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76 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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Goal and Indications for Drug
ConcentrationMonitoring
e primary goal of therapeutic drug monitoring is to maximize
the benet of a drug to a patient in the shortest possible time
while minimizing the risk of drug toxicity. e number of hospitalizations or oce visits used to adjust therapies or manage
and diagnose adverse drug reactions may therefore be reduced,
resulting in overall cost savings.
Drug concentration measurements should not be performed
unless the result will aect some future action or decision. Moni
toring should not be done simply because the opportunity presents itself; it should be used discriminatingly to answer clinically
relevant questions and resolve or anticipate problems in drug
therapy management.14 e clinician should always ask, “Will
this drug concentration value provide more information to me
than sound clinical judgment alone?”9 e following examples
provide clinical situations and clinical questions that drug concentration measurements might be able to impact:
•
erapeutic conrmation: A patient is on a regimen that
appears to oer the maximum benet with acceptable side
eects. Question: What drug concentration is associated with
a therapeutic eect in this patient for future reference?
•
Dosage optimization: A patient has a condition in which the
clinical response is not easily measured and has been initiated
on a standard regimen of a drug. ere is modest improve-
ment, and no symptoms of toxicity are evident. Question:
Can I increase the dose to further enhance the eect? If so, by
how much?
•
Conrmation of suspected toxicity: A patient is experi-
encing certain signs and symptoms that could be related to
the drug. Question: Are these signs and symptoms most likely
related to a dose that is too high? Can I reduce the daily dose
to maintain ecacy and if so, by how much?
•
Avoidance of inecacy or toxicity: A patient is initiated
on a standard regimen of an antibiotic that is known to be
poorly absorbed in a small percentage of patients. Sustained
subtherapeutic concentrations of this drug can lead to drug
resistance. Question: Will a higher daily dose be needed in this
patient? A patient has been satisfactorily treated on a regimen
of Drug A. e patient experiences a change in health or
physiologic status or a second drug, suspected to interact
with Drug A, is added. Question: Will a regimen adjustment
be needed to avoid inecacy or toxicity?
•
Distinguishing nonadherence from treatment failure:
Apatient has not responded to usual doses and nonadher-
ence is a possibility. Question: Is this a treatment failure, or
does the patient need counseling on adherence?
Characteristics of Ideal Drugs for
TherapeuticDrug Monitoring
Not all drugs are good candidates for therapeutic drug moni
toring. ose for which drug concentration monitoring will be
most useful have the following characteristics15:
•
Readily available assays: Methods for drug concentration
measurement must be thoroughly evaluated for sensitivity,
specicity, accuracy, and precision and be available to the
clinician at a cost to justify the information to be gained.
Chromatographic methods are most likely used in laboratory settings and are considered in many cases to be the
reference methods. Increased interest in methods for use in
ambulatory settings, however, has led to the development
of immunoassay systems purported to be fast, reliable, and
cost-eective.
•
Lack of easily observable, safe, or desirable clinical
-
-
endpoint: Clinically, there is no immediate, easily monitored,
and predictable clinical parameter to guide dose titration.
For example, waiting for arrhythmias or seizures to occur or
resume may be an unsafe and undesirable approach to dosing
antiarrhythmics and antiepileptics.
• Dangerous toxicity or lack of eectiveness: Toxicity or lack
of eectiveness of the drug presents a danger to the patient.
For example, serum concentrations of the antifungal drug,
ucytosine, are not routinely monitored. However, specialized
monitoring may be done to ensure that concentrations are
less than 100 mg/L to avoid gastrointestinal (GI) side eects,
blood dyscrasias, and hepatotoxicity. As another example,
specialized monitoring of the protease inhibitors (PIs) may
emergence of antiviral resistance is observed with sustained
exposure to subtherapeutic concentrations.
•
Unpredictable dose–response relationship: e presence
of an unpredictable dose–response relationship, such that a
dose rate that produces therapeutic benet in one patient
may cause toxicity in another patient. is would be true
for drugs that have signicant interpatient variation in pharmacokinetic parameters, drugs with nonlinear elimination
behavior, and drugs with pharmacokinetic parameters that
are aected by concomitant administration of other drugs.
For example, patients given the same daily dose of phenytoin can demonstrate a wide range of serum concentrations
andresponses.
