التقدير الدوائي
THERAPEUTIC DRUG MONITORING
PATIENT
DATA/BACKGROUND:
Please
provide some guidelines on when to draw serum levels and the therapeutic
ranges for the aminoglycosides, cyclosporine, vancomycin, lithium,
quinidine, digoxin, procainamide, chloramphenicol, quinidine, and the
antiepileptics.
RESPONSE:
Therapeutic
drug monitoring is the process of using drug concentrations,
pharmacokinetic principles, and pharmacodynamic criteria to optimize drug
therapy in individual patients. Optimization is primarily accomplished by
minimizing the potential for toxicity and increasing the probability of
the desired therapeutic effect. Misconceptions exist surrounding the use
of therapeutic ranges such as the assumption that the therapeutic ranges
for most drugs have been well defined from controlled clinical trials.
Another misconception is that concentrations in the therapeutic range will
always result in the desired clinical response. A therapeutic range should
never be considered in absolute terms (Evans et al, 1986).
A
variety of factors exist which influence the interpretation of drug
levels: time, route, and dose of the drug, the time levels are obtained,
handling and storage conditions of samples, precision and accuracy of the
analytical method, validity of pharmacokinetic models and assumptions,
concurrent drug therapy, and the individual's disease state (or other
concurrent disease states) and biological tolerance to drug therapy (Evans
et al, 1986).
AMINOGLYCOSIDES
THERAPEUTIC
RANGE FOR AMINOGLYCOSIDES
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DRUG
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PEAK
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TROUGH
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Soft
Tissue and other less severe Infections
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Life
Threatening Infections
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Soft
Tissue and other less severe Infections
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Life
Threatening Infections
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12-16
mcg/mL |
25-35
mcg/mL |
1-4
mcg/mL |
Less
than 10 mcg/mL |
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5-8
mcg/mL |
8-10
mcg/ml |
1
mcg/mL |
1-2
mcg/mL |
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5-8
mcg/mL |
8-10
mcg/mL |
1
mcg/mL |
1-2
mcg/mL |
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5-8
mcg/mL |
8-10
mcg/mL |
1
mcg/mL |
1-2
mcg/mL |
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ELIMINATION HALF-LIFE:
Normal renal function: 2-3 hours (Strongly dependent on renal function)
VOLUME OF DISTRIBUTION: 0.25 liter/kilogram
PHARMACOKINETIC MODEL: linear; 2 compartment*, with significant distribution
phase (Evans et al, 1986; Winters, 1988).
*Patients in renal failure may exhibit 3 compartment
pharmacokinetics (Evans et al, 1986).
TIMING OF SAMPLES (under steady state conditions):
Peak: 1 hour after initiation of a 30-minute infusion. Generally,
an acceptable infusion time ranges from 20 to 40 minutes;
however, if an infusion time is greater than 40 minutes,
peak levels should be obtained 30 minutes after the
completion of an infusion (Winters, 1988).*
Trough: immediately prior to the next dose
(Evans et al, 1986; Dudley, 1989).
*
Some clinicians recommend the collection of blood samples 1 hour after the
initiation of a 15- to 45-minute intravenous infusion to allow for the
completion of the distribution phase (Dudley, 1989).
INTERPRETATION
O
The
relationship between serum aminoglycoside concentration and toxicity has
been controversial. A higher risk of oto- and nephrotoxicity has generally
been associated with elevated peak and trough serum concentrations
(Dudley, 1989; Evans et al, 1986). For GENTAMICIN, TOBRAMYCIN, and
NETILMICIN, the risk of ototoxicity and nephrotoxicity is elevated if peak
concentrations are consistently maintained above 12 to 14 mcg/mL. For
AMIKACIN, peak concentrations above 32 to 34 mcg/mL have been associated
with a higher risk of oto- and nephrotoxicity (Evans et al, 1986). For
GENTAMICIN, tobramycin, and netilmicin trough levels greater than 2 mcg/mL
have been associated with a higher incidence of ototoxicity and
nephrotoxicity. Trough levels exceeding 8 to 10 mcg/mL for amikacin are
associated with a higher risk of toxicity (Dudley, 1989; Evans et al,
1986). Peak and trough serum levels should only be utilized as guidelines,
not as absolute values.
