TDM Booklet Practical Guidev3

Dept of pharmacology & biochemistry lab
A Practical guide for optimization TDM (1)
Prepared by Dr. Ahmed Shaker Ali

Ahmedshaker21@yahoo.com
Drug monitoring specialist at KAUH 19972007
Associate professor of pharmacology dept of pharmacology 20072009
TDM-our
Logo
Optimal
sampling
Dose Accurate
adjustment analysis
Interpretation
6/27/2006 Ahmed S. Ali 5
1430 H/ 2009
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Dept of pharmacology & biochemistry lab

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1430 H/ 2009

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INTRODUCTION

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BASIC PHARMACOKINETIC PARAMETERS

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VARIABILITY IN PK PARAMETER VALUES

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WHAT IS TDM ?

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Indication of TDM:

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Criteria for Optimal TDM service

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GENERAL GUIDELINES

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1. OPTIMIZING TDM OF ANTIEPILEPTIC DRUGS

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1.1. Justify is the purpose of monitoring

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1.2.Consider the method of analysis, units

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1.3. considereMonitoring of other parameters

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1.4. Consider a schedule for starting & repeating TDM

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1.5. Insure optimal sampling

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1.6. Consider the following Criteria for judging the results

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1.7. Consider Other factors may influence serum levels:

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1.8 Enhance patient compliance,

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1.2.OPTIMIZING TDM OF ANTIBIOTICS.

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1.2.1.Introduction.

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1.2.2 Justify the reason for TDM,

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1.2.3 Provide clear instructions for sampling

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1.2.4 Provide essential information :

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1.2.5 Consider the following points before interpretation of results.

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1.2.6 Pharmacokinetic (PK) approach for optimal dosing

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1.3. OPTIMIZING TDM OF CYCLOSPORINE A

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1.3.1. Introduction:

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1.3.2.Trough level monitoring (C0) is simple but of little benefit

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1.3.3.Area under curve monitoring (AUC) is accurate but not practical

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1.3.4. Twohour post dose monitoring (C2) is simple and accurate

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1.3.4 Recommended Target .C2 levels ±20 % in adult KTP11

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1.4. INTERPRETATION OF SERUM DRUG LEVELS

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1.4.1.Judgment is essential

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1.4.2. Management of abnormal values

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1.4.2.1. verify analytical or preanalytical errors.

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1.4.2.2.Review patient’s specific data & investigations

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1.4.2.3 Consider the PK/PD variables

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1.4.2.4. Consider other reasons

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II OPTIMAL SAMPLING FOR TDM

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2.1. Introduction:

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2.2.Optimal sampling time:

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2.2.10. optimal sampling time & reference range , notes about individual drugs are provided in part 2.
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REFERENCES

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4.1 references for Sections 1.1, 1.2 & 1.4

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4.3. References for Section 1.3

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4.3. Additional references for aminoglycosides

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INTRODUCTION
Pharmacokinetics: Study of the time course of a drug and its metabolites in the body
after administration by any route.
An appropriate response to a drug requires the appropriate concentration of drug at the
site of action. The dosage regimen required to attain and maintain the appropriate
concentration depends on Pharmacokinetics. The appropriate concentration and dosage
regimen depend on the patient's clinical state, severity of the disorder, presence of
concurrent disease, use of other drugs, and other factors.
Because of individual differences, drug administration must be based on each patient's
needstraditionally, by empirically adjusting dosage until the therapeutic objective is
met. This approach is frequently inadequate because optimal response may be delayed or
serious toxic reactions may occur. Alternatively, a drug can be administered according to
its expected absorption and disposition (distribution and elimination in a patient, and
dosage can be adjusted by monitoring plasma drug concentration and drug effects. This
approach requires knowledge of the drug's pharmacokinetics as a function of the patient's
age and weight and the kinetic consequences of concurrent diseases (eg, renal, hepatic,
or cardiovascular disease or a combination of diseases).
BASIC PHARMACOKINETIC PARAMETERS