•
Narrow therapeutic range: e drug concentrations associated with therapeutic eect overlap considerably with the
concentrations associated with toxic eects, such that the
zone for therapeutic benet without toxicity is narrow. For
example, the therapeutic range of total serum concentrations of phenytoin is widely accepted to be 10 to 20 mg/L
for most patients; the upper limit of the range is only twice
the lowerlimit.
•
Good correlation between drug concentration and ecacy
or toxicity: is criterion must apply if we are using drug
concentrations to adjust the dosage regimen of a drug. For
example, a patient showing unsatisfactory seizure control
with a serum phenytoin concentration of 8 mg/L is likely
to show improved control with a serum concentration of
15mg/L.
Other than availability of an assay, it may not be necessary for
a drug to fulll the previously listed characteristics for drug concentration monitoring to help guide clinical decision-making.
Newer drugs that do not yet have clearly dened therapeutic
ranges may be monitored only under special circumstances
16-20
CHAPTER 5 • InTERPRETATIon of SERum DRugConCEnTRATIonS 77
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(eg, to ensure adherence). Other drugs may not have a clearly
dened upper or lower limit to the therapeutic range but are
monitored under special circumstances to ensure ecacy
or avoid toxicity. e fact remains, the drug concentration is
important for answering a specic clinical question: Will the
information provided by this measurement help to improve the
patient’s drug therapy?
Information Needed for Planning and
Evaluating Drug Concentrations
Drug concentrations should be interpreted in light of full information about the patient, including clinical status. Information
surrounding the timing of the sample relative to the last dose
is especially critical and is one of the biggest factors making
drug concentrations unusable or cost-ineective.
provides a list of the essential information needed for a drug
concentration request. Laboratory request forms or computer
entry forms must be designed to encourage entry of the most
important information. All relevant information should be
included on both the request form and the report form to facilitate an accurate interpretation. It is particularly important to
verify the time of the sample draw because phlebotomists or
computer-generated labels commonly identify samples with the
time of the intended draw instead of the actual draw time. Some
hospital laboratories have minimized the number of inappropriate samples by refusing to run any samples that are not accompanied by critical information, such as the timing of the sample
relative to the last dose; however, this practice can be cumbersome and is not widely used.5 e laboratory report form should
also include the assay used; active metabolite concentration (if
measured); and parameters reecting the sensitivity, specicity,
and precision of the method.
Accuracy and completeness of the information provided on a
laboratory request form are particularly important in light of the
many problems that can occur during the therapeutic drug monitoring process. A drug concentration that seems to be illogical,
given the information provided on the form, may be explained
by a variety of factors, as shown in Table5-2 (Minicase 1).
5,21-23
Table5-1
Considerations for Appropriate Interpretation
of Drug Concentrations
To appropriately interpret a drug concentration, it is important
to have as many answers as possible to the following questions:
•
erapeutic range. What do the studies show to be the
usual therapeutic range? How frequently will patients show
response at a concentration below the lower limit of the
usual range? How frequently will patients show toxicity at
a concentration above or even below the upper limit of the
usual range? What are the usual signs and symptoms indi-
cating toxicity?
•
Sample timing. Was the sample drawn at a steady state? Was
the sample drawn at a time during the dosing interval (if
intermittent therapy) that reects the intended indication
for monitoring (a peak, a trough, a “random” concentration,
or an average concentration)? During the dosing interval,
when is a peak concentration most likely to occur for the
formulation administered? Does the formulation exhibit a
lag time for release, absorption, or distribution such that the
lowest concentration will occur into the next dosing interval?
• Use of concentrations for dose adjustment. Does the drug
display rst-order (linear) pharmacokinetic elimination
behavior such that an increase in daily dose will produce
a proportional increase in the average drug concentration?
Will more complex adjustment methods be needed for drugs
that display nonlinear elimination behavior? Is the dosage
adjustment method focused on attaining specic peaks,
troughs, or specic average concentrations?
•
Protein binding, active metabolites, and other considerations. How are total drug concentrations in serum inter
preted in cases of altered serum protein binding? How are
concentrations or contributions of active metabolites considered along with parent drug? Is the drug administered as
a racemic mixture and if so, do the enantiomers dier in
activity and pharmacokinetic behavior? Do certain physiologic or pathologic conditions aect a patient’s response to
the drug at a given concentration?
Each of these categories is described in general in the section
that follows and, more specically, for each drug or drug class
in the Applications section.