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ANTIEPILEPTIC AGENTS:
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CARBAMAZEPINE:(click
for more information) |
THERAPEUTIC RANGE: 4 to 12 mcg/mL (Bauer, 1989; Garnett, 1989;
Evans et al, 1986; Lott,1988).
ELIMINATION HALF-LIFE: 15 hours at steady state (Winters,1988)
VOLUME OF DISTRIBUTION: 1.4 liters/kilogram (Winters, 1988)
INTERPRETATION:
Optimal
serum concentrations of carbamazepine vary considerably between patients
(Bauer, 1989; Garnett, 1989; Evans et al, 1986; Lott, 1988). Once steady
state has been achieved, plasma samples may be obtained any time relative
to the dose. Due to auto-induction of metabolism the half-life will change
during the first few weeks of therapy. Plasma levels drawn during the
initiation of therapy may be useful in determining a relationship between
patient response and concentration, but they may not be useful in
predicting the long-term response of plasma levels to a particular dose
(Winters, 1988).
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ETHOSUXIMIDE: |
THERAPEUTIC RANGE: 40 to 100 mcg/mL (Bauer, 1989; Garnett, 1989;
Lott, 1988; Evans et al, 1986).
ELIMINATION HALF-LIFE:
Adult: 50 hours
Child: 30 hours (Winters, 1988)
VOLUME OF DISTRIBUTION: 0.7 liter/kilogram (Winters, 1988)
TIMING OF SAMPLES: trough levels are suggested for consistency, but not
crucial because of the long half-life (Winters, 1988)
INTERPRETATION:
Steady
state will generally be attained in 7 to 10 days after the maintenance
dose has been established. Many patients with absence seizures respond at
a concentration in the 125 to 150 mcg/mL range.
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PHENOBARBITAL:(click
for more information) |
THERAPEUTIC RANGE: 10 to 25 mcg/mL (possibly up to 40 mcg/mL)
(Bauer, 1989; Garnett, 1989; Lott, 1988)
ELIMINATION HALF-LIFE: 5 days (Winters, 1988)
VOLUME OF DISTRIBUTION: 0.7 liter/kilogram (Winters, 1988)
PHARMACOKINETIC MODEL: 3 compartments (Evans et al, 1986)
TIMING OF SAMPLES: just prior to the next dose, but timing is not critical
(Evans et al, 1986;Winters, 1988); however, if
administered intravenously the sample should be taken at
least 1 hour after infusion avoid the distribution phase
(Winters, 1988).
INTERPRETATION:
Serum
concentrations of phenobarbital will reach steady state about 20 to 30
days after initiation of therapy. At that time, serum levels should be
checked and the patient reassessed. Although it is ideal to measure the
concentration just prior to each daily dose, phenobarbital's half-life is
so long, daily fluctuations are minor; therefore, serum levels may be
obtained at any convenient time (Evans et al, 1986). Plasma levels drawn
in the first 1 to 2 weeks of therapy are not useful for predicting the
eventual steady state concentrations
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PHENYTOIN:(click
for more information) |
THERAPEUTIC RANGE: 10 to 20 mcg/mL (Evans et al, 1986; Garnett,1989;Lott, 1988)
ELIMINATION HALF-LIFE: varies with plasma concentration (Winters, 1988).
VOLUME OF DISTRIBUTION: 0.65 liter/kilogram (Winters, 1988).
PHARMACOKINETIC MODEL: nonlinear (capacity limited metabolism)
(Evans et al, 1986)
TIMING OF DOSE: just prior to the next dose (Evans et al, 1986; Garnett, 1989;
Lott, 1988)
INTERPRETATION:
There
are a few patients who are seizure free with concentrations below 10
mcg/mL, therefore, clinical evaluation of the patient should also be
considered when interpreting serum levels (Evans et al, 1986; Garnett,
1989; Lott, 1988). Trough levels are generally used to monitor therapy.
Peak phenytoin levels may be helpful in a patient who may be experiencing
side effects (Garnett, 1989).
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VALPROIC
ACID:(click
for more information) |
THERAPEUTIC RANGE: 30 to 100 mcg/mL (possibly up to 150 mcg/mL or greater)
(Bauer, 1989; Garnett, 1989;Lott, 1988; Evans et al, 1986).
