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96 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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• Lamotrigine. e considerable pharmacokinetic variability
among patients taking lamotrigine, due in part to signicant drug–drug interactions, makes it a good candidate for
therapeutic drug monitoring.
lamotrigine is 2.5 to 15 mg/L.
133,151
e therapeutic range of
26,135,152
It has been suggested
that concomitant therapy with other antiepileptics may alter
the response to lamotrigine or its side-eect prole.
151
e
half-life of lamotrigine can range from 15 to 30 hours on
monotherapy.
133
us, one should wait at least 1 week before
obtaining samples aer initiating or adjusting lamotrigine
therapy.
151
is drug exhibits linear pharmacokinetics; therefore, dose rate adjustments result in proportional changes in
average serum concentrations. Because it is only 55% bound
to serum proteins, measurements of unbound lamotrigine
concentrations in serum are not necessary.
•
Levetiracetam. Serum concentration monitoring of levetiracetam is more important in pregnant women and in
infants and children because of the higher clearance in these
patients.
26,153
Furthermore, levetiracetam levels have been
shown to be aected by weight and medication coadministra-
154
tion.
Routine monitoring of levetiracetam is not required
for most patient populations due to the predictable dose
response. e half-life ranges from 6 to 8 hours in adults,
and a steady state should be attained within 1 week.
135
Serum
concentrations between 5 and 45 mcg/mL are considered to
be therapeutic.
155
Serum protein binding of levetiracetam is
<10%, eliminating the need for measurement of unbound
levetiracetam concentrations.
135
Ideally, serum concentrations should be drawn in the morning as a trough concentration due to diurinal variation in concentrations
• Oxcarbazepine. e pharmacologic eect of oxcarbazepine
is primarily related to serum concentrations of its active
monohydroxy metabolite, licarbazepine. A therapeutic range
of licarbazepine is 12 to 35 mg/L.
156
e elimination half-life
of licarbazepine is variable, ranging from 7 to 20 hours, and
is prolonged in renal impairment. e serum protein binding
of licarbazepine is low at 40%.
•
Pentobarbital. As a sedative hypnotic, therapeutic eects
of pentobarbital are seen at 1 to 5 mg/L; toxicity occurs at
concentrations >10 mg/L. Pentobarbital is 45% to 70% bound
to protein and is primarily eliminated via the kidneys. erapeutic concentrations have not been established for antiepileptic purposes.
•
Pregabalin. Pregabalin is approved as adjunctive treatment
157
for partial onset seizures and for the treatment of bromyalgia or diabetic, spinal cord injury-related, and postherpetic neuralgia. It has excellent bioavailability estimated at
98% and poor protein binding with very few drug interactions.
158
It is primarily eliminated via the kidneys and,
therefore, requires dose adjustment in patients with kidney
dysfunction. ere are no known signicant active metab-
159
olites.
24to 48hours.
as 3to 8mg/L.
Pregabalin reaches a steady state concentration at
147,148
e therapeutic range has been dened
160,161
• Tiagabine. Tiagabine shows pronounced interpatient phar-
macokinetic variability due to strong protein binding and
hepatic metabolism.
162
Trough concentrations between 20
and 100 mcg/L are associated with improved seizure control,
but there is wide variation in response at any given total
concentration.
26,133,134
is could, in part, be due to variable
serum binding (96% bound in serum on average). Salicylate,
naproxen, and VPA have been shown to displace tiagabine
from serum proteins.
133,134
Tiagabine half-life ranges from
5 to 13 hours and may be even shorter in the presence of
enzyme-inducing drugs.
134,153
Tiagabine shows linear elimi-
nation behavior aer therapeutic doses.
•
Topiramate. Topiramate concentrations are particularly
inuenced by interactions with other drugs, with concentrations as much as 2-fold lower when enzyme-inducing drugs
are administered concurrently.
18 to 23 hours, and it has linear elimination behavior.
163
e half-life ranges from
133,134,151
Topiramate is <40% bound to serum proteins but shows saturable binding to red blood cells, thus suggesting that whole
blood might be a preferable specimen for monitoring.
134,151
Eective serum concentrations are generally reported to be
between 2 and 25 mg/L.
164
No active metabolites have been
identied. Routine therapeutic drug monitoring is only
recommended in patients with hepatic or renal impairment.
162
Saliva concentrations have a strong correlation with serum
and may be a viable option for monitoring chronic therapy.
•
Zonisamide. The pharmacokinetics of zonisamide are
165
variable among patients and also highly inuenced by interactions with other drugs.
133
Zonisamide is approximately
40% bound to serum albumin, and, like topiramate, shows
saturable binding to red blood cells, suggesting that whole
blood monitoring might be preferable.
135,151
e half-life is
50 to 70 hours but may be as short as 25 hours when enzyme
inducers are coadministered.
135
Some reports suggest nonlinear behavior at higher doses. e serum concentration range
associated with response is 10 to 38 mg/L; cognitive dysfunction is reported at concentrations >30 mg/L.
metabolites have been identied.
135
26,135,151
No active
Antimicrobials
Aminoglycosides
erapeutic ranges. Aminoglycosides have been used for
decades to treat infections caused by multidrug-resistant
microorganisms. Most commonly used IV aminoglycosides
today include amikacin, gentamicin, and tobramycin.48 ey
are bactericidal and their ecacy is depends highly on peak
concentration aer an infusion.
ity occurs when the peak:minimum inhibitory concentration
(MIC) ratio is between 8:1 and 10:1.
postantibiotic eect (PAE) in which bacterial killing continues
even aer the serum concentration falls below the MIC.73 e
concentration-dependent killing and PAE of aminoglycosides
explain why extended-interval, or once-daily (pulse), dosing is
shown to be safe and eective in many patients. Studies have
shown improved peak concentrations of aminoglycosides aer
extended-interval dosing of aminoglycosides when compared
with multiple daily dosing regimens (ie, thrice-daily dosing).
Additionally, lower trough concentrations have been reported
166
Optimal bactericidal activ-
167-169
ey also exhibit a
CHAPTER 5 • InTERPRETATIon of SERum DRugConCEnTRATIonS 97
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at the end of the dosing interval compared with multiple daily
dosing regimens, reducing the risk of drug accumulation.
170
As a
result, extended-interval aminoglycosides have been associated
with improvement in ecacy and decreased nephrotoxicity.
171-174
Nephrotoxicity and ototoxicity are the most frequently reported
adverse eects of aminoglycosides. Ototoxicity is associated with
a prolonged course of treatment (for >7 to 10 days) with peaks
above 12 to 14 mg/L for gentamicin and tobramycin and 35 to
40mg/L for amikacin.73 One study noted there was not a signicant dierence in the incidence of ototoxicity between oncedaily and multiple-daily dosing aminoglycosides.
170
Patients
with trough concentrations above 2 to 3 mg/L (gentamicin and
tobramycin) or 10 mg/L (amikacin) for >5 to 7 days are predisposed to increased risk of nephrotoxicity.73 e risk of nephrotoxicity is even further increased when aminoglycosides are
given concomitantly with other nephrotoxic agents.
erapeutic ranges for peaks and troughs are reported for
the aminoglycosides and pertain only to dosing approaches
that involve multiple doses during the day. For gentamicin and
tobramycin, peaks between 6 and 10 mg/L and troughs between
0.5 and 2 mg/L are recommended.