THE THERAPEUTIC RANGE
e therapeutic range is also known as the “therapeutic window,”
“therapeutic reference range,” “optimal plasma concentration,”
and “target range.” e therapeutic range is best dened as
“ranges of drug concentrations in blood that specify a lower limit
below which a drug induced therapeutic response is relatively
unlikely to occur and an upper limit above which tolerability
decreases or above which it is relatively unlikely that therapeutic
improvement may be still enhanced.”
ranges are population-based averages for which most patients
are expected to respond with acceptable side eects. us, there
will always be some patients who exhibit therapeutic eect at
drug concentrations below the lower limit, while others will
experience unacceptable toxicity at concentrations below the
upper limit. erefore, a patient’s therapy is always best guided
by a patient’s individual therapeutic concentration and corre
lated clinical response. It may be most benecial to measure
drug concentrations when a patient has attained the desired
clinical response and establish the obtained drug concentration as the optimal concentration for an individual patient.
Figure5-1 illustrates how the probability of response and tox-
icity increases with drug concentration for a hypothetical drug
and how a therapeutic range might be determined based on these
relative probabilities. Figure5-2 shows how patterns for response
and toxicity can change in two dierent patients receiving the same
drug. If the hypothetical drug in question has an active metabolite
that accumulates more than the parent drug in renal impairment
and if that metabolite contributes more to toxicity than to ecacy, then the individual therapeutic range in the patient with renal
impairment will be narrower. Concentration monitoring of the
active metabolite would be especially important in that situation.
1,24-26
erapeutic reference
25,26
-
-
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TABLE 5-1. Information Needed to Order and/or Interpret a Laboratory Value
TYPE OF DATA SPECIFIC DATA WHY NECESSARY
Patient identication •
Patient demographics
and characteristics
History and physical
examination
Specimen information • Time of collection
Name, address, identication number,
and physician name
Age, gender, ethnicity, height, weight,
•
and pregnancy
Condition being treated
•
• Organ involvement (renal, hepatic,
cardiac, GI, and endocrine)
• Fluid balance and nutritional status
• Labs (albumin, total protein, liver
function enzymes, INR, bilirubin, serum
creatinine or creatinine clearance,
thyroid status, and electrolyte
abnormalities)
• Smoking and alcohol history
• Source of specimen: blood, urine, or
other body uid site of collection
•
Order of sample, if part of a series
• Type of collection tube
• Time of receipt by laboratory
All blood samples look alike and could easily be switched
among patients without appropriate identication
The therapeutic range for a given drug may depend on
the specic indication being treated (eg, digoxin for atrial
arrhythmias versus heart failure); if there is no history
of prior drug concentration measurements, information
about concurrent disease states, physiologic status,
and social habits may help with initial determination
of population pharmacokinetic parameters, in order to
determine if the resulting concentration is expected or
not; information about renal function and albumin is
important if a total drug concentration is being measured
for a drug normally highly bound to serum proteins; it is
also important to know if any endogenous substances
due to diseases will interfere with the assay; electrolyte
abnormalities may affect the interpretation of a given
concentration (eg,
Laboratories often retain samples for several days
and detailed information will help to nd a sample if
important pre, post, or random samples are needed;
the time of collection relative to the dose is extremely
important for proper interpretation (Close to a trough?
Closer to a peak?); knowing the type of collection tube
is important because of the many interferences that
may occur; it is important to know the collection site
relative to the administration site, if an IV route is used;
if a series of samples is to be drawn, the labeled timing
of the collection tubes can get mixed up
digoxin)
Drug information •
Drug concentration
history
Purpose of assay and
urgency of request
GI = gastrointestinal;
INR = International Normalized Ratio.
Source: Adapted with permission from references 16 and 17.
