
depend upon the continuous maintenance of effect
site concentrations at or above a minimum effective
value.
When the effect site kinetics are slow, the
steady-state effect site drug concentration curve is
rather flat and the minimum effect site drug concen-
tration is more nearly proportional to the average
Drug Therapy
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