The pharmacokinetic behavior of most drugs can be summarized by the following
parameters, whose formulas are listed in table 1 the parameters are constants, although
their values may differ from patient to patient and in the same patient under different
conditions.
Bioavailability expresses the extent of drug absorption into the systemic circulation
The absorption rate constant expresses the speed of absorption. These parameters
influence the maximum (peak) concentration, the time at which the maximum
concentration occurs (peak time), and the area under the concentrationtime curve (AUC)
after a single oral dose. During longterm drug therapy, the extent of absorption is the
more important measurement because average concentration depends on it; the degree of
fluctuation is related to the absorption rate constant.
The apparent volume of distribution is the amount of fluid that would be required to
contain the drug in the body at the same concentration as in the blood or plasma. It can
be used to estimate the dose required producing a given concentration and the
concentration expected for a given dose. The unbound concentration is closely associated
with drug effects, so unbound fraction is a useful measure, particularly when plasma
protein binding is alterede.g., by hypoalbuminemia, renal or hepatic disease, or
displacement interactions. The apparent volume of distribution and the unbound fraction
in plasma are the most widely used parameters for drug distribution
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The rate of elimination of a drug from the body varies with the plasma concentration.
The parameter relating elimination rate to plasma concentration is total clearance,
which equals renal clearance plus extra renal (metabolic) clearance The fraction,
excreted unchanged helps assess the potential effect of renal and hepatic diseases on
drug elimination. A low fraction indicates that hepatic metabolism is the likely
mechanism of elimination and that hepatic disease may therefore affect drug elimination.
Renal diseases produce greater effects on the kinetics of drugs with a high fraction
excreted unchanged.
The extraction rate of a drug from the blood by an eliminating organ, such as the liver,
cannot exceed the rate of drug delivery to the organ. Thus, clearance has an upper limit,
based on drug delivery and hence on blood flow to the organ. Furthermore, when the
eliminating organ is the liver or gut wall and a drug is given orally, part of the dose may
be metabolized as it passes through the tissues to the systemic circulation; this process is
called firstpass metabolism. Thus, if extraction (clearance) of a drug is high in the liver
or gut wall, oral bioavailability is low, sometimes precluding oral administration or
requiring an oral dose much larger than an equivalent parenteral dose. Drugs with
extensive firstpass metabolism include hydralazine, isoproterenol, lidocaine,
meperidine, morphine, nifedipine, nitroglycerin, propranolol, testosterone, and
verapamil.
The elimination rate constant is a function of how a drug is cleared from the blood by
the eliminating organs and how the drug distributes throughout the body.
Halflife (elimination) is the time required for the plasma drug concentration or the
amount of drug in the body to decrease by 50%. For most drugs, halflife remains the
same regardless of how much drug is in the body. Exceptions include phenytoin,
theophylline, and heparin.
Mean residence time (MRT), another measure of drug elimination, is the average time
a drug molecule remains in the body after rapid IV injection. Like clearance, its value is
independent of dose. After an IV bolus,
AUMC is the area under the first moment of the plasma concentrationtime curve. For a
drug with onecompartment distribution characteristics, MRT equals the reciprocal of
the elimination rate constant.
VARIABILITY IN PK PARAMETER VALUES

