The biggest practical issue is taking the sample at
the correct time: these times differ for digoxin (6 h
post-dose), gentamicin (peak and trough), lithium
(12 h post-dose), phenytoin (no specific timing)
and cyclosporine (trough). The timing of samples
for acetaminophen/paracetamol and salicylates is
discussed below. Using the wrong tube is another
error: read the laboratory request because some
assays require serum, plasma or whole blood.
(Reynolds and Aronson, 1993).
It is useful to consider these same criteria during
drug development. Should the product label carry
information about, and should the risk manage-
ment program include, plasma concentration mon-
itoring? A few worked examples may be of use.
Narrow ‘ therapeutic window ’
Theophylline is a classic example. Its bronchodi-
lator effects are related to plasma concentrations in
the range of 5–20 mg l^1 , while higher concentra-
tions are associated with tachyarrythmias and other
serious adverse effects. This is a drug with a narrow
‘therapeutic window’. Elderly patients commonly
have several risk factors that can lead to unexpect-
edly high serum concentrations after administra-
tion of standard doses: reductions in renal
clearance, reduced volume of distribution and an
increased probability of concomitant disease and
other therapies (Ohnishiet al., 2003). Monitoring
plasma levels is thus helpful in avoiding the
adverse effects of theophylline.
Maximizing probability of efficacy
Itraconazole is an antifungal agent of the triazole
class (Buchowskyet al., 2005). This drug is com-
monly employed in patients with immunocompro-
mise, and thus patients for whom it is prescribed
have a substantial burden of concomitant disease
and other therapies. Furthermore, itraconazole has
several pharmacokinetic complexities: there is sub-
stantial inter- and intrapatient variability in the
dose–plasma concentration relationship, plasma
protein binding is substantial, there is at least one
active metabolite, this drug is a CYP 3A4 substrate
and it is compatible with P-glycoprotein transporta-
plasma concentration and efficacy is quite variable,
levels above 250 ng ml^1 are more often associated
with efficacy. Thus, this is a drug where the multi-
plicity of factors, both predictable and idiosyncratic,
is so great that it can be worth checking that the
appropriate dose has been chosen for effective
plasma concentrations.Antiepileptic drugs
There is no doubt that selective drug level monitor-
ing can help reduce seizures and minimize adverse
events when using antiepileptic drugs (AEDs).
Glauser and Pippenger (2000) have enumerated
the five situations when this is useful: finding a
baseline efficacious concentration for comparison
when things go awry later on, evaluating lack or
loss of efficacy, evaluating intolerability, judging
when to change AED(s) and providing some infor-
mation as to the scope and latitude for changing
dose size. For example, for clozapine nonrespon-
sive patients might benefit from dose increase
beyond a threshold concentration of 350–
400 ng ml^1 (Bellet al., 1998). Zonisamide has a
therapeutic range of 10–40mgml^1 , although the
dose required can vary when concomitant pheny-
toin or carbamazepine is being administered, as
well asvice versa(Mimaki, 1998).Acetaminophen/paracetamol
Overdose with this over-the-counter drug is such a
public health hazard that some mention of it must be
made here. In the European Community and North
America, this is the most common of all drugs taken
in overdose, and this injury probably creates the
largest number of candidates for transplantation of
precious donor livers. Jones and Dargan (2001)
provide a definitive, condensed account, and rightly
term this a ‘deceptive’ poisoning. Evidence of hepa-
tic injury, sadly, may only arise 24 h or more after
ingestion, by which time opportunities to limit
absorption of the overdose will have been lost.
Renal injury can also occur.
The toxicity of acetaminophen/paracetamol is
plasma concentration dependent. However, it
should be remembered that plasma concentra-376 CH28 MONITORING DRUG CONCENTRATIONS IN CLINICAL PRACTICE