175
e approximately 4-fold
higher MIC for amikacin explains why peaks between 20 and
30mg/L and troughs between 1 and 8 mg/L are recommended.
175
ere is no therapeutic range when the extended-interval dosing method is used; doses are given to attain peaks that are
approximately 8- to 10-fold the MIC, and troughs are intended
to be nondetectable within 4 hours of administration of the
nextdose.
166,175
ere has been some concern over the years that aminoglycosides are overmonitored. Uncomplicated patients who have
normal renal function, do not have life-threatening infections,
and will be treated for <5 days may not need to have serum aminoglycoside concentrations measured.
176
At the other extreme,
dosage individualization using serum concentrations of aminoglycosides is necessary in patients who are expected to be
on prolonged treatment courses (≥5 days) or in whom unusual
pharmacokinetic parameters are expected.
173-180
Sample timing. For extended-interval dosing patients with
normal renal function, a steady state is never reached because
each dose is washed out prior to the next dose. e method
developed by Nicolau et al (the Hartford nomogram) requires
that a single blood sample be obtained between 6 and 14 hours
aer the end of the rst infusion.
167,181
is sample is referred
to as a random sample, but the time of the collection must be
documented. e concentration is used with a nomogram to
determine if a dierent dosing interval should be used.
48,167
Concentrations that are too high according to the Hartford
nomogram indicate that the drug is not being cleared as well
as originally predicted, suggesting the need for a longer dosing
interval. For traditional dosing, it is important to wait until a
steady state is reached before obtaining serum concentrations.
e half-lives of the aminoglycosides are 1.5 to 3 hours for
adults with normal renal function but as long as 72 hours in
patients with severe renal impairment.73 A conservative rule of
thumb is that steady state is reached aer the third or fourth
dose.48 Some patients may have blood samples drawn immediately aer the rst dose (“o the load”) to determine their
pharmacokinetic parameters for purposes of dosage regimen
individualization. ese would most likely be patients who are
anticipated to have unpredictable or changing pharmacokinetic parameters, such as those in a critical care unit, and who
require immediate eective treatment because of life-threatening infections.
Two blood samples are sucient for purposes of individualizing traditional aminoglycoside dosing therapy and provide reasonable estimates of aminoglycoside pharmacokinetic
parameters.
be accurately recorded.
182
It is crucial that the times of the sample collections
48,166
e two samples should be spaced
suciently apart from each other so that an accurate determination of the log-linear slope can be made to determine the
elimination rate constant. e rst sample, sometimes referred
to as the measured peak, should be drawn no earlier than 1 hour
aer the end of a 30-minute infusion.
182-185
However, it is usually
drawn within 30 minutes prior to the start of infusion of the next
dose (assumed to be the trough).
48,164,176
Once the elimination
rate constant has been calculated using these two concentrations, the true peak and true trough can be calculated and their
values compared with desired target peaks and troughs.
Use of concentrations for dosage adjustment. Various extended-
interval dosing methods are used to take advantage of the
concentration-related killing and PAE of aminoglycosides.
e original Hartford method involves giving a milligram- perkilogram dose that is administered to attain a peak concentration that is approximately 10 times the MIC. en a sample is
obtained between 6 and 14 hours aer the end of the infusion
and compared with a nomogram, which indicates the appropriate maintenance dosing interval—usually 24, 36, or 48 hours.
Serum concentrations of aminoglycosides obtained during
traditional dosing are used to determine an individual patient’s
pharmacokinetic parameters as well as the true peak and true
trough to compare these to desired target concentrations. Equations that account for time of drug infusion are used to determine an appropriate dosing interval and dose.
185
Other dosage
adjustment methods include nomograms and population pharmacokinetic (Bayesian) methods.
177,185
Protein binding, active metabolites, and other considerations.
Aminoglycosides are <10% bound to serum proteins, and
unbound concentrations will always reect total concentrations in the serum.
175
e metabolites of the aminoglycosides
are inactive.
Vancomycin
erapeutic range and clinical considerations. Vancomycin isa
glycopeptide antibiotic that is used intravenously to treat grampositive organisms, including those resistant to other antibiotics
(ie, methicillin-resistant Staphylococcus aureus [MRSA]).
emergence of vancomycin-resistant enterococci, vancomycinresistant S aureus, vancomycin-intermediate S aureus (VISA),
and heteroresistant VISA has led to the need to optimize and
restrict vancomycin use. Major toxicities associated with vancomycin are nephrotoxicity and ototoxicity. Another adverse eect
known as red man syndrome (intense ushing, tachycardia, and
hypotension) is a histamine-related reaction associated with
rapid infusion.
73,186
48,73
176
167
e
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Although some institutions may monitor both peaks and
troughs of vancomycin, this practice has been questioned
because of a lack of standardization in associating timing of
sample draw and peak concentration. In contrast to aminoglycosides, the most important pharmacodynamic parameter of
vancomycin when used against S aureus isolates is 24-hour AUC
to MIC, with a target of 400 to 600 mg × h/L. Historically, due to
ease of use and practicality, trough concentrations served as surrogates for the AUC/MIC target, with troughs of 15 to 20 mg/L
recommended for infections caused by S aureus isolates with
MICs ≤1.
187
Although this traditional trough-based monitoring recommendation has been widely practiced in recent years,
benets for maintaining higher troughs are not well supported,
and more recent evidence has emerged noting that trough concentrations may not correlate well with AUC values—risking
either overexposure (and increased risk of associated toxicities)
or underexposure (and increased risk of emergence of antimicrobial resistance). erefore, new guidelines recommend that
in patients with suspected or conrmed MRSA infections that
individualized AUC/MIC ratio of 400 to 600 mg × h/L is targeted using AUC-guided dosing and monitoring, which can be
accomplished by either two-point kinetics or through the use of
Bayesian soware programs (preferred method). ere remains
a gap in available evidence on the most appropriate AUC/MIC
ratio target for non-MRSA infections, which the recent guidelines have not addressed. erefore, the use of the aforementioned targets for non-MRSA infections should be extrapolated
with caution if opted to be used in these scenarios.
187
Sample timing. e half-life of vancomycin is 7 to 9 hours in
adults with normal renal function and 120 to 140 hours in
patients with renal failure. A shorter half-life of 3 to 4 hours
has been noted in certain patient populations (ie, obesity, burn
victims).
73,188
For AUC-guided dosing and monitoring, either
a two-point kinetic or Bayesian soware approach can be followed. With two-point kinetics, it is recommended that once
steady state is achieved, one concentration be obtained at the
postdistribution phase (peak concentration at 1 to 2 hours
aer infusion) and a second concentration at the end of the
dosing interval (trough). If Bayesian soware is used, one or
two vancomycin concentrations (with one of the concentrations being a trough) should be obtained to help estimate the
AUC although a two-concentration approach is preferred. e
latter approach does not require steady-state concentration to
be reached rst, thereby allowing for early AUC target assessment. Of note, a trough concentration may be appropriate
to estimate the AUC using the Bayesian approach in certain
patient populations.
187
For traditional (historical) concentration monitoring, samples should be obtained as troughs within
30 minutes to 1 hour of the start of the next infusion.