Many factors affecting pharmacokinetic parameters should be considered when tailoring
drug administration for a particular patient. Even with dosage adjustment, however,
sufficient variability usually remains; thus, drug response and, in some cases, plasma
drug concentration must be closely monitored.
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Age and weight: For some drugs, the effects of age and weight on pharmacokinetics
are well established. For persons aged 6 mo to 20 yr, renal function appears to correlate
well with BSA. Thus, for drugs primarily eliminated unchanged by renal excretion,
clearance in children varies with age according to change in BSA. For persons > 20 yr,
renal function decreases about 1%/yr. Thus, dosage of these drugs can be adjusted by
age. BSA also correlates with metabolic clearance in children, although exceptions are
common. For newborns and infants, renal and hepatic functions are not fully developed,
and generalizations, except for the occurrence of rapid change, are less accurate.
Renal function impairment: Renal clearance of most drugs appears to vary directly
with creatinine clearance, regardless of which renal disease is present. The change in
total clearance depends on the contribution of the kidneys to total elimination. Thus, total
clearance should be proportional to renal function (creatinine clearance) for drugs
excreted unchanged and to be unaffected for drugs eliminated by metabolism.
Renal failure may change the apparent volume of distribution, which decreases for
digoxin because of decreased tissue binding and increases for phenytoin, salicylic acid,
and many other drugs because of decreased binding to plasma proteins.
Physiologic stress: Concentration of the acutephase protein 1acid glycoprotein
increases during physiologic stress (eg, MI, surgery, ulcerative colitis, Crohn's disease).
Consequently, the of several drugs (eg, propranolol, quinidine, disopyramide) to this
protein increases, and the apparent volume of distribution of these drugs decreases
accordingly.
Hepatic disease: Hepatic dysfunction can change metabolic clearance, but good
correlates or predictors of the changes are unavailable. Hepatic cirrhosis can dramatically
reduce drug metabolism and often results in reduced plasma protein binding because of
lowered plasma albumin. Acute hepatitis, with elevated serum enzymes, usually does not
alter drug metabolism.
Other diseases: Heart failure, pneumonia, hyperthyroidism, and many other diseases
can alter the pharmacokinetics of drugs.
Drug interactions: Pharmacokinetic parameter values and, therefore, drug response
may be affected by drug interactions. Most interactions are graded, and the extent of the
interaction depends on the concentrations of both drugs. Thus, determining and adjusting
drug dosage is difficult
Dosage: In some instances, changes in dose, dosing rate, or duration of therapy alter a
drug's kinetics. For example, as dose is increased, the bioavailability of griseofulvin
decreases because of the drug's low solubility in the fluids of the upper GI tract. For
phenytoin, steadystate plasma concentration increases disproportionately when dosing
rate is increased, because the metabolizing enzyme has a limited capacity to eliminate
the drug, and the usual dosing rate approaches the maximum rate of metabolism. Plasma
carbamazepine concentration decreases during longterm use because carbamazepine
induces its own metabolism. Other causes of dosagedependent kinetic changes are
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saturable plasma protein and tissue binding (eg, phenylbutazone), saturable secretion in
the kidneys (eg, highdose penicillin), and saturable metabolism during the first pass
through the liver (eg, propranolol).
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WHAT IS TDM ?
Therapeutic drug monitoring (TDM) is the process of quantifying drug concentrations in
patients and using these measurements to design individualized dosing regimens (dose,
formulation, route, and frequency of administration). The potential for TDM to improve
care is being increasingly recognized When performed correctly, TDM has been shown
to efficiently maximize efficacy and minimize toxicity in many patient populations TDM
has become a routine method to maintain "therapeutic" concentrations of numerous
drugs . However, it requires drug concentrations to be interpreted for each specific
patient's complete clinical, pharmacokinetic, and pharmacodynamic information.
Unfortunately, too many laboratories report (and laboratory certifying bodies accept)
"numbers only"—i.e., concentration without complete and accurate medical and drug
dosing information. When done poorly, as in a "numbers only" laboratory, TDM has not
been effective and can be dangerous (1 3 ).
Indication of TDM:
oDrugs with a narrow therapeutic index where therapeutic drug levels do not differ
greatly from levels associated with serious toxicity .e.g digoxin
oPatients who have impaired clearance of a drug with a narrow therapeutic index are
candidates for drug monitoring.. Example: Patients with renal impairment have
decreased clearance of vancomycin and therefore are at a higher risk for vancomycin
toxicity.
oDrugs whose toxicity is difficult to distinguish from a patient’s underlying disease
may require monitoring. Example: Theophylline in patients with chronic obstructive
pulmonary disease.
oDrugs whose efficacy is difficult to establish clinically May require monitoring of
plasma levels. Example: Phenytoin.
Criteria for Optimal TDM service
 A good clinical indication for the test such as : no response to treatment;
suspected noncompliance; signs of toxicity;
 The collection of an appropriately timed and dated specimen with proper patient
information;
 Adequate clinical information to allow the interpretation of results.
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GENERAL GUIDELINES
1. OPTIMIZING TDM OF ANTIEPILEPTIC DRUGS