ELIMINATION HALF-LIFE:
Adult: 10 to 12 hours
Child: 6 to 8 hours (Winters, 1988).
VOLUME OF DISTRIBUTION: 0.14 liter/kilogram (ranges between 0.1 and 0.5 L/kg)
(Winters, 1988).
PHARMACOKINETIC MODEL: 2 compartments, rapid distribution phase
(Evans et al, 1986)
TIMING OF SAMPLES: prior to the next dose (Winters, 1988; Evans et al, 1986).
INTERPRETATION:
Plasma
concentrations of valproic acid should be drawn 2 to 4 days after
initiating therapy or changing therapy (adding other antiepileptic drugs,
changing the dose) (Winters, 1988). Valproic acid concentrations may vary
up to 100% over a single dosing interval. Therefore valproic acid levels
should be taken at the same time in relationship to dosing. The optimal
time would be just prior to the morning dose, but this is not always
practical (Evans et al, 1986).
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CARDIAC
DRUGS
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DIGOXIN:(click
for more information) |
THERAPEUTIC RANGE: 0.5 to 2 ng/mL (Bauer, 1989; Evans et al, 1986).
ELIMINATION HALF-LIFE: 2 days (Winters, 1988)
VOLUME OF DISTRIBUTION: 7.3 liters/kilogram (Winters, 1988)
PHARMACOKINETIC MODEL: 2 compartments (Winters, 1988)
TIMING OF SAMPLES: at least 6 to 8 hours after the dose
(preferably 12 to 24 hours) (Evans et al,1986).
INTERPRETATION:
Any
adjustment in dose requires a period 4 to 5 times the half-life (8 to 10
days) before new steady state conditions are achieved (Evans et al, 1986).
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PROCAINAMIDE:(click
for more information) |
THERAPEUTIC RANGE:
Ventricular arrhythmias: 4 to 10 mg/L (Auriccho,1988;Evans et al, 1986).
ELIMINATION HALF-LIFE: 3.3 hours (Evans et al, 1986)
VOLUME OF DISTRIBUTION: 2 liters/kilogram (Evans et al, 1986)
PHARMACOKINETIC MODEL: 2 compartments (Evans et al, 1986)
TIMING OF SAMPLES:
Oral: prior to the next dose
Intravenous (using the 2-infusion technique):
2 and 12 hours after starting therapy and every 24 hours thereafter
(Evans et al, 1986).
INTERPRETATION:
In
patients with normal renal function steady state procainamide levels are
attained 12 to 18 hours after initiating oral therapy. Some patients,
particularly those with ventricular tachycardia associated with chronic
heart disease may require and tolerate higher procainamide concentrations
of 10 to 20 mg/L (these guidelines do not include the use of NAPA levels).
The 2-infusion technique for the intravenous administration of
procainamide was designed to rapidly and safely attain plasma procainamide
levels in the range of 4 to 8 mg/L (a loading infusion over 1 hour
followed by a maintenance infusion). (Evans et al, 1986).
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QUINIDINE:(click
for more information) |
THERAPEUTIC RANGE (assay method dependent):
Nonspecific assays (protein precipitation method): 3 to 8 mcg/mL
Specific assays (thin layer chromatography or high performance liquid
chromatography): 1 to 4 mcg/mL (Auricchio, 1988; Evans et al, 1986).
ELIMINATION HALF-LIFE: 7 hours (Winters, 1988)
VOLUME OF DISTRIBUTION: 2.7-3 liters/kilogram (Winters, 1988)
PHARMACOKINETIC MODEL: 2 compartments (Evans et al, 1986)
TIMING OF SAMPLES: prior to dose (Winters, 1988)
INTERPRETATION:
A
plasma concentration should be drawn at least 24 hours after initiating
quinidine therapy, unless signs of toxicity develop. If toxicity appears,
a plasma level will assist in determining if the dose should be reduced or
held (Winters, 1988). The range of therapeutic efficacy for quinidine is
highly dependent on the specificity of the assay used and by the presence
of active metabolite(s). The therapeutic range for quinidine when
determined with a relatively nonspecific assay is generally higher and
wider than ranges that are determined by more specific procedures
(Auricchio, 1988; Evans et al, 1986).