Use of concentrations for dosage adjustment. Because of
the increased risk of nephrotoxicity in patients with serious
MRSA infections, a trough-only based monitoring approach,
targeting troughs of 15 to 20 mg/L, is no longer recommended
and an AUC-monitoring approach is advocated instead. Of
note, the aforementioned recommendation is only for serious
MRSA infections. Whether a traditional trough-only monitoring versus an AUC-guided dosing and monitoring approach
is best for other infections has not been determined. Besides
serious MRSA infections, monitoring is recommended for
patients at high risk for nephrotoxicity, patients with unstable
renal function, and patients receiving extended courses of vancomycin therapy (ie, >3 days). Vancomycin elimination is linear, and an increase in the dose (without a change in the dosing
interval) can be expected to provide a proportional change in
the trough serum concentration. It must be cautioned that
vancomycin has a pronounced distribution phase, making the
standardization of any peak sample to be especially important.
More sophisticated prediction methods for dosing adjustments must be used if the dosing interval is adjusted with or
without a change in dose.
Many methods have been proposed for vancomycin dosage
regimen adjustments.
73,78,188,189
A relatively simple method, proposed by Ambrose and Winter, permits the use of a single trough
concentration (drawn within 1 hour of the start of the next infusion) along with an assumption of the population distribution
volume to predict the necessary pharmacokinetic parameters
needed for individualization.
186
Once those parameters are
determined, equations that account for drug infusion can be
used to target desired peak and trough vancomycin concentrations. For AUC-guided dosing, monitoring of AUC exposure
is recommended in obesity and patients with changing renal
function. More frequent monitoring may be needed in patients
exhibiting hemodynamic instability.
Protein binding, active metabolites, and other considerations.
Vancomycin is 30% to 55% bound to serum proteins in adults
with normal renal function. e binding is lower (19%) in
patients with ESRD.
189
With binding this low, total concentrations of vancomycin provide reliable reection of the unbound
concentrations in serum. Vancomycin metabolites are inactive
and thus do not contribute to antibacterial eect or toxicity.
b-Lactams
erapeutic range and clinical considerations. e β-lactam
antibiotics demonstrate time-dependent bactericidal killing with
ecacy related to the percentage of the dosing interval that free
drug concentration remains above the MIC (fT>MIC). Studies
have shown that the killing potential of β-lactams is maximized at concentrations that are three to four times the MIC,
with higher concentrations providing little, if any, additional
190
benet.
β-lactams by increasing dosing frequency or infusion duration.
Generally, fT>MIC of 40%, 50%, and 50% to 70% is required
for the bactericidal killing potential of carbapenems, penicillins, and cephalosporins, respectively.
an increase in Vd and changes in antibiotic clearance (either
increased or decreased), β-lactam antibiotic pharmacokinetics may be altered in critically ill patients. Additionally, obesity
can similarly alter antibiotic pharmacokinetic parameters. As a
result, standard doses of antibiotics may be suboptimal, leading
to inadequate concentrations and even toxicities in some situations.
ill patients did not achieve a pharmacokinetic/pharmacodynamic target of 50% fT>MIC when standard antibiotic doses
were used.
erefore, it is important to optimize exposure of
191
As demonstrated by
192
Roberts and colleagues noted that one-h of critically
193
Historically, therapeutic drug monitoring of
CHAPTER 5 • InTERPRETATIon of SERum DRugConCEnTRATIonS 99
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β-lactam was not undertaken because these agents lack a narrow
therapeutic window and toxicity that would necessitate monitoring. As the incidence of multidrug-resistant microorganisms
continues to increase, dosing optimization of currently available
antibiotics is more important than ever and provides a potential
role for β-lactam therapeutic drug monitoring, especially in the
critically ill patient population and other patients with known
pharmacokinetic variability.
190,194
Antifungal Agents
Flucytosine (5-FC)
erapeutic range and clinical considerations. Flucytosine is a
synthetic antifungal agent used in combination with amphotericin B for treatment of select systemic fungal infections (ie, cryptococcal meningitis).
that time above MIC is the most important pharmacodynamic
parameter related to outcome with ucytosine therapy.
tosine has signicant interpatient pharmacokinetic variability.
Although no exact target range for serum concentrations of
ucytosine has been established, most clinicians agree that peak
serum concentrations (2 hours postdose) of ucytosine should be
kept below 100 mg/L to avoid dose-related hepatotoxicity, bone
marrow suppression, and GI disturbances.
concentrations should not fall below a trough concentration of
<20 to 40 mg/L to avoid the development of resistance.
Hepatotoxicity and bone marrow suppression are usually reversible with discontinuation. Indications for monitoring ucytosine include avoidance of toxicity—particularly in patients with
impaired renal function or those receiving concomitant amphotericin B—and avoidance of development of resistance due to
sustained low concentrations.
Sample timing. Flucytosine is minimally protein bound (2%
to 4%) and undergoes minimal hepatic metabolism. It is primarily (90%) excreted in the urine as unchanged drug, with
an elimination half-life of 4 to 5 hours in patients with normal renal function and upwards of 250 hours in ESRD.
Maximum serum concentration is reached within 1 to 2 hours
aer an oral dose at steady state in patients with normal renal
function.
199
erefore, a 2-hour postdose concentration of
ucytosine should be obtained aer three to ve doses have
been administered, noting that steady state may not be reached
for approximately 10 days in patients with renal failure.
Trough concentrations, if indicated, should be drawn within
30 minutes of the next dose.
Use of concentrations for dosage adjustment. Because there
are no reports of nonlinear elimination behavior, a given
increase in dose should produce a proportional increase in
serum ucytosine concentration. erapeutic drug monitoring is considered standard of care for the use of ucytosine and
it is recommended that serum concentrations be obtained at
72 hours aer therapy initiation, when there are concerns with
adherence, or if there are signs of drug-related toxicities.
Azole Antifungals
erapeutic ranges and clinical considerations. e incidence
of fungal infections has been on the rise as the number of patients
at risk has increased (eg, patients receiving immunosuppressive
195
In vivo and animal studies have noted
196
Flucy-
166,197,198
Additionally,
166,197-199
167,195-197
196,197,200
199
195,196
therapy). Azole antifungal agents are used to treat several dierent fungal infections, including invasive candidiasis, aspergillosis, and mucormycosis. e primary reason for monitoring
azole antifungal drugs is to ensure ecacy and safety as they
have demonstrated wide interpatient pharmacokinetic variability. Suboptimal azole antifungal concentrations have been
associated with treatment failure and fungal breakthrough,
whereas high concentrations have been related to toxicities (eg,
hepatotoxicity).
Itraconazole. Itraconazole concentrations are known to be
relatively low in patients with AIDS or acute leukemia, most
likely due to malabsorption and concurrent administration of
enzyme-inducing drugs.
201
Additionally, absorption of the oral
capsule formulation greatly depends on the gastric pH; itraconazole capsule formulation demonstrates improved absorption
in an acidic environment. is necessitates the administration
of the oral capsule with a full meal or acidic beverage (eg, cola).
Conversely, the oral liquid solution’s absorption is improved
when not taken with food.