Commonly monitored anticonvulsant drugs ACDs are carbamazepine, phenytoin,
Valproic acid, & Phenobarbital. The following guidelines aims to optimize TDM of
these ACD in case of longterm therapy of epilepsy in children and adults
1.1. Justify is the purpose of monitoring
• Clinician must specify the reason for TDM in the request form to support
interpretation.
• TDM of ACDs may have several purposes:
• monitoring compliance
• following the results of AED dosage changes
• establishing a patient's maximum tolerated serum level
• looking for early signs of adverse effects (e.g., hepatic )
• Support management of toxicity
• Inadequate response, or altered clinical response ; etc
• Management of drug interactions especially with other ACDs.
1.2.Consider the method of analysis, units
Monitoring of Total AED serum levels is the most common procedure. Total serum
levels can be misleading in some patients. Free unbound serum levels of phenytoin and
valproate should be checked in patients with low albumin levels or patients who are
taking multiple drugs that are tightly proteinbound. Results may presented in ug/ml or
umol/L, appropriate conversion is required to compare results from different labs if
different units are used.
1.3. considereMonitoring of other parameters
In many cases Serum level alone don’t insure safe use of ACDs Other tests may include
measurements of electrolyte levels, liver and kidney function tests, and bloodcell counts,
depending on the patient's history and the type of adverse effects reported with the AED
being used.
1.4. Consider a schedule for starting & repeating TDM
TDM often performed after initiation of treatment and should be repeated at the at
steady state .The frequency of testing usually requires clinical judgment on the necessity
for testing. For example when high level ( up side of ref range ) of phenytoin or
Phenobarbital is observed, further follow up must be considered to insure no further
accumulation .
1.5. Insure optimal sampling
At steady state optimal sampling time is not critical for Phenobarbital, phenytoin &
carbamazepine due to long halflife. i.e random sample are practically acceptable.
However the optimal sampling time given below provide more consistent results
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 To evaluate efficacy ,
Obtain a trough level (just before next dose), once the steady state conditions have been
reached, ( practically after 45 halflives of the drug ) Written instructions to the patient
: “do not take your morning pill until you have had your blood taken
 Transiant toxicity:
Collect blood samples when the signs of toxicity are present (usually associated with
peak level; 12 hr after IV dose or 46 hr after oral administration of conventional
formulations of phenytoin or carbamazepine , and 23 hr in case of Valproic acid ) .
Written instructions to the patient “go to the lab and have your blood taken when your
symptoms are present
 Management of toxicity
Collect a Random sample, repeat measurement in view of the observed level and clinical
need
1.6. Consider the following Criteria for judging the results
Clinical Judgment
Drug concentrations can’t replace clinical assessment of patients for efficacy and adverse
effects. The drug concentration can only be regarded as a guide for dose adjustment
Dosages should be changed based on clinical grounds such as seizure breakthrough or
side effects, not because of the serum level. Using blood levels to check for compliance
is not always reliable. pharmacokinetic and pharmacodynamic variables:
Many PK/PD variables including formulations, route of administration, attaining steady
state , interaction with other ACDs should be considered for both optimal dosing and
interpretation of results.) Several PK /PD variables showed be considered for appropriate
interpretation of results for example the free level of phenytoin is higher in case of co
administration of Valproic acid Neonates subjected to neonatal asphyxia have a
significant reduced clearance of Phenobarbital. Phenytoin is is erratically absorbed orally
in neonates. range”. {more examples will be given under Interoperation of results)
Therapeutic ranges are only provided as a guide.
Great interindividual variations in pharmacokinetic (absorption, biotransformation,) and
pharmacodynamic (clinical response and adverse effects) of antiepileptic drugs are
observed. Patients may develop toxic symptoms at levels “within the therapeutic
range”. Some patients may require and tolerate concentrations above the “therapeutic.
1.7. Consider Other factors may influence serum levels:

laboratory error
generic substitution for brandname AEDs
variable potency of pills (following improper storage, for example)
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menstrual cycle (midcycle serum AED levels may be higher than during the
premenstrual period or menses)
1.8 Enhance patient compliance,
We observed that patient noncompliance is the main reason for very low level of
Antiepileptic drugs. Irregular drug intake prior to drug concentration measurement
(noncompliance confounds the interpretation of the result.)
1.9. Provide the required information in TDM request FORM:
Providing these information will take few mints but may allow proper interpration , safe
of time & reagents. These include patient age, sex, weight, other illness, how long the
patient was taking the current dose, when the last 23 doses were taken, and the sample
collection time. Other medications, presence of disease that alters protein binding or liver
impairment.
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1.2.OPTIMIZING TDM OF ANTIBIOTICS.
1.2.1.Introduction.
The following guidelines aim to insure proper utilization of TDM service to enhance
efficacy and minimize toxicity of commonly monitored antibiotics; aminoglycosides
( Gentamaicin , amikacin ), and vancomycin .
1.2.2 Justify the reason for TDM,
Debate exists concerning determination of vancomycin peak level and aminoglycosides
peaklevel in case of once daily dosing, However, peak levels though to be of little value
in some cases may be valuable in other situations e.g. neonates or renal impairment
( small doses are given at extended interval )etc
1.2.3 Provide clear instructions for sampling
Different instructions for sampling are currently applied depending on the drug being
tested and regimen. Clear instruction should be written to guide personnel responsible
for sampling e.g. take sample for trough (pre ) within 30 min before next dose, sample for
peak gentamicin level 30 min after end of infusion.
N.B :Samples for peak levels taken later than specified time may provide false lower
values. Samples for trough level taken earlier may provide false higher results . Such
results may be misleading and confusing
1.2.4 Provide essential information :
Some information are essential for interpretation and avoiding artifacts or misleading
results. These include demographic characteristics, diagnosis , site severity of infection ,
treatment regimen including other medication, sampling time , renal function, clinical
response and any other observations seemed of value for interpretation..
1.2.5 Consider the following points before interpretation of results.
ATherapeutic range only serves as a guide
Individual patients results should be interpreted in light clinical status and variables
including , severity and site of infection, duration of treatment, administration of other
nephrotoxic drugs etc . e.g values higher than ref range may be acceptable in life
threatening infections. Slightly high trough level is acceptable in case of short courses
but review of regimen should be considered in case of long courses. Results are usually
presented either in mg/L or umol/L appropriate conversion are required to compare these
values .
BEfficacy of aminoglycoside is concentrationdependent
Usually High peak ( 810 MIC ) is recommended to enhance the efficacy. Very Low
trough level for short period 35 hr minimizes the toxicity and usually doesn’t reduce the
efficacy ( due to Post antibiotic effect ) . This explains why regimens of relatively high
doses and longer interval are more recommended.
C Efficacy of vancomycin is time dependent :
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High peak usually don’t enhance efficacy in most infections ( except meningitis due to
low penetration of the drug) trough level within ref range 37 umol/L should be
maintained. Thus regimens of small dose and short interval are usually preferred.
D High once daily dosing (OD) of aminoglycosides has different. protocol
Several approaches are proposed for sampling and interpretation 1 determination of
trough level only to monitor potential toxicity ( level should be very low ). 2Taking a
timed random sample ( 614 hr ) post dose and applying Hartford Hospital OD
Aminoglycosides Nomogram to guide the dosing interval.( Nicolau et al 1996 ) It is
applied only to gentamicin 7 mg/kg once daily. 3Computerized PKapproach has been
proposed by TDM unit to predicate the level in view of dose, renal function and sampling
time This concept was evaluated in limited number of patients and showed good results
) Further evaluation is. currently in progress .( Ali AS 2005
Confirm and verify the reason for abnormal values
Review sampling time, review previous results and clinical status of the patients to trace
any supporting evidence . Low peak low trough may indicate suboptimal dosing, high
peak high trough may indicate potential toxicity.– Peak level very close to trough level
suggest wrong sampling. If the results still confusing , repeat the measurement at the
specified time.
1.2.6- Pharmacokinetic (PK) approach for optimal dosing
Many programs are available that make this approach simple and practical..[ e.g
Antibiotic Kinetics http://www.rxkinetics.com/ The basic procedures are: Take two
accurately timed samples ,( t1 & t2 ,) determine serum level (C1, C2 ) , estimation of
the halflife is performed using conventional PK equation ( Ke=Ln (C1/C2)/ (t2t1), half
life =0.693/ ke ). Scientific calculators or Excel [ used by staff of the unit ] are valuable
when these programs are not available.
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1.3. OPTIMIZING TDM OF CYCLOSPORINE A
1.3.1. Introduction:
Cyclosporine A (CsA) has been the mainstay of most immunosuppressive standard
protocols and used for management of some autoimmune diseases. CsA blocks the signal
to lymphocytes to produce IL1, IL2, IL3, IL4, and interferon gamma. CsA is a
lipophillic molecule, with complex and highly variable pharmacokinetics (PK) profile.
It’s bioavailability is dependent on food, bile, diurnal variation and other interacting
factors. Bioavailability was improved by using microemulsion formulation (Neoral). CsA
is extensively metabolized in the liver by the cytochrome P450 3A system, which is
subject to considerable interindividual variation and drug interaction .It is eliminated
mainly through the bile, renal elimination < 1 %. Distribution of CsA depends on
biological carriers such as lipoproteins and erythrocytes in blood. Cyclophilin, a binding
protein for CsA influences distribution of CsA in the body. The drug has narrow
therapeutic index. Elevated CsA level can increase the risk of Nephrotoxicity, while its
decrease can increase the risk of graft rejection. Therefore CsA is considered a critical
dose drug and therapeutic drug monitoring (TDM) is an integral part of CsA therapy.
CsA is strongly bond to erythrocyte (5060%) in temperature dependant pattern,
therefore wholeblood concentrations is the matrix of choice for its analysis. CsA has
several metabolites some of them are biologically active and HPLC is the only assay that
is completely specific for the parent drug. 1
1.3.2.Trough level monitoring (C-0) is simple but of little benefit
Trough concentrations correlate poorly with clinical response. Trough level alone is not
a reliable factor to predict either acute rejection or nephrotoxicity2
1.3.3.Area under curve monitoring (AUC) is accurate but not practical
Variability in absorption was considered as a risk factor for chronic rejection. AUC
precisely reflects the variability in absorption and total drug exposure3 AUC has been
considered the most sensitive pk predictor for acute and chronic rejection in kidney
transplant patients (KTP). Limited AUC (AUC04) approach has been recommended as
an accurate alternative way to extended AUC012 method4 however, due to multiple
blood sampling AUC approach: is impractical, especially in the outpatient setting.
1.3.4. Two-hour post dose monitoring (C-2) is simple and accurate
C2 is practical, simple, and effective way to improve outcomes in organ transplant
patients. Target C2 level showed good relationship with “Neoral” doses and considered
as a good measure for CsA absorption (total drug exposure), hence simplify dosage
regimen adjustment57. Good correlation between C2 level and AUC04. (r2=0.85) was
observed8,9 . Use of C2 is organ transplant patients proved to be superior to C0 in
terms of efficacy and safety profile of CsA. C2 with neoral reduces the incidence and
severity of acute rejection, improves renal function, and lowers the incidence of
hypertension. In KTP C2 shown to predict sub clinical rejections10,11. Success of this
approach requires compliance to TDM guidelines: Samples should be taken exactly 2h
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post morning dose. (to avoid diurnal variation). The time to reach the target level ranges
between 35 days in KTP
1.3.4 Recommended Target .C-2 levels ±20 % in adult KTP11
Time (month) 1 2 3 46 712 >12

level ug/ml; (umol/L) 1.7 (1400) 1.5 (1250) 1.3(1080) 1.1(910) 0.9(750) 0.8(660)