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CHLORAMPHENICOL:(click
for more information) |
THERAPEUTIC RANGE: 10 to 25 mcg/mL (Dudley, 1989; Evans et al, 1986).
ELIMINATION HALF-LIFE:
Adult: 2.25-5.1 hours
Child: 1.61-10.1 hours
(Evans et al, 1986)
VOLUME OF DISTRIBUTION:
Adult: 0.55-0.92 liter/kilogram
Child: 0.63-1.55 liter/kilogram
(Evans et al, 1986)
TIMING OF SAMPLES:
Oral: peak level 1.5 to 3 hours after dose
Intravenous: peak level 0.5 to 1.5 hours after the completion of a 30-minute
intravenous infusion (Dudley, 1989; Evans et al, 1986).
INTERPRETATIO
In
an adult, monitoring of chloramphenicol levels should start 12 to 24 hours
after starting therapy; in an infant after 2 to 3 days (Evans et al,
1986). No data exist to correlate serum concentrations to efficacy (Bauer,
1989; Dudley, 1989; Evans et al, 1986). The infusion method and repeated
therapy should be taken into account when monitoring chloramphenicol
concentrations. Inter- and intrapatient variation in chloramphenicol
pharmacokinetics and a narrow therapeutic index support the need to
individualize chloramphenicol therapy. Peak concentrations following the
administration of chloramphenicol succinate intravenously may be variable
due to variable rates of hydrolysis, rates of administration, and the site
of infusion (Dudley, 1989; Evans et al, 1986).
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CYCLOSPORINE:(click
for more information) |
THERAPEUTIC RANGE:
Polyclonal Radioimmunoassay: 300 to 800 ng/mL
High Performance Liquid Chromatography: 100 to 150 ng/mL
Monoclonal Radioimmunoassay: 95 to 205 ng/mL
(McMillan, 1989)
ELIMINATION HALF-LIFE: 19 hours (Prod Info Sandimmune(R),1991)
VOLUME OF DISTRIBUTION: 3.5 to 13 liters/kilogram
(Tech Info Sandimmune(R), 1991)
PHARMACOKINETIC MODEL: linear at therapeutic doses (may Exhibit nonlinear
characteristics at toxic blood levels) (Evans et al, 1986)
TIMING OF SAMPLES: just prior to dose on a 12- or 24-hour Dosing interval
(Evans et al, 1986; Draxler & Canafax, 1988)
INTERPRETATION:
Blood
levels should be monitored 2 to 3 times during the first few weeks of
therapy or if the route of administration is changed (Draxler &
Canafax, 1988; Evans et al, 1986). After several months, stable patients
can be monitored less frequently. After cyclosporine has reached steady
state, trough concentrations yield the most useful information for
therapeutic monitoring (Evans et al, 1986). The therapeutic range of
cyclosporine levels vary according to the assay technique used. The
polyclonal radioimmunoassay (RIA) method is less specific for cyclosporine
than high performance liquid chromatography (HPLC). Metabolites of
cyclosporine are also detected by polyclonal RIA. Polyclonal RIA may be
faster and easier to use than HPLC. Monoclonal RIA is more specific for
cyclosporine than monoclonal RIA; however, it has not been used clinically
as commonly as the other two methods. Cyclosporine levels should be
monitored in whole blood because cyclosporine is significantly bound to
the cellular component of blood and plasma cyclosporine levels are subject
to change with varying temperature (McMillan, 1989; Rodighiero, 1989). A
diurnal variation in the clearance of cyclosporine appears to exist,
therefore the concentration of this agent should be monitored at a
specific time of the day (Draxler & Canafax, 1988). A technique for
monitoring cyclosporine therapy by measuring the area under the plasma
concentration-time curve has been studied (Grevel et al, 1989; Grevel
& Kahan, 1991). However, this technique requires a large number of
venipunctures and assays for each dosing period which may not be practical
for many clinical settings.