196
e newest formulation of itraconazole uses SUper-Bio-Available technology, which enhances
the bioavailability of poorly soluble drugs, thereby increasing
the relative bioavailability of itraconazole to 173% and involves
less interpatient variability in plasma concentrations.
conazole displays nonlinear pharmacokinetics. It undergoes
signicant rst-pass metabolism into several metabolites—
most importantly, hydroxy-itraconazole—with levels approximately double those of itraconazole. Although some isolates
of yeasts and mold are more susceptible to hydroxy-itraconazole or itraconazole, they have comparable in vitro antifungal
activity.
202
It has been noted that mortality and breakthrough
infections are more common with itraconazole trough concentrations <0.5mg/L and toxicity with concentrations >3 mg/L.
Ecacy has been associated with itraconazole concentrations
of 0.5 to 1mg/L. Itraconazole accumulates slowly and reaches
concentrations of 0.5 to 1 mg/L aer 1 to 2 weeks. Due to slow
accumulation, a loading dose is recommended to assist with
reaching therapeutic concentrations sooner, namely in serious
fungal infections. Additionally, itraconazole inhibits CYP3A4,
leading to a number of signicant drug interactions.
interpatient and absorption variability based on the administered formulation, some consider the serum concentration
monitoring of itraconazole to be essential in patients with lifethreatening fungal infections.
205
Measuring itraconazole concentrations is recommended to ensure adequate absorption,
monitor the need for dosage changes (eg, when interacting
medications are added or discontinued), and assess adherenceto therapy. Because of a long elimination half-life (34 to
42 hours aer multiple doses), the concentration of itraconazole can be drawn at any time during a dosing interval once
steady state is reached (at approximately 2 weeks).
206,207
Voriconazole. Voriconazole is a rst-line treatment option
for invasive aspergillosis and other invasive fungal infections.
It exhibits nonlinear pharmacokinetics (Michaelis-Menten)
related to saturable clearance mechanisms. is leads to greatly
variable and unpredictable changes in drug exposure secondary
to dosage adjustments and interpatient pharmacokinetic vari-
196,202
ability.
e most important pharmacodynamic parameter
202,203
204
Due to
Itra-
100 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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is AUC/MIC with a value of >25 associated with clinical ecacy
in infections due to Candida and Aspergillus spp. Voriconazole
has excellent bioavailability; however, it is metabolized by several signicant CYP450 enzymes (ie, CYP2C9, CYP3A4, and
CYP2C19). ese enzymes may have signicant interpatient
variability due to enzyme polymorphism and, therefore, lead
to varying voriconazole concentrations.
196
Suboptimal voriconazole concentrations have been associated with suboptimal
response and treatment failure. Additionally, elevated voriconazole concentrations have been correlated with toxicities, which
include hepatotoxicity, visual disturbances, and hallucinations.
Based on available data, voriconazole concentrations between
1 mg/L and 4 to 6 mg/L are recommended to increase ecacy
and decrease risk of toxicity. A trough concentration (eg, end of
12-hour dosing interval) should be drawn within the rst week
of therapy initiation or dosage adjustment.
196,204,208,209
Posaconazole. Posaconazole is indicated for the treatment of
several invasive fungal infections, including mucormycosis.
Posaconazole is available as an oral suspension, delayed-release
tablet, and IV solution.
210
e oral formulations (oral suspension and delayed-release tablet) are not interchangeable because
of noted pharmacokinetic dierences. e oral formulations
are inuenced by food intake. Additionally, the oral suspension
is inuenced by gastric pH. It is recommended that the oral suspension be given with a high-fat meal to enhance bioavailability
(by 2.6 to 4 times).
204,208
Similar to previously mentioned azole
antifungals, posaconazole demonstrates large interpatient variability in its pharmacokinetic parameters. An exposure- toxicity
relationship is still unknown for posaconazole.
196,202,208,209
Because
of the prolonged half-life of posaconazole (26 to 35 hours),
steadystate is not reached until the end of rst week of therapy,
and serum concentrations can be measured at any time during the interval at that point.
204,208
Greater clinical response to
posaconazole has been related to higher drug concentration
exposure. Although a recommended trough concentration has
not been dened, some have suggested a trough of >0.7 mg/L or
>0.9 mcg/mL for prophylaxis, and a trough of >1 mg/L for primary therapy and >1.25 mg/L for salvage therapy or >1.8 mg/L
in treatment of invasive fungal infections.
202,204
Fluconazole. erapeutic drug monitoring of uconazole is
not required due to predictable concentrations based on currently available data. Additionally, it is less aected by drug–
drug interactions. Of note, an AUC/MIC ratio >25 to 50 is
related to improved clinical outcomes.
196,202,205
Isavuconazole. Although most patients achieve concentrations
>1 mg/L with standard recommended doses, therapeutic drug
monitoring of isavuconazole is not recommended at this time
because of lack of ecacy or toxicity thresholds in the treatment of invasive aspergillosis or mucormycosis.
202,211
Antimycobacterials
Drugs that are FDA-approved and considered rst line as part
of an initial four-drug regimen are isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Of these, isoniazid and rifampin are the most important based on their relatively
high potency and favorable side-eect proles. Second-line
agents that are more toxic must be used if drug resistance
emerges and include ethionamide, cycloserine, capreomycin,
para-aminosalicylic acid, and dapsone.
212
e practice of therapeutic drug monitoring for antituberculosis drugs varies among experts. It is used to provide insight
into drug dosing and dose adjustments. Scenarios in which
therapeutic drug monitoring may be benecial include poor
response despite therapy adherence and drug-susceptible regimens, severe GI abnormalities in which absorption may be questioned, and drug–drug interactions.
213
Low concentrations of
isoniazid and rifampin have been associated with slow disease
response, relapse, and emergence of drug resistance.
214
In fact,
poor treatment outcomes have been related to low tuberculosis
(TB) drug exposure, noting an estimated 9-fold increase in treatment failure.
215
As a result, it is essential that adequate concentrations of these antimycobacterial drugs be present in serum
for eective treatment and avoidance of negative consequences.
is does not always occur, even in patients in whom adherence has been documented.
212
Lower-than-expected concentra
tions of antimycobacterial drugs have been reported in patients
with diabetes and in individuals with HIV infections, which
in some cases was associated with malabsorption.
216-218
ere is
also considerable potential for drug–drug interactions among
the antimycobacterial drugs, given the eects of rifampin, isoniazid, and the uoroquinolones in either inducing or inhibiting cytochrome P450 isozymes.
219
Drugs used to treat patients
with HIV may also contribute to additional drug–drug interaction concerns.
A study in patients without HIV who are infected with TB who
were not responding to treatment as expected showed that 29%
to 68% of them had serum antimycobacterial drug concentrations below target ranges.
220
In another study, a small percentage
of nonresponding patients all showed suboptimal concentrations
of rifampin.
221
Aer dosage adjustments were made, all patients
responded to treatment. e authors recommended that low
serum rifampin concentrations be suspected in patients who do
not respond aer 3 months of supervised drug administration or
earlier in patients with HIV infection, malnutrition, known GI or
malabsorptive disease, or hepatic or renal disease.
Most TB drugs display AUC/MIC as the most important pharmacodynamic parameter; however, the relationship between
dose or serum concentrations and toxicity is not well established
(exceptions include pyrazinamide, ethambutol, and cycloserine). Several TB drugs display signicant interpatient variability,
necessitating therapeutic drug monitoring of these agents to avoid
potential associated treatment failure, relapse, and toxicity.