Name of drug to be assayed
• Current dosage regimen, including route
• Type of formulation (sustained-release,
delayed-release, or prompt-release)
• Length of time on current regimen
• Time of last dose
• Concurrent drug therapy
• Duration of IV infusion
• Dates and times of prior concentration
measurements
• Response and drug regimen schedules
associated with prior concentrations
• Therapeutic conrmation
• Suspected toxicity
• Anticipated inefcacy or toxicity due to
change in physiologic/health status or
drug–drug interaction
• Identication of drug failure
• Suspected overdose
It is important to know if the concentration was drawn
at a steady state and when the concentration was
drawn relative to the last dose; it is also important to
know if there are any potential drug interferences with
the assay to be used
It is important to know what drug concentrations
have been documented as effective or associated
with toxicity; it is also important to know how drug
concentrations have changed as a consequence of
dosage regimen
This forces the clinician to have a specic clinical
question in mind before ordering a sample; it also aids
in the interpretation of results
CHAPTER 5 • InTERPRETATIon of SERum DRugConCEnTRATIonS 79
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TABLE 5-2. Common Reasons Why Drug Concentration Results Do Not Make Sense
CATEGORY OF FACTOR SPECIFIC EXAMPLES
Related to drug administration
or blood sampling logistics
Related to pharmacokinetics •
Related to the laboratory •
•
Wrong dose or infusion rate administered
• Dose skipped or infusion held for a period of time
• Dose given at time other than recorded; blood drawn as ordered
• Dose given at right time; blood drawn at time other than recorded
• Sample taken through an administration line, which was improperly ushed prior to
sample withdrawal
• Sample taken from the wrong patient
• Improper or prolonged storage prior to delivery to laboratory
• Wrong collection tube/device used
• Patient was dialyzed between doses
Sample is drawn prior to steady-state attainment
• Orders for digoxin samples are not clearly specied to be drawn at least 6 hours
postdistribution
• Samples are ordered at the wrong times relative to last dose to reect specic needs
(eg, peaks and troughs)
• Concentrations of active metabolites are not ordered when appropriate
•
Concentrations for total drug are ordered for a drug with unusual serum protein binding
without recognition that the usual therapeutic range of total drug will not apply
• Samples after IV administration are drawn prior to completion of distribution phase
(eg, vancomycin, aminoglycosides)
The wrong drug is assayed
• Critical active metabolites are not assayed
• Interferences or artifacts caused by endogenous substances (bilirubin, lipids, and
hemolysis) or concurrent drugs
• Improper or prolonged storage prior to assay
• Technical errors with the assay
Related to the patient •
Patient does not adhere to therapy
• Taking interacting medications that may increase or decrease a drug’s concentration
• Patient-specic laboratory parameters important for a drug’s pharmacokinetic prole
are altered (eg, albumin)
Source: Adapted with permission from references 17 and 25.
Drug concentration monitoring is oen criticized by claims
that therapeutic ranges are not suciently well dened.
10,11
e
lack of clearly dened therapeutic ranges for older drugs is partially attributable to how these ranges were originally determined. Eadie describes the process that was typically used for
determination of the therapeutic ranges of the antiepileptic
drugs: “ese ranges do not appear to have been determined
by rigorous statistical procedures applied to large patient populations. Rather, workers seem to have set the lower limits for
each drug at the concentration at which they perceived a reasonable (although usually unspecied) proportion of patients
achieved seizure control, and the upper limit at the concentration above which overdosage-type adverse eects appear to
trouble appreciable numbers of patients, the values then being
rounded o to provide a pair of numbers, which are reasonably
easy to remember.”
14
In an ideal world, studies to dene therapeutic ranges for drugs should use reliable methods for measurement of response and should be restricted to patients with
the same diseases, age range, and concurrent medications.1 In
recent years, the U.S. Food and Drug Administration (FDA) has
recognized the importance of determining concentration versus
response relationships early during clinical trials.
27
Anything that aects the pharmacodynamics of a drug,
meaning the response at a given drug concentration, aects the
therapeutic range, including the following factors:
•
Indication. Drugs that are used for more than one indi-
cation are likely to be interacting with dierent receptors.
Thus, a different concentration versus response profile
might be expected depending on the disease being treated.
For example, higher serum concentrations of digoxin are
needed for treatment of atrial brillation as compared with
heart failure. Higher antibiotic drug concentrations may
be needed for resistant organisms or to penetrate specic
infected tissuesites.
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MINICASE 1
Importance of Documenting Drug Administration Times
Michael T., an 86-year-old man (95 kg, 178 cm, baseline SCr 0.78), is
receiving vancomycin monotherapy for treatment of a gram-positive
bacteremia (unknown source). According to the medical chart, he
receives four doses of vancomycin 2,000 mg q 12h infused over
2 hours on a schedule of 7 a.m./7 p.m. The estimated/predicted
half-life of vancomycin in Michael T. based on estimated creatinine
clearance is 6 hours. A concentration drawn at 6 a.m. the following
morning is reported as 16 mg/L. Based on the current information,
the regimen of vancomycin 2,000 mg q 12h is continued. A repeat
concentration 3 days later at 6:30 a.m. reveals a vancomycin trough
concentration of 27 mg/L. Renal function, as indicated by creatinine
clearance, has not changed in this patient. The pharmacist receives
a call to assess and interpret this concentration. If accurate, a
dosage adjustment will be necessary to avoid toxicities.