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LITHIUM:(click
for more information) |
THERPAEUTIC RANGE: 0.3 to 1.3 mEq/L (Evans et al, 1986)
ELIMINATION HALF-LIFE: 20 hours (Winters, 1988)
VOLUME OF DISTRIBUTION: 0.7 liter/kilogram (Winters, 1988)
PHARMACOKINETIC MODEL: linear, 2 compartment (Winters, 1988)
TIMING OF SAMPLES: in the morning before the dose is taken
and at least 12 hours after the evening
dose (Evans et al, 1986)
INTERPRETATION:
Samples
should be obtained under steady state conditions (therapy constant for at
least 7 days). However, the therapeutic effect may not appear for 14 to 21
days (Winters, 1988). Controversy surrounds the therapeutic range of
lithium due to a lack of standards of blood test sampling (Evans et al,
1986). For treating acute episodes, some clinicians have recommended
lithium levels of 0.8 to 1.5 mEq/L and 0.6 to 1.2 mEq/L for maintenance.
Initially, lithium levels should be monitored every 4 to 7 days during
titration and every 1 to 3 months thereafter (Saklad & Kastenholz,
1988).
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THEOPHYLLINE:(click for more information)
THERAPEUTIC RANGE: 10 to 20 micrograms/milliliter (peak serum concentration) to prevent
symptoms and decrease the need for rescue therapy in patients with chronic
asthma on theophylline monotherapy (Weinberger & Hendeles, 1996).
However, some patients may experience relief with lower concentrations
(Weinberger & Hendeles, 1996).
ELIMINATION HALF-LIFE: 54 to 76 hours, premature neonates ; 1.2 to 7 hours, children ; 6 to 12
hours, adults
VOLUME OF DISTRIBUTION (Vd): 450 mL/kg (Hendeles et al, 1995; Koup et al, 1976; Levy et al,
1974)
TIME TO PEAK SERUM CONCENTRATION (Weinberger & Hendeles, 1996): (1) Slo-bid Gyrocap
capsule- 3 to 7 hours after morning dose when given every 12 hours. (2)
Theo-24 capsul Variable depending on whether taken in the morning after an
overnight fast, after breakfast, or in the evening. (3) Theo-Dur tablet- 3 to 7
hours after morning dose when given every 12 hours. (4) Uni-Dur tablet- 8 to
12 hours after once-daily evening dose. (5) Uniphyl tablet- 8 to 12 hours after
once-daily evening dose.
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Repeat serum concentrations every 6 to 12 months. More frequent intervals may be necessary if the patient's condition is unstable or factors that alter elimination are present (Prod Info Slo-Phyllin(R) tablets and syrup, 2000; Prod Info Theolair-SR theophylline sustained- release tablets, 2000; Prod Info Slo-bid Gyrocaps theophylline extended release capsules, 2000; Prod Info SloPhyllin GG theophylline- guaifenesin syrup, 2000). |
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Only use results from laboratories that measure serum levels in duplicate. If results are inconsistent with the clinical situation, repeat the measurement before increasing the dose (Hendeles & Weinberger, 1983). |
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PATIENT DATA/BACKGROUND: |
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RESPONSE: |
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Serum theophylline levels are an invaluable monitoring tool in theophylline dosing. Dosing of theophylline may be complicated due to the extensive variation in bioavailability among patients. Theophylline has a relatively low therapeutic index. Therefore, appropriate dosing is critical, and should be based on patient response and tolerance, pulmonary function, and serum theophylline concentrations (AHFS, 1990). |
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In general, therapeutic serum theophylline concentrations range from 5 to 15 ug/mL. Toxicity usually appears at concentrations above 20 ug/mL. Peak theophylline levels are better correlated with efficacy and toxicity than trough levels (Kelly & Smith, 1988; Hendeles et al, 1986). The recommended time to obtain a peak serum theophylline concentration level after an initial intravenous aminophylline dose is 30 minutes after completion of the loading dose (Anon, 1995). For an orally administered theophylline solution or uncoated tablet and extended-release theophylline preparations, 1 to 2 hours and 3 to 12 hours after the initial dose, respectively, is recommended (AHFS, 1990; Hendeles et al, 1986). The manufacturers of once-a-day theophylline preparations recommend obtaining peak theophylline serum concentration levels at 12 hours and 8 to 12 hours after a dose of Theo-24(R) and Uniphyl(R), respectively (Kelly & Smith, 1988). Trough levels may be obtained just prior to the next dose of theophylline (AHFS, 1990), however these levels do not generally provide any clinical relevant information (Hendeles et al, 1986). On each occasion, blood samples should be obtained during the same dosing interval to minimize the circadian variation in theophylline absorption. |