222
Specialized laboratories have been developed that oer sensitive and specic assays for serum concentrations for the most
commonly used antimycobacterial drugs.
212
As more specic
information about the ecacy of therapeutic drug monitoring
of these drugs becomes available, more laboratories and services
of this type will likely be available.
223
Antiretrovirals
Therapeutic Ranges and Clinical Considerations
Overall, there is a paucity of published literature correlating clinical outcomes in adults infected with HIV and drug
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concentrations. Signicant interpatient variability exists in
regard to pharmacokinetics of antiretroviral drugs. erapeutic
concentration ranges, therefore, have not been established for
most antiretrovirals.
224,225
Furthermore, antiretroviral regimens
are administered as xed doses; therefore, dose adjustments, as
seen with other drug classes requiring therapeutic drug monitoring, may not be feasible or useful.
226
Although routine monitoring of antiretroviral agents is not recommended, there are
some scenarios in which therapeutic drug monitoring should
be considered. ese situations include instances in which
signicant drug–drug or drug–food interactions may lead to
reduced ecacy or toxicities; physiologic and anatomic changes
(eg, GI) that may impair drug absorption or metabolism; pregnancy in which women do not achieve virologic clearance; and
cases in which treatment-experienced patients have developed
virologic failure.
227
ere is some evidence that favors limited
serum concentration monitoring of drugs used in the treatment of HIV-1 infection, in particular, the PIs and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs).
228,229
ese drugs, particularly the PIs, show marked interpatient
variability in their pharmacokinetics, and their serum concentrations correlate with virologic response and failure.
230,231
Asubstudy of the randomized, prospective clinical trial AIDS
erapy Evaluation in the Netherlands showed that patients who
underwent serum drug concentration monitoring for antiretroviral drugs had a signicantly higher likelihood of virological response as compared with those who did not undergo
monitoring.
230
Of note, the study was conducted in antiretroviralnaive patients. e same results have not been shown in subsets
of antiretroviral- experienced patient populations. Assays for
drug concentrations are available commercially for some antiretrovirals although there is a lag time in results being reported.
Minimum concentration (C
tration parameter.
229
Minimum eective concentrations have been
) is the proposed target concen-
min
226,227
determined for the most common PIs based on in vitro determinations of drug concentrations (corrected for serum binding)
required for 50% or 90% inhibition of replication in a patient’s
virus isolate (IC50 or IC90). Attention has turned more recently,
however, to the use of a new parameter that may be a better predictor of response. e inhibitory quotient (IQ) is the ratio of
the trough plasma concentration to the IC50 or IC90.
230
A high IQ
indicates more drug is present in the patient than is needed for a
virologic response, whereas a low IQ indicates inadequate drug
concentrations or a resistant virus. Recent studies show the virologic response may be better related to IQ than to trough concentrations alone.
230
Future studies may focus on the denition
of therapeutic ranges of IQ rather than minimum concentrations.
Some clinicians advocate the monitoring of PI and NNRTIs
in all patients upon the initiation of therapy to ensure adequate
concentrations; others reserve the use for selected situations,
including patients with renal or liver disease, pregnant patients,
children, patients at risk for drug interactions, and patients with
suspected toxicity.
230,232
Sample Timing
Half-lives of NNRTIs average 25 to 50 hours, and steady state is
reached aer a week in most patients.
is reached within 2 days for the PIs, which have half-lives ranging
233
However, a steady state
from 2 to 12 hours.
233
Predose samples are recommended as the
minimum eective concentrations, and IQs are based on the
lowest drug concentration during the dosing interval. ere
may be logistical problems with this timing, however, in cases
in which the drug is administered once daily in the evening.
Some drugs, such as nelnavir, exhibit a lag in their absorption,
such that the lowest concentration actually occurs about an hour
aer administration of the next dose.
Use of Concentrations for Dosage Adjustment
Dosage adjustments of antiretroviral drugs, for the most part,
should result in proportional changes in the trough serum drug
concentration, provided the dosing interval is not altered. As
mentioned previously, antiretroviral doses are xed; therefore,
there is no guidance on dose adjustment based on available
drug concentrations. Reports showing serum drug concentrations to be unpredictable aer dosage adjustments in some
patients suggest that nonadherence with antiretroviral regimens
is a major concern.
231
Serum concentrations of amprenavir, lopi
navir, nelnavir, and saquinavir may be dicult to maintain
above their minimum eective concentrations because of rapid
clearances and large rst-pass eects. Rather than increasing
their dose, ritonavir, a potent inhibitor of CYP3A4-mediated
metabolism in the gut wall and liver, may be coadministered
as a pharmacoenhancer. is results in decreased GI enzyme
metabolism of the PI, higher trough concentrations, and, in
most cases, prolonged elimination half-lives.
234
Protein Binding, Active Metabolites,
and Other Considerations
e serum protein binding of nevirapine and indinavir is 50% to
60%, whereas the protein binding of the other antiretrovirals is
242,245
>90%.
for these drugs in serum.
Albumin and AAG are the primary binding proteins
232
As would be expected, there is considerable variability in the unbound fraction of these drugs in serum.
In addition, AAG concentrations are elevated in patients with
HIV-1 infection and can return to normal with treatment. us,
the same total concentration of the drug would be expected
to reect a lower concentration of response early in treatment
as compared with later. Clearly, total concentrations of the PIs
and NNRTIs should be cautiously interpreted if unusual serum
binding is anticipated, but no clear guidelines are yet available.
Only nelnavir has a metabolite that is known to be active.
Although studies indicate the measurement of the metabolite is
probably not crucial, there is likely to be considerable variability among and within patients in the presence of this metabolite.
Cardiac Drugs
Digoxin
erapeutic range and clinical considerations. Since the
advent of therapeutic drug monitoring, there has been a
dramatic reduction in digoxin toxicity.
is not necessary unless digoxin toxicity is expected, the patient
has declining renal function, there is a suspected change in
pharmacokinetics due to changing condition, or there is an
initiation of concomitant interacting medications.
ally, patients with electrolyte abnormalities (eg, hypokalemia,
236
Routine monitoring
237
Addition-
230
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102 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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hypomagnesemia, and hypercalcemia), hypothyroidism,
myocardial ischemia, and acidotic states are at higher risk of
toxicity. Patients with hyperthyroidism are believed to be more
resistant to digoxin.
30
Digoxin’s inotropic eect is the basis for its use for the management of heart failure, while its chronotropic eects are the basis
for the management of atrial arrhythmias, such as atrial brillation and atrial utter. e commonly reported therapeutic range
is 0.5 to 2 mcg/L in adults and 1 to 2.6 mcg/L in neonates.
76,235,237
e lower end of the range (0.5 to 1 mcg/L) is generally used for
treatment of heart failure.
238
Results of the Digitalis Investigation
Group trial found in a post hoc analysis that concentrations of 0.5
to 0.8 mcg/L in men with heart failure (le ventricular ejection
fraction <46%) reduced hospitalizations.
239
Dosing strategies for
patients with heart failure have been established based on kidney function, age >70 years, ideal body weight, and height.
240-242
Higher serum digoxin concentrations may be required for treatment of atrial arrhythmias (0.8 to 1.5 mcg/L), with concentrations up to 2 mcg/L previously showing benet in some patients.73
More recent studies have shown an increased mortality in patients
treated with digoxin with a serum concentration of >1.2 mcg/L;
however, as noted previously, routine monitoring is not indicated.