1.4. INTERPRETATION OF SERUM DRUG LEVELS

1.4.1.Judgment is essential
Measurement of the serum drug concentration (SDC) is of little value without
appropriate interpretation, which requires consideration of pharmacodynamic (PD) and
pharmacokinetic (PK) profiles of the drug as well as patient specific profiles (i.e. various
variables affecting PK/PD of the drug).
1.4.2. Management of abnormal values
Many variables influence SDC and patient clinical response. Therefore judgment is
always essential before approval of results or clinical decision. TDM request form should
contain accurate information that allows TDM staff to provide the appropriate
comment . The following are the most important practical issues :
1.4.2.1. verify analytical or pre-analytical errors.
TDMstaff should confirm accuracy of the results , double check any abnormal results
after appropriate review of all procedures, QC etc. Preanalytical errors, also should be
considered before approval of unexpected results. Clinicians should consider all
possibilities before final decision . ( wrong request, dosing error, sampling timer error
, etc ) . Frequently repeating the test is the most simple and straightforward procedure
1.4.2.2.Review patient’s specific data & investigations
Many variables should be considered, including, age, other medications, severity of
illness, clinical response, signs of toxicity. Certain biochemical parameters, e.g. reduced
creatinine clearance (Clcr < 80 ml / min ) can help to support abnormally high
random digoxin or trough gentamicin/ amikacin levels . Specific ECG abnormalities
support elevated digoxin level. Note that many adverse effects are not concentration
dependent and some other parameters should be evaluated e.g CBC to monitor
hematological disorders due to carbamazepine
1.4.2.3 Consider the PK/PD variables
Most hospitalized patients are supposed to receive standard dosage regimens. However,
some have toxic symptoms, others have inadequate efficacy. Several PK and PD variables
can explain these abnormal responses—. Properly interpreted TDM results can identify
clinically important problems. Important special populations where TDM is useful
either predict or prevent toxicity or improve therapeutic outcomes include : neonates &
elderly, patients with impaired renal or liver function , dosing problems,& patients who
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have unusual PK as a result drug interaction, physiological, environmental, disease, or
genetic factors (1).
Neonates & elderly
PK and PD behavior (16) differ greatly in neonates & elderly , compared with "normal"
adult populations. All PK processes are involved. Dosing uncertainty is a problem in
both the very old and the very young as a result of erroneously measured, refused,
vomited, repeated, or forgotten doses. Dosing errors are more documented in neonates
.Weight can change dramatically in neonates during a single course of therapy.
Distribution of drugs is also altered in these populations because of differences in body
composition Clearance of drugs (both metabolic and renal) is altered by age and disease
related changes, as well as by drug and diet interactions.,. The ability to tolerate or
communicate drug effects is also diminished at both extremes of age. A number of
unique, practical additional considerations are present in neonates (19).
• Therapeutic ranges for some drugs are quite different; e.g., therapeutic theophylline
concentrations are lower for neonates (5–15 mg/L) than for adults (10–20 mg/L).
• Time of drug administration is not simple to determine in neonates; it may take hours for
a dose, even if administered into an intravenous line, to actually reach a neonate (20).
• Assay interference from endogenous substances is also more common than in adults; e.g.,
digoxinlike immunoreactive substances (DLIS) (21)..
• Metabolic pathways may differ qualitatively as well as quantitatively. Caffeine is present
in significant quantities in neonates who are given theophylline—a result of the
metabolism of theophylline.
• Protein binding can be quite different in neonates, producing very different therapeutic
ranges for highly proteinbound drugs such as phenytoin. ( 2560 umol )
Impaired renal or liver function
Tests of organ function (renal or hepatic) are commonly used to predict which patients
are at greater risk of unusual PK behavior. Significant increase of Serum creatine level
( 25% of base line value ) can support toxicity due to aminoglycosides
Nonlinear kinetic
Form mostt therapeutic drugs measured, clearance is independent of plasma drug
concentration, so that a change in dose is reflected in a similar change in plasma level. If,
however, clearance is dose dependent , dosage adjustments produce disproportionately
large changes in plasma levels and must be made cautiously. Example: Phenytoin
Multiple medications and drug interactions
Patients on multiple drugs are also more likely to have altered and changing PK or PD
characteristics For example patients are more susbtable to aminoglycoside toxcicity in
case of coadministeration of other nephrotoxic drugs e.g fursimide or vanvomycin
Altered Protein binding of drugs.
All routine drug level analysis involves assessment of both proteinbound and free drug.
However, pharmacologic activity depends on only the free drug level. Changes in protein
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binding (eg, in uremia or hypoalbuminemia) may significantly affect interpretation of
reported levels for drugs that are highly proteinbound. Example: Phenytoin. In such
cases, where the ratio of free to total measured drug level is increased, the usual
therapeutic range based on total drug level will not apply.
1.4.2.4. Consider other reasons
Non compliance :
Poor compliance is seen in patients with lifethreatening asthma (25) and is also one of
the most common causes of organ transplantrejection episodes in adolescents, for
example (26). Overdose by the patient or his family is a form of overcompliance and can
occur as a result of poor understanding, or a desire to hasten or increase the magnitude
of effects. TDM unit at KAUH documented a case of seriously toxic Valproic acid
( 17000 umol/L) level in a child 2 yr due to administration of the drug by nursing bottle
by his mother.
Dosing errors
• TDM can be useful to detect over and under dosing e.g., errors in dosage calculations
(especially 10fold errors),
• .For many serious conditions, use of less than maximally effective doses is much more
toxic (i.e., dangerous) than is overdosing. For example, mortality is greatly increased by
under dosing of aminoglycosides in patients with serious infections
• Patients receiving enteral feedings are at risk of under dosing of anticonvulsant
medications because the tubefeeding solutions may interfere with drug absorption. Poor
bioavailability of phenytoin was observed in neonates .
• Renal patients are also often underdosed because of confusion between their need for
lower maintenance doses (low renal clearance) and their need for greater than usual
loading doses to achieve therapeutic concentrations (larger volumes of distribution). A
septic, anaphoric patient may need 4 or 5 mg/kg as an initial gentamicin dose rather than
the 2.5 mg/kg given to a "normal" patient,
.
II- OPTIMAL SAMPLING FOR TDM