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Patients receiving an intravenous loading dose and continuous theophylline infusion according to general dosing guidelines should have theophylline levels obtained at the following times: 30 minutes after completion of the initial loading dose; once the continuous infusion is initiated, a second level drawn after one expected half-life (8 hours in non-smoking adults and 4 hours in children age 1 to 9 years); and 12 to 24 hours after any dose modification of the continuous infusion. Subsequently, daily serum theophylline concentrations should be obtained once the patient is stabilized on continuous theophylline infusion (Anon, 1995; Kelly & Smith, 1988). |
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Yearly serum theophylline concentrations are recommended for adult patients receiving oral maintenance theophylline preparations. Pediatric patients, especially during growth phases, should have theophylline levels checked every 6 months. Additionally, serum theophylline concentrations should be obtained when the patient's physiology, disease state, or pulmonary function changes, or if the patient is experiencing theophylline-related side effects (Kelly & Smith, 1988; Hendeles et al, 1986). |
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In patients in whom reductions in protein binding occur (premature neonates, elderly, patients with hepatic cirrhosis, uncorrected acidemia, and women in their third trimester of pregnancy), measurement of unbound serum theophylline concentrations provides a more accurate means of dosage adjustment and assessment (Anon, 1995). The recommended range for unbound theophylline concentration is 6 to 12 mcg/mL. |
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CONCLUSION: |
End of Document
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VANCOMYCIN: |
THERAPEUTIC RANGE:
Peak serum concentration: 25 to 40 mg/L
Trough serum concentration: 5 to 10 mg/L
(Dudley, 1989; Matzke & Flaherty, 1988; Matzke & Kovarik, 1988).
ELIMINATION HALF-LIFE: 6-10 hours (Winters, 1988)
VOLUME OF DISTRIBUTION: 0.7 liter/kilogram (ranges from 0.5 to 1 L/kg)
(Winters, 1988)
PHARMACOKINETIC MODEL: 2 or 3 compartments (Winters, 1988; Evans et al, 1986)
TIMING OF SAMPLES:
Peak: at least 1 hour after the discontinuation of an infusion
Trough: just before or within 1 hour of the next scheduled dose
(Dudley, 1989; Matzke & Flaherty, 1988;Matzke & Kovarik, 1988)
INTERPRETATION:
The
therapeutic range for vancomycin peak and trough concentrations were
derived primarily from observations that, at these concentrations toxicity
typically does not occur and that trough levels remained above the MIC for
most organisms. There is limited data associating vancomycin peak
concentrations with efficacy, however, adequate trough concentrations may
better correlate with outcome. Data associating vancomycin concentrations
with toxicity is also limited, and it remains unclear whether increased
serum levels are the cause or the effect of decreased renal function.
There may be some evidence that high troughs are associated with
nephrotoxicity. The relationship between vancomycin concentrations and
ototoxicity is even less clear. There is a trend toward monitoring trough
levels ONLY in most patients based on this information. Adequate trough
levels may be associated with efficacy (trough 1 to 2 times the MIC of the
organism), and identifying a high trough may help avoid nephrotoxicity. If
trough levels are in the therapeutic range, the chances of the peak being
above 40 micrograms/milliliter is unlikely. Patients who may require both
a peak and trough would include those receiving concomitant ototoxic or
nephrotoxic drugs, patients with infections in the central nervous system,
patients with endocarditis, or patients with infected hardware. Also
included in this group would be patients with impaired or rapidly changing
renal function (Wilhelm and Estes, 1999).
CONCLUSION
A
wide variety of drugs are monitored via serum levels to optimize therapy,
minimize toxicity, and aid therapeutic decisions. For many drugs the
timing of the sample relative to the dosing schedule is critical. Clinical
evaluation of the patient is always important in interpreting drug levels.
End of Document
REFERENCE: MICROMEDEX(R) Healthcare Series Vol. 111 expires 3/2002
DESIGNED BY HASHIM TAYEB (Bsc PHARM)
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