Fiy percent of patients with serum digoxin concentrations
>2 mcg/L show some form of digoxin toxicity; toxicity may be
experienced at lower concentrations, and management should
be based on symptoms.
73,243
Symptoms of toxicity include muscle weakness; GI reports (anorexia, nausea, vomiting, abdominal pain, and constipation); CNS eects (headache, insomnia,
confusion, vertigo, and changes in color vision); and serious
cardiovascular eects (second- or third-degree atrioventricular
bradycardia, premature ventricular contractions, and ventricular
tachycardia) (Table5-4).
73,237
Sample timing. e average digoxin half-life in adults with
normal renal function is approximately 2 days; at least 7 days
are recommended to attain a steady state.
237
In the case of treatment of digoxin overdose with digoxin-immune Fab fragments
(a fragment of an antibody that is very specic for digoxin),
blood samples for serum digoxin measurements should not be
obtained sooner than 10 days aer administration of the frag-
235,237
ments.
Samples drawn during the absorption and distribution
phases aer administration of digoxin cannot be appropriately
TABLE 5-4. Digoxin Toxicities
245
Cardiac effects • Arrhythmias
• Sinus bradycardia
CNS/GI effects • Anorexia, nausea, vomiting,
abdominal pain
• Visual disturbances: halos,
photophobia, color perception
dysfunction (red-green or
yellow green), scotomata
• Fatigue, weakness, dizziness,
headache, confusion, delirium,
psychosis
5 –
4.5 –
4 –
3.5 –
3 –
2.5 –
2 –
Serum conc., mcg/L
1.5 –
1 –
0.5 –
0 –
l l l l l
0 6 12 18 24
Digoxin concentration
in serum
Digoxin concentration
in myocardium
Time, hr
FIGURE 5-5. Simulated plot showing concentrations of
digoxin in serum (microgram/liter) and concentrations
in myocardial tissue (units not provided) after a dose of
digoxin at steady state. Tissue concentrations do not
parallel concentrations in serum until at least 6 hours
after the dose.
interpreted by comparison with the usual therapeutic range.
Digoxin concentrations in blood do not reect the more important concentrations in myocardial tissue until at least 6 hours
aer the dose (some say at least 12 hours).
blood samples should be drawn anytime between 6 hours aer
the dose and right before the next dose (Figure5-5). Ideally,
blood samples would be drawn as a trough concentration just
prior to the next dose.
Inappropriate timing of samples for digoxin is problematic.
One study revealed that 55% of the samples submitted to the
laboratory for digoxin analysis lacked clinical value because of
inappropriate timing.
247
In another study, standardization of
digoxin administration and blood sampling times resulted in a
dramatic reduction in inappropriately timed samples (ie, timed
at 5:00 p.m. for digoxin administration and timed at 7:00 a.m. for
blood sampling).
248
Another recommendation is that the laboratory immediately contact the clinician if digoxin concentrations
are >3.5 mcg/L.
237
If it is conrmed that the sample was drawn
too early aer the dose, another sample should be requested. If
monitoring is considered at the initiation of therapy, serum concentrations should be drawn within 12 to 24 hours of the loading
dose; if no loading dose is administered, clinicians should wait 3
to 5 days aer therapy initiation to evaluate concentrations.
should be noted that concentrations drawn aer administering
a loading dose can assist in ensuring adequate concentrations
are achieved; however, they cannot guide maintenance dosing.
Use of concentrations for dose adjustment. Because of the
linear elimination behavior of digoxin, a given increase in
thedaily digoxin dose produces a proportional increase in the
serum concentration at that time during the dosing interval. To
determine steady-state concentrations aer dose adjustments,
obtain a serum concentration 5 to 7 days aer any dose change,
237,245,246
erefore,
249
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CHAPTER 5 • InTERPRETATIon of SERum DRugConCEnTRATIonS 103
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and periodically thereaer, particularly in instances of potential
change in pharmacokinetics, as detailed previously. In patients
with ESRD, steady state may not be obtained for 15 to 20 days.
249
Protein binding, active metabolites, and other considerations.
Digoxin is only 20% to 30% bound to serum proteins.29 erefore, total concentrations in serum will reect the pharmacologically active unbound concentration. e biologic activity
of digoxin metabolites is modest compared with the parent
drug, and variable presence of metabolites should not aect
the interpretation of a digoxin serum concentration.
Other Cardiac Drugs
Amiodarone. Amiodarone is used for the treatment of life-
threatening recurrent ventricular arrhythmias that do not
respond to adequate doses of other antiarrhythmics and is
commonly used in the management of recurrent atrial brillation/utter. e primary metabolite, desethylamiodarone
(DEA), has similar electrophysiologic properties as amiodarone and accumulates at concentrations similar to or higher
than the parent drug, especially in patients with renal failure.
Concentrations of amiodarone and desethylamiodarone demonstrate linear pharmacokinetics with increasing doses of amiodarone.
250
e concentration versus eect relationship for
amiodarone is poorly dened; some say that serum concentrations between 0.5 and 2.5 mg/L are associated with eectiveness
with minimal toxicity.
reported at plasma concentrations >2.5 mg/L.
235
e occurrence of toxicity has been
251-253
Laboratories
that measure serum amiodarone concentrations report only the
parent drug, despite high concentrations of the active metabolite. In general, therapeutic drug monitoring of amiodarone is of
limited benet because activity of the drug is mostly associated
with concentrations in the tissue.
246
Serum concentrations might
be most useful in cases of suspected nonadherence or toxicity.
Lidocaine. Lidocaine is a type 1B antiarrhythmic used as
second-line therapy for the acute treatment for ventricular
tachycardia and brillation with modern use primarily as olabel for pain. e therapeutic range is generally considered
to be 1.5 to 5 mg/L with concentrations >6 mg/L considered
to be toxic.
73,238,255
Minor side eects—drowsiness, dizziness,
euphoria, and paresthesias—may be observed at serum concentrations >3 mg/L. More serious side eects observed at
concentrations >6 mg/L include muscle twitching, confusion,
agitation, and psychoses, whereas cardiovascular depression,
atrioventricular block, hypotension, seizures, and coma may
be observed at concentrations >8 mg/L.
73,237,255
Lidocaine concentrations are not monitored as commonly with short-term
use because its eect (abolishment of the electrocardiogrammonitored arrhythmia or pain relief) is easy to directly observe
and is generally not indicated when used for pain management
given administration is generally limited to single doses. Electrocardiogram monitoring may be indicated and is typically
part of institutional protocols. Indications for drug concentration monitoring should be restricted to situations in which the
expected response is not evident or when decreased hepatic
clearance is suspected or anticipated: liver disease, heart failure, advanced age, severe trauma, and concurrent drugs such
as β-adrenergic blockers, uvoxamine, or cimetidine.
235
235,237,254
Additionally, serum concentrations should be monitored in
the case of extended use, although infusion duration beyond
6 hours is not recommended.
256
e half-life of lidocaine
ranges from 1.5 hours to as long as 5 hours in patients with
liver disease; thus, steady state may not be attained for 18 to
24 hours.