QUESTION: What are the possible explanations for apparent changes
in serum vancomycin results? Which vancomycin concentration
accurately reflects the current dosage regimen?
DISCUSSION: For any drug requiring therapeutic drug monitoring,
one must first consider whether the concentrations accurately
represent a steady state. With an estimated vancomycin half-life of
6 hours, a steady state should have been reached after four doses
•
Active metabolites. As shown in Figure 5-2, variable
or 48 hours. Because vancomycin depends greatly on the kidney for
elimination, a second consideration would be renal function. Of note,
this patient’s creatinine clearance is unchanged. Laboratory errors or
assay interference/artifacts could lead to difficulty in interpretation
of serum drug concentrations. In the case of aminoglycosides, for
example, coadministration of piperacillin–tazobactam may lead
to in vitro inactivation, which may lead to falsely subtherapeutic
concentrations. However, no such interferences were noted for
vancomycin in this case. Finally, it is important to confirm the
accuracy of blood sampling or drug administration times. After
investigating this patient’s medication administration record further,
it is discovered that his third vancomycin dose was held, and no
adjustment to timing of orders was performed. For this reason,
the measured concentration of 16 mg/L was in fact 24 hours after
thelast dose and therefore did not reflect a true 12-hour trough
on the 2,000mg q 12h regimen. After analysis of subsequent
administration times and doses of vancomycin, the dose is
adjusted to 2,000 mg q 24h. If the first measured concentration
had been initially noted to be drawn 24 hours after the previous
dose, the clinician could have predicted an elevated vancomycin
concentration on the every-12-hour regimen, and a dose adjustment
would have been made at that time.
• Concurrent drug treatment. In a manner similar to active
presence of an active metabolite can shi the therapeutic
range for that individual patient up or down. ese metabolites may behave in a manner similar to the parent drug
or may interact with dierent receptors altogether. In either
case, the relationship between parent drug concentration and
•
response will be altered.
metabolites, the presence of other drugs that have similar
pharmacodynamic activities will contribute to ecacy or
toxicity but not to measurement of the drug concentration.
e therapeutic range will be shied.
Patient’s age. While there is limited information concerning developmental changes in pharmacodynamics in the
Therapeutic Range:
100 –
80 –
60 –
40 –
% of Patients
20 –
0 –
0 4 8 12 16 20 24 28
10–20 mg/L
A
B
Concentration, mg/L
FIGURE 5-1. The therapeutic range for a hypothetical drug. Line A is
the percentage of patients displaying a therapeutic effect; line B is the
percentage of patients displaying toxicity.
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Toxicity
Toxicity
Response
Without
Serum
Drug
Concentration,
mg/L
Toxicity
No Response
Patient A,
normal amounts
of active
metabolite
Response
Without
Toxicity
No Response
Patient B,
accumulated
active metabolite
FIGURE 5-2. Representation showing how the individual
therapeutic range of a hypothetical drug can differ in a
patient with renal impairment because of accumulated
active metabolite.
to identify them as nonresponders, responders, or toxic
responders (see Chapter6).
31-33
One such drug is bupropion,
for which wide patient variability in response is associated
with genetic polymorphisms of CYP2B6.
•
Variable serum protein binding. eoretically, only the
34
unbound concentration of drug in blood is capable of establishing equilibrium with pharmacologic receptors, thus
making it a better predictor of response than total drug
concentration. Most drug concentrations in serum, plasma,
or blood, however, are measured as the summed concentration of bound and unbound drug. It is likely that some of the
patients who show toxicity within the conventional therapeutic range have abnormally low protein (eg,albumin) binding
and high concentrations of an unbound drug in blood.35
Low protein binding of a drug in blood can be the result
of either reduced protein concentrations or the presence of
other substances in blood that displace the drug from protein
binding sites. Phenytoin would be an example of a drug
requiring consideration of plasma proteins in evaluation of
serum concentrations.