2.1. Introduction:
TDM is an important function of modern clinical laboratories. When used properly it
improves drug therapy. To be effective TDM requires the acquisition of a valid specimen,
rapid and accurate determination of drug concentration and appropriate interpretation.
These elements should be considered as a network and efforts should be directed to
optimizing all of them. In fact, determination of drug level is of little value and may be
misleading without interpretation that requires clinical judgment in light of
pharmacokinetic (PK), pharmacodynamic (PD) and patient profile .i.e. in the context of
dose, time of last dose , severity of illness, clinical response, biochemical profile ,
investigations etc. We demonstrated that errors in sampling time and noncompliance are
the main reason for abnormal serum levels of antibiotics & antiepileptic drug
17
respectively. Therefore we calls for multidisciplinary efforts and cooperation of Total
quality management , & Continuous education depts., physicians, nurses, phlebotomists,
Pharmacists, Pharmacologists, lab technologists to insure optimal TDM service.
2.2.Optimal sampling time:
Optimal sampling time depends on the drug's PK characteristics ( halflife, distribution ),
purpose of TDM, and dosing regimen.
2.2.1 Why sampling time is critical for some drugs ?
2.2.1.1.Antibiotics :
commonly monitored antibiotics have relatively short halflife ( gentamicin & amikacin
23 hr , vancomycin : 5 hr ) in patients with normal renal function. After IV
administered their serum level will decline rapidly. For example sampling for a peak
level ( post dose ) 1 hr later than the specified time will lead to a false low level ;
sampling for a trough level (pre dose ) 1 2 hr earlier will lead to false high level.
2.2.1.2.Cyclosporine A .
Peak level [ C2; 2 hr post dose ] is recommended in transplant patient to evaluate