73,255
Because lidocaine is administered as a continuous infusion, there are no uctuations in concentrations, and
blood lidocaine serum concentrations can be drawn anytime
once steady state is reached. Adjustments of lidocaine infusion rate should result in a proportional increase in lidocaine
serum concentration. e unbound percentage of lidocaine is
normally 30% but can range from 10% to 40% due to variations in AAG concentrations.
73,237
e combination of higher
total concentrations of lidocaine during prolonged infusions
and a lower unbound fraction mean that unbound lidocaine
concentrations during prolonged infusions are probably thera-
257
peutic.
e monoethylglycinexylidide metabolite of lidocaine
has 80% to 90% of the antiarrhythmic potency of lidocaine,
and its concentration accumulates in renal failure.
Mexiletine. Several early studies with mexiletine have estab-
73,254
lished a linear association with serum concentrations and toxicity. Currently, the clinically used therapeutic range is 0.8 to
2mcg/mL; however, it should be noted the establishment of
this therapeutic range was in the prophylaxis of ventricular
tachycardia aer myocardial infarction, not in the treatment of
ventricular tachycardia, which is the most common use.
Despite the potential benet of therapeutic drug monitoring
for mexiletine in some patient populations, specically those
with hepatic dysfunction, serum concentrations are not widely
used and when they are used, they do not oen result in a
change to therapy.
Procainamide. Although the oral formulation is no longer avail-
able in the United States, the IV form of procainamide is used
for patients with atrial brillation or utter who require cardioversion.
261,262
e therapeutic range of procainamide is complicated by the presence of an active metabolite, NAPA, which has
dierent electrophysiologic properties than the parent drug.
Procainamide is a type 1A antiarrhythmic, whereas NAPA is
a type III antiarrhythmic.
73,235,237
e enzyme that acetylates
procainamide is bimodally distributed, such that patients are
either slow or fast acetylators. In addition, NAPA depends more
on the kidneys for elimination than procainamide.
247,263
patients respond when serum procainamide concentrations are
between 4 and 8 mg/L; some patients receive additional benet
with concentrations up to 12 mg/L.
261
erehave been reports
of patients requiring concentrations between 15 and 20 mg/L
without adverse eects.
261
Serum concentrations of NAPA associated with ecacy are reported to be as low as 5 mg/L and as
high as 30 mg/L. Most clinicians consider toxic NAPA concentrations to be >30 to 40 mg/L.
237
Some clinicians feel that NAPA
does not need to be monitored except in patients with renal
impairment.
261
Most laboratories automatically measure both
procainamide and NAPA concentrations in the same sample.
e practice of summing the two concentrations and comparing
it to a therapeutic range for summed procainamide and NAPA
(oen reported as 10 to 30mg/L) is to be discouraged.
To do this validly, the molar units of the two chemicals would
258-260
Most
73,237,261
104 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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need to be used.
pare each chemical to its own reference range.
238
e best practice is to independently com-
73,237,265
Side eects
to procainamide and NAPA are similar. Anorexia, nausea, vomiting, diarrhea, weakness, and hypotension may be seen with
procainamide concentrations >8 mg/L, although concentrations
>12 mg/L may be associated with more serious adverse eects:
heart block, ventricular conduction disturbances, new ventricular arrhythmias, and even cardiac arrest.73 Indications for procainamide and NAPA serum concentration monitoring include
recurrence of arrhythmias that were previously controlled,
suspected toxicity or overdose, anticipated pharmacokinetic
alterationscaused by drug–drug interactions (including amiodarone, cimetidine, ethanol, ooxacin, quinidine, ranitidine, and
trimethoprim), and disease state changes (renal failure or heart
failure, in particular).
73,237,261,263
e half-life of procainamide in
adults without renal impairment or heart failure ranges from
2.5 hours (fast acetylator) to 5 hours (slow acetylator).
73,237
e
half-life of NAPA is longer, averaging 6 hours in patients with
normal renal function and 30 hours or longer in patients with
renal impairment.
73,261
us, a steady state of both chemicals is
not observed until at least 18 hours in patients with good renal
function or as long as 4 days in renal impairment. e lower
clearance of procainamide at higher doses has been attributed to
nonlinear hepatic clearance.
264
e clinician should be aware that
increases in infusion rate may produce somewhat greater-thanproportional increases in serum procainamide concentration
in some patients, particularly those with serum concentrations
at the upper end of the therapeutic range. Procainamide is only
10% to 20% bound to serum proteins.
235,238
us, total procainamide and NAPA concentrations always reect the pharmacologically active unbound concentrations of these drugs.
Quinidine. e therapeutic range of quinidine for treatment
of severe malaria due to Plasmodium falciparum is reported as
3 to 6 mg/L.
265
When used in combination with verapamil for
prevention of atrial brillation, the therapeutic range of quinidine is reported to be 2 to 6 mg/L, although use of quinidine
is not strongly recommended due to a 3-fold increased risk
of cardiac death when compared with other antiarrhythmic
265-268
agents.
Common side eects are anorexia, nausea, and
diarrhea; more serious side eects include cinchonism, hypotension, and ventricular arrhythmias.
73,237
Torsades de pointes
is more likely to occur at lower concentrations of the therapeutic range, thus complicating the interpretation of quinidine
concentrations.
235
Indications for monitoring of quinidine
concentrations include therapeutic conrmation, suspected
toxicity, recurrence of arrhythmias, drug–drug interactions,
suspected nonadherence, and changes in formulation.
73,237,268
e half-life of quinidine is reported to range from 4 to 8 hours
in adults and up to 10 hours in patients with liver disease.
Steady state should be attained within 2 or 3 days in patients
with normal hepatic function, and most clinicians agree that
samples should be drawn as a trough within 1 hour of the
next dose.
between 70% and 80% bound to albumin and AAG.
73,235,237,268
Quinidine is a weak base that is normally
237
e
unbound fraction of quinidine was shown to be decreased in
patients with atrial brillation or atrial utter, and the unbound
quinidine concentration was shown to correlate better with
electrocardiogram interval changes than total quinidine.
A total quinidine concentration that is >5 mg/L could be therapeutic with respect to unbound quinidine concentration. e
dihydroquinidine impurity may be present in amounts that
are between 10% and 15% of the labeled amount of quinidine
and is believed to have similar electrophysiologic properties as
quinidine.
237
e 3-hydroxyquinidine metabolite has activity
that is less than the parent (anywhere between 20% and 80%
have been reported), is less highly bound to serum proteins,
and demonstrates accumulation with chronic treatment.
Cytotoxic Drugs
Although cytotoxic drugs have some characteristics that make
them ideal candidates for therapeutic drug monitoring (narrow
therapeutic indices and variable pharmacokinetics), they have
many more characteristics that make therapeutic drug monitoring dicult or unsuitable.
diate indication of pharmacologic eect to aid denition of a
therapeutic range (the ultimate outcome of cure could be years).
ey are given in combination with other cytotoxic drugs, such
that concentration versus eect relationships for any single drug
is dicult to isolate. ey are used to treat cancer, which is a
highly heterogeneous group of diseases, each possibly having
its own concentration-versus-eect relationships. In summary,
cytotoxic drugs are not routinely monitored because they need
more clearly dened therapeutic ranges. If ranges are established, they are usually more helpful to avoid toxicity than to
dene zones for ecacy.