In summary, the therapeutic range reported by the laboratory
is only an initial guide and not a guarantee of desired clinical
response in any individual patient. Every eort must be made to
consider other signs of clinical response and toxicity in addition
to the drug concentration measurement. erapeutic ranges for
the most commonly monitored drugs discussed in the Applications section of this chapter are reported in Table5-3.
pediatric population, it is understood that the numbers and
anities of pharmacologic receptors change with progression
of age, particularly into advanced age.28 Age-related changes
in pharmacodynamics and pharmacokinetics would be
expected to result in a shi of the therapeutic range.
• Electrolyte status. Electrolytes play a critical role in cardiac
function and therefore may aect the pharmacodynamics of
a given drug. As an example, hypokalemia, hypomagnesemia, and hypercalcemia are all known to increase the cardiac
eects of digitalis glycosides and enhance the potential for
digoxin toxicity at a given serum concentration.
•
Concurrent disease. Some disease states may alter the
29
pharmacodynamics and, in some cases, the pharmacokinetics of a given drug and subsequently alter the therapeutic
range. As an example, patients with underlying heart disease
(corpulmonale, coronary artery disease) have increased
sensitivity to digoxin.
•
Variable ratios of enantiomers. Some drugs are adminis-
29
tered as racemic mixtures of enantiomers, which may have
dierent response/toxicity proles as well as pharmacokinetic
behaviors. us, a given concentration of the summed enantiomers (using an achiral assay method) is associated with
dierent concentrations of response or toxicity in patients
with dierent proportions of the enantiomers. is has been
extensively studied for disopyramide.
•
Variable genotype. ere is growing evidence that response
30
to certain drugs is genetically determined. For selected drugs,
patients may be genotyped before starting drug treatment
SAMPLE TIMING
Incorrect timing of sample collection is the most frequent source
of error when therapeutic drug monitoring results do not agree
with the clinical picture.
23,36
Warner reviewed ve studies in
which 70% to 86% of the samples obtained for therapeutic drug
monitoring purposes were not usable. In most cases, this was the
result of inappropriate sample timing, including lack of attention to the time required to reach a steady state.23 ere are two
primary considerations for sample timing: (1) how long to wait
aer initiation or adjustment of a dosage regimen and (2) when
to obtain the sample during a dosing interval.
At Steady State
When a drug regimen (a xed dose given at a regularly repeated
interval) is initiated, concentrations are initially low and gradually increase until a steady state is reached. Pharmacokinetically, steady state is dened as the condition in which the rate
of drug entering the body is equal to the rate of its elimination.
For therapeutic drug monitoring, a steady state means that drug
concentrations have leveled o at their highest and, when given
as the same dose at a xed interval, the concentration versus
time proles are constant from interval to interval. is is illustrated in Figure5-3 for a continuous infusion and a chronic
intermittent dosage regimen.
Drug concentration measurements should not be made until
the drug is suciently close to a steady state so that the maximum benet of the drug is ensured. e time required to reach
82 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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TABLE 5-3. Data to Aid Interpretation of Concentrations of Drugs That Are Commonly Monitored
CONSIDERATIONS FOR
INTERPRETATION: PROTEIN
RECOMMENDED
CONCENTRATIONS RECOMMENDED TIMING
Bronchodilators
BINDING, ACTIVE METABOLITES,
OTHER FACTORS
Theophylline Adult: 5–15 mg/L
Child: 5–10 mg/L
Neonate: 5–10 mg/L
Trough or C
occurs in 24 hr for an average