adequate absorption. We frequently document random sampling which can lead to a
false impression of inadequate absorption or inadequate dose
2.2.2.2. Digoxin :
Digoxin has long distribution phase, peak tissue concentration occurs 610 hr after
administration. Tthe appropriate time of should be > 6 hr after administration to
insure correlation between tissue concentration and plasma level.
2.2.2.3.Acetaminophen & Methotrexate
No interoperation of the serum level could be provided unless sampling time relative to
the time of administration is carefully reported.
2.2.3.Why trough level is recommended for many drugs taken orally ?
Time of Peak level of dugs administered orally ( e,g antiepileptic drug ) is affected by
several variables including , formulation, food etc. For these reasons it is practically
difficult to obtain consistent peak levels, hence trough level (pre dose) is usually
satisfactory as representative of overall effect specially for those with long halflife ( e.g.
phenytoin, Phenobarbital & carbamazepine ).
2.2.4.What is the importance of sampling at steady state (SS) ?
Sampling at SS ( usually trough level) is important to adjust dosage regimens or to
evaluate drug efficacy in case of drugs used chronically (e.g. antiepileptic, digoxin,
Theophylline ). For practical purpose, SS is considered to be attained after regular
administration for a period ≈ 5 halflives. Examples : Theophylline in adults it has a half
18
life of ≈ 6 hr, SS is attained after 24 30 hr , in neonates it has longer halflife ( 30
hrs ) , SS requires at least 67 days. However, when a loading dose is provided a shorter
interval is required to attain SS. Digoxin ss requires at least 5 days after initiation of
therapy and 23 days after changing the dose. Actual carbamazepine SS is attained
after 34 weeks because it stimulate its own metabolism, leading to shorter half life
2.2.5.Can we take the sample before SS ?
Serum drug level can be determined before attaining SS in certain situations e.g
suspected or documented toxicity, over dose, evaluation of the loading dose , patients
with impaired renal or liver function.
2.2.6 What is the optimal sampling time for drugs given by low IV infusion?
Theophylline may be indicated in severe asthma . A loading dose of is usually

administered by slow IV, You may evaluate peak level 1 hr after end of administration.
The maintenance dose is usually administered by constant rate Iv infusion. In this case
Theophylline. serum level depends on infusion rate and SS is usually attained after 6 hr
of stating infusion. Due to its short halflife , ideal sampling time should be within 6 12
hr during infusion or within 1 hr after stopping infusion. Sampling several hours after
stopping of infusion may show false low level .
2.2.7.When we take a random sample?
Random sample is acceptable for phenytoin, phenobarbital & carbamazepine due to their
long halflife. i.e the drug concentration does not change rapidly during dosing interval.
Random sample is valuable in case of suspected digoxin toxicity, suspected non
compliance for all drugs taken orally. Sometimes unreasonable high level is observed , in
such cases TDM lab usually request a random sample to verify if the previous level is
due to sample contamination during sample withdrawal ( i.e by the traces of the pure
drug)
2.2.8.When we take a timed sample ?
Timed samples are samples taken at specified times post dose. It is a recommended
approach for evolution of high dose once daily (OD) regimen of aminoglycosides. It is
essential for evaluation of potential Methotrexate or acetaminophen toxicity. It is also
valuable for evaluation of pharmacokinetic parameters e.g patients with renal
impairment.
2.2.9.Additional Notes:
Antibiotics : In adult patients with normal renal function determination of Peak level
is no longer a routine practice in case of OD dosing of aminoglycosides & vancomycin.
For practical purpose sampling for Aminoglycosides starts after 4th dose (multiple daily
dosing) or after the 1st dose in case of high single daily dosing (OD) regimen.
19
Cyclosporine A Trough level ( before next dose ) may be requested when , toxicity or
using CsA for management of some diseases
2.2.10. optimal sampling time & reference range , notes about individual
drugs are provided in part 2.
. In case of PK studies, dialysis patients , unconventional dosing regimen consult
TDM staff or the clinical pharmacist for appropriate guidance.
20
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24
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27

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BASIC PHARMACOKINETIC PARAMETERS

VARIABILITY IN PK PARAMETER VALUES

1. OPTIMIZING TDM OF ANTIEPILEPTIC DRUGS

1.6. Consider the following Criteria for judging the results

1.7. Consider Other factors may influence serum levels:

Time (month) 1 2 3 46 712 >12

1.4. INTERPRETATION OF SERUM DRUG LEVELS

II- OPTIMAL SAMPLING FOR TDM

Peak level [ C2; 2 hr post dose ] is recommended in transplant patient to evaluate

Theophylline may be indicated in severe asthma . A loading dose of is usually

4.3. References for Section 1.3

4.3. Additional references for aminoglycosides

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TDM Booklet Practical Guidev3

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Hak Cipta:

Format Tersedia

Dept of pharmacology & biochemistry lab

Prepared by Dr. Ahmed Shaker Ali

BASIC PHARMACOKINETIC PARAMETERS

VARIABILITY IN PK PARAMETER VALUES

1. OPTIMIZING TDM OF ANTIEPILEPTIC DRUGS

1.6. Consider the following Criteria for judging the results

1.7. Consider Other factors may influence serum levels:

Time (month) 1 2 3 4­6 7­12 >12

1.4. INTERPRETATION OF SERUM DRUG LEVELS

II- OPTIMAL SAMPLING FOR TDM

Peak level [ C2; 2 hr post dose ] is recommended in transplant patient to evaluate

Theophylline may be indicated in severe asthma . A loading dose of is usually

4.3. References for Section 1.3

4.3. Additional references for aminoglycosides

Anda mungkin juga menyukai

Time (month) 1 2 3 46 712 >12