Methotrexate
erapeutic range. Methotrexate is the only antimetabolite drug
for which serum concentrations are routinely monitored.
acts by blocking the conversion of intracellular folate to reduced
folate cofactors necessary for cell replication. Although cancer
cells are more susceptible to the toxic eects of methotrexate, healthy host cells are also aected by prolonged exposure
to methotrexate. It is for this reason that leucovorin, a folate
analogue that prevents further cell damage, is administered
following high-dose methotrexate treatments.
ments of serum methotrexate concentrations at critical times
aer high-dose methotrexate regimens are imperative to guide
the amount and duration of leucovorin rescue treatments, thus
preventing methotrexate toxicity. Institution of protocols for
methotrexate serum concentration monitoring for this purpose
has resulted in dramatic reductions in high-dose methotrexaterelated toxicity and mortality.
Although it is known that methotrexate concentrations must
be suciently high to prevent relapse of the malignancy, the
specic range of concentrations related to ecacy has been difcult to dene.
trexate concentrations and toxicity has been much more clearly
dened. Prolonged high concentrations of methotrexate can
lead to nephrotoxicity, myelosuppression, GI mucositis, and
liver cirrhosis.
erally indicated when relatively low doses of methotrexate are
given for chronic diseases such as rheumatoid arthritis, asthma,
and psoriasis and maintenance for certain cancers.
274
However, the relationship between metho-
272,274
Serum concentration monitoring is not gen-
272,273
ey lack a simple, imme-
272
274
Measure-
269,270
263,271
272
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Sample timing. e timing of samples for determination of
methotrexate concentrations depends highly on the administration schedule. As one example of such a protocol, a
methotrexate dose may be administered by IV infusion over
36 hours followed by a regimen of leucovorin doses administered overthe next 72 hours.
275
Additional or larger leucovorin
doses might be given depending on the methotrexate concentrations in samples drawn at various times aer the start of
the methotrexate infusion. It is important that methotrexate
concentrations continue to be monitored until they are below
the critical concentrations (usually between 0.05 µM/L and
0.1µM/L).
272,275
Use of concentrations for dosage adjustment. Methotrexate
dose adjustments and leucovorin doses are based on institution-specic protocols.
Protein binding, active metabolites, and other considerations.
Methotrexate binding to albumin in serum ranges from 20%
272
to 57%.
Although studies have shown the unbound fraction
of methotrexate to be increased by concomitant administration of nonsteroidal anti-inammatory drugs, salicylate, sulfonamides, and probenecid, the implications for interpretation
of methotrexate concentrations are probably negligible.
275
e
methotrexate metabolite, 7-hydroxymethotrexate, has only
one-one hundredth the activity of methotrexate but may cause
nephrotoxicity due to precipitation in the renal tubules.
274
Other Cytotoxic Drugs
Petros and Evans provide an excellent summary of cytotoxic
drugs and the types of measurements that have been used to
predict their toxicity and response.
response or toxicity and serum concentration or AUC versus
time curve for total drug have been shown for busulfan, carboplatin, cisplatin, cyclophosphamide, docetaxel, etoposide,
5-uorouracil, irinotecan, paclitaxel, teniposide, topotecan, and
vincristine.
274,276,277
e strong correlation between busulfan AUC
and bone marrow transplant outcome led the FDA to include
instructions for AUC monitoring in the package insert for IV
busulfan. Unbound AUC values for etoposide and teniposide,
which demonstrate concentration-dependent binding, correlate
more strongly with toxicity than corresponding total plasma
AUC values.
278
Systemic drug clearance has been predictive of
response/toxicity for amsacrine, uorouracil, methotrexate,
and teniposide.
274,279
Steady-state average serum concentrations or concentrations at designated postdose times have also
been predictive of response/toxicity for cisplatin, etoposide, and
methotrexate.
274
Finally, concentrations of cytosine-arabinoside
metabolite in leukemic blasts and concentrations of mercaptopurine metabolite in red blood cells have been predictive
of response or toxicity for these drugs. Correlations between
systemic exposure and response/toxicity for cyclophosphamide,
carmustine, and thiotepa have also been reported.
doxorubicin has been found to be associated with peak plasma
concentrations.
281
Although most studies up to this point have
focused on the use of cytotoxic drug concentration measurements to minimize toxicity, future studies will increasingly focus
on the use of drug concentrations to maximize ecacy.
274
Correlations between the
280
Toxicity of
Immunosuppressant Drugs
Immunosuppressant drugs are used for a variety of indications,
including prevention of rejection in organ transplant or treatment
of autoimmune diseases. erapeutic drug monitoring is widely
used to ensure adequate doses are attained and to avoid toxicity.
Although this chapter discusses commonly used therapeutic
ranges, individualized targets may be used based upon patientspecic factors, time from transplant, or institutional protocols.
Cyclosporine
erapeutic range and clinical considerations. Cyclosporine is
a potent cyclic polypeptide used for prevention of organ rejection in patients who have received kidney, liver, bone marrow,
or heart transplants.
psoriasis, rheumatoid arthritis, and other autoimmune diseases.
e therapeutic range of cyclosporine depends highly on the
specimen (whole blood or serum/plasma) and assay. Whole
blood is preferred given that cyclosporine binds to erythrocytes
and lipoproteins. Most transplant centers use whole blood with
one of the more specic assays—high-performance liquid chromatography or immunoassays that use monoclonal antibodies
(monoclonal radioimmunoassay or monoclonal uorescence
polarization immunoassay).
peutic range for whole blood troughs using one of these specic
methods is 100 to 500 mcg/L.
of this range may be desired initially aer transplantation and
in patients at high risk for rejection.
also depends on the specic organ transplantation procedure
and the stage of treatment aer surgery (higher concentrations
during induction and lower concentrations during maintenance
to minimize side eects) as well as comedications.
it is important that the therapeutic range guidelines established
by each center be used. Although most centers still use singletrough concentrations to adjust cyclosporine doses, the area
under the blood concentration versus time curve is believed to
be a more sensitive predictor of clinical outcome.
have investigated the use of single cyclosporine concentrations
measured 2 hours aer the dose as a surrogate for the AUC value
suggest a better clinical outcome as compared with the use of
single-trough concentrations.
Cyclosporine has a narrow therapeutic index and extremely
variable pharmacokinetics among and within patients. e
implications of ineective therapy and adverse reactions are
serious. us, it is imperative that cyclosporine concentrations
be monitored in all patients starting immediately aer transplant
surgery. e primary side eects associated with high cyclosporine blood concentrations are nephrotoxicity, neurotoxicity,
hypertension, hyperlipidemia, hirsutism, and gingival hyper-
73,285,287
plasia.
Blood cyclosporine concentrations should also be
monitored when there is a dosage adjustment, signs of rejection
or adverse reactions, suspected nonadherence, or the initiation
or discontinuation of drugs known to induce or inhibit cyclosporine metabolism.
Sample timing. Monitoring is oen done immediately aer sur-
gery before a steady state is reached. Initially, concentrations may
be obtained daily or every other day, then every 3 to 5 days, and
282
It is also used for the management of
73,283,284
e commonly cited thera-
73,285
Troughs at the higher end
285
e therapeutic range
73,284-287
287
Studies that
283,288,289
285,287
us,
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