adult nonsmoker receiving
steady state
ss,avg
a maintenance infusion, but
may take longer for sustainedrelease products
Antiepileptics
Carbamazepine 4–12 mg/L Trough or C
steady state
ss,avg
may require up to 2–3 wk after
initiation of full dose rate due
to autoinduction
Phenobarbital 10–40 mg/L Anytime during interval; steady
state may require up to 3 wk
Phenytoin Based on total phenytoin
concentrations:
Trough or C
may require up to 3 wk
steady state
ss,avg
Adult: 10–20 mg/L
Infant: 6–11 mg/L
Neonate: 8–15 mg/L
Concentrations up to 20 mg/L may
be necessary in some patients; the
caffeine metabolite is of minor
signicance in adults but may
contribute to effect in neonates;
theophylline has been replaced by
safer bronchodilators in children, and
by caffeine in neonates
Lower total concentrations may be
more appropriate in patients with
decreased protein binding (liver
disease, hypoalbuminemia, and
hyperbilirubinemia), or in patients
taking other anticonvulsants
Many drug interactions; consider
impact on concentration when
starting/stopping interacting
medications
Measurement of unbound phenytoin
concentrations (therapeutic range
of 1–2 mg/L) may be preferred
in most patients; lower total
phenytoin concentrations may be
more appropriate in patients with
decreased protein binding due to
hypoalbuminemia (eg, liver disease,
nephrotic syndrome, pregnancy, cystic
brosis, burns, trauma, malnutrition,
AIDS, and advanced age), ESRD,
concurrent use of salicylic acid or VPA
Valproic Acid (VPA) Epilepsy: 50–100 mg/L
(total)
Mania: 50–125 mg/L (total)
Trough or C
ss,avg
Steady state may require up
to 5 days
Lower total VPA concentrations may
be more appropriate in patients with
hypoalbuminemia (liver disease, cystic
brosis, burns, trauma, malnutrition,
and advanced age), hyperbilirubinemia,
ESRD, and concurrent use of salicylic
acid; VPA shows interpatient variability
in unbound fraction because of
nonlinear protein binding; total
concentrations increase less than
proportionately with increases in daily
dose, while unbound concentrations
increase proportionately
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TABLE 5-3. Data to Aid Interpretation of Concentrations of Drugs That Are Commonly Monitored, cont’d
CONSIDERATIONS FOR
INTERPRETATION: PROTEIN
RECOMMENDED
CONCENTRATIONS RECOMMENDED TIMING
Antimicrobial Drugs
BINDING, ACTIVE METABOLITES,
OTHER FACTORS
Amikacin Traditional dosing:
Peaks: 20–30 mg/L
Troughs: < 8 mg/L
Gentamicin,
tobramycin
Traditional dosing:
Peaks: 6–10 mg/L
Troughs: < 1–2 mg/L
Traditional dosing: steady state
should be based on estimated
half-life, particularly in patients
with renal impairment
Extended-interval dosing: per
institution specic protocol
(consider two-point and
patient-specic kinetics)
Desired peak will depend on
infection site (ie, high inoculum
infections necessitating higher
peaks)
Traditional dosing: steady state
should be based on estimated
half-life, particularly in patients
with renal impairment
Extended-interval dosing: per
institution specic protocol
(consider two-point and
patient-specic kinetics)
Desired peak depends on
infection site (ie, high inoculum
infections necessitating higher
peaks)
Vancomycin AUC-guided monitoring for
serious MRSA infections:
>400–600 mg × hr/L
Troughs/traditional based
monitoring: 10–20 mg/L
AUC-guided monitoring: one
concentration obtained at
1–2 hr postinfusion (C
) and a
max
second concentration obtained
at the end of dosing interval
(trough, C
) once steady state
min
is reached; if using Bayesian
software, may obtain trough
concentration (at end of dosing
interval) only; can be drawn
prior to reaching steady state
Trough-based monitoring:
Concentration within 30
min to
1 hr of next dose; steady state
may require up to 2–3 days
in patients with normal renal
function
AUC-guided monitoring is reserved
for invasive MRSA infections; there
is not enough data to assess which
monitoring approach (AUC-guided vs.
trough-only monitoring) should be
followed in noninvasive MRSA or other
infections
(continued )
84 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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TABLE 5-3. Data to Aid Interpretation of Concentrations of Drugs That Are Commonly Monitored, cont’d
CONSIDERATIONS FOR
INTERPRETATION: PROTEIN
RECOMMENDED
CONCENTRATIONS RECOMMENDED TIMING
Antifungal Agents
BINDING, ACTIVE METABOLITES,
OTHER FACTORS
Itraconazole Trough concentration
>0.5–1 mg/L
Posaconazole Trough >1 mg/L Concentration can be drawn at
Voriconazole Lower limit: >1 mg/L
Upper limit: <4–6 mg/L
Cardiac Drugs
Digoxin 0.5–1.2 mcg/L NEVER sooner than 6
Concentration can be drawn
at any time during a dosing
interval once steady state is
reached
any time during dosing interval
once steady state is reached at
end of rst week of therapy
Trough concentration (eg, prior
to next dose) within rst week
of therapy initiation or dosage
adjustments
Steady state may be reached
in 1–2 days; however, it is
recommended to wait at least
5 days to measure trough
concentration
hr after
an oral dose; steady state
may require up to 7 days with
normal renal function
Variability in absorption and
concentrations noted between
different formulations (eg, oral
capsules versus oral solution)
Variability in absorption and
concentrations noted between
different formulations (eg, oral
tablets versus oral suspension)
Toxicity more likely within therapeutic
range in patients with hypokalemia,
hypomagnesemia, hypercalcemia,
underlying heart disease, and
hypothyroidism; patients with
hyperthyroidism may be resistant at
a given digoxin concentration, drug
interactions
Cytotoxic Drugs
Methotrexate Therapeutic levels: variable
High-dose regimen:
0.1–1 µM/L
Low-dose regimen:
<0.2 µM/L
Immunosuppressant Drugs
Cyclosporine 100–500 mcg/L (whole
blood, using specic assay)
Per protocol for determination
of leucovorin rescue regimen
Trough or 2-hr after dose;
steady state may require up
to 5 days
Decreased protein binding is observed
in some situations, but implications for
interpretation of total concentrations
are unclear
Highly variable unbound fraction in
blood; higher total concentrations
may be acceptable in patients with
hypercholesterolemia or prior to acute
rejection episodes (increased serum
binding); lower total concentrations
might be acceptable in patients with
decreased binding in serum (low
cholesterol)
CHAPTER 5 • InTERPRETATIon of SERum DRugConCEnTRATIonS 85
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TABLE 5-3. Data to Aid Interpretation of Concentrations of Drugs That Are Commonly Monitored, cont’d
CONSIDERATIONS FOR
INTERPRETATION: PROTEIN
RECOMMENDED
CONCENTRATIONS RECOMMENDED TIMING
BINDING, ACTIVE METABOLITES,
OTHER FACTORS
Tacrolimus Initiation: 20 mcg/L
Maintenance: 5–10 mcg/L
Goal concentrations may
be patient and institution
specic
Trough concentrations three
times a week initially until
concentrations are stabilized;
monitoring intervals can be
extended with maintenance
therapy
Psychotropics
Lithium Acute management:
0.5–1.2 mEq/L
Maintenance:
12 hr after the evening dose
on BID or TID schedule; steady
state may require up to 1 wk
0.6–0.8 mEq/L
a steady state can be predicted if the drug’s half-life is known,
as shown here:
NUMBER OF
HALF-LIVES
PERCENTAGE OF STEADY
STATE ATTAINED
2 75%
3 88%
4 94%
5 97%
is means the clinician should wait three half-lives at a
minimum before obtaining a sample for monitoring purposes.
Therapeutic range may shift slightly
with concomitant immunosuppressant
medications and by indication; many
drug interactions; consider impact on
concentration when starting/stopping
interacting medications
Monovalent cation, which is not bound
to plasma proteins; does not undergo
metabolism
e clinician also should anticipate that the “usual” half-life in
a given patient may actually be longer due to impaired elimination processes, and it may be prudent to wait longer if possible.
e half-lives of drugs that are typically monitored are reported
in the Applications section, and typical times to steady state are
reported in Table5-3.
Sometimes drugs are not given as a xed dose at a xed interval, or they may undergo diurnal variations in pharmacokinetic
handling.
37,38
Although the concentration-versus-time proles
may dier from each other within a given day, the patterns from
day to day will be the same if steady state has been attained. In
cases of irregular dosing or diurnal variations, it is important
that drug concentration measurements on dierent visits be
obtained at similar times of the day for comparative purposes.
An unusual situation is caused by autoinduction, as exempli-
ed by carbamazepine. e half-life of carbamazepine is longer
Constant Rate Infusion
25 –
20 –
15 –
10 –
Conc., mg/L
5 –
0 –
0 20 40
Time, hr
C
ss
25 –
20 –
15 –
10 –
Conc., mg/L
5 –
0 –
0 20 40
Intermittent Oral Dosing
Time, hr
FIGURE 5-3. Concentration versus time plots for a constant infusion and intermittent therapy after initiation
of therapy, without a loading dose. The half-life for this hypothetical drug is 8 hours. Thus, 88% of the eventual
average steady-state concentration (C
) is attained in 24 hours.
ss,avg
C
ss,max
C
C
ss,min
ss,avg
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