TDM

DR. RUTH NAMYALO

 Definition
• Therapeutic drug monitoring (TDM) is the clinical practice of measuring
specific drugs at designated intervals to maintain a constant concentration in
a patient's bloodstream, thereby optimizing individual dosage regimens.

• Therapeutic drug monitoring is generally defined as the clinical laboratory

measurement of a chemical parameter that, with appropriate medical
interpretation, will directly influence drug prescribing procedures

• TDM refers to the individualization of drug dosage by maintaining plasma or

blood drug concentrations within a targeted therapeutic range or window.
 Overview
• By combining knowledge of pharmaceutics, pharmacokinetics, and
pharmacodynamics, TDM enables the assessment of the efficacy and safety of a
particular medication in a variety of clinical settings.

• The goal of this process is to individualize therapeutic regimens for optimal patient
benefit.

• It is unnecessary to employ TDM for the majority of medications, and it is used

mainly for monitoring drugs with narrow therapeutic ranges, drugs with marked
pharmacokinetic variability, medications for which target concentrations are difficult
to monitor, and drugs known to cause therapeutic and adverse effects.
 Overview
• TDM is based on the principle that for some drugs there is a close
relationship between the plasma level of the drug and its clinical effect and
that certain drugs have a narrow therapeutic range; – In concentrations
above the upper limit of the range, the drug can be toxic; – In
concentrations below the lower limit of the range, the drug can be
ineffective.

• Another assumption is that drug metabolism varies from patient to patient

therefore, not all patients have the same response at similar doses.
 Indications
 Low therapeutic index.

 Poorly defined clinical end point; when a precise therapeutic end point is difficult to
define, monitoring of drug levels may be of considerable therapeutic assistance.

 Non compliance.

 Therapeutic failure.

 Drugs with saturable metabolism.

 Wide variation in the metabolism of drugs.

 For diagnosis of suspected toxicity & determining drug abuse

Monitoring aims to promote optimum drug treatment by maintaining serum drug

concentration within a ‘Therapeutic Range’
 Indications

Drugs with steep dose response curve (small increase in dose can result
in a marked increase in desired/undesired response e.g. theophylline)

When another drug alters the relationship between dose & plasma
concentration e.g. plasma concentration of lithium is increased by thiazide.

Renal disease (alters the relationship between dose & the plasma
concentration. Important in case of digoxin, lithium & aminoglycoside
antibiotics.
 Indications
TDM is unnecessary when:

Clinical outcome is unrelated either to dose or to plasma concentration.

Dosage need not be individualized.

Pharmacological effects can be clinically quantified (BP, HR, RBS, urine volume)

When concentration effect relationship remains unestablished.

Drugs with wide therapeutic range such as beta blockers and calcium channel
blockers.

Hit and run drugs e.g. Omeprazole

 Therapeutic index
• A ratio that compares the blood concentration at which a drug becomes
toxic and the concentration at which the drug is effective.

• The ratio between the dosage of a drug that causes a lethal effect and the
dosage that causes a therapeutic effect.

• The larger the therapeutic index (TI), the safer the drug is. If the TI is small
(the difference between the two concentrations is very small), the drug
must be dosed carefully and the person receiving the drug should be
monitored closely for any signs of drug toxicity.
 TI
• A more dangerous drug has a lower therapeutic index and may require
regular monitoring of drug levels.
• Examples include: Warfarin, Lithium, Digoxin, Phenytoin, Gentamicin,
Amphotericin, 5-fluoro-uracil, Zidovudine.
• It is generally considered that a drug has a good safety profile if its TI
exceeds the value of 10
 TI
• LD50 stands for median lethal dose, and ED50 stands for median effective
dose.

• LD50 refers to the dose that would produce a lethal effect in 50% of the
population, whereas ED50 refers to the dose that will produce the desired
therapeutic effect in 50% of the population.

• TD50 refers to the minimum drug dose that would produce a toxic effect in
50% of the population

• For example, if the TD50 is 200 and the ED50 is 20 mg, the TI would be 10.
 Margin of safety
• A clinician would consider a drug safer if it had a TI of 10 than if it had a TI of 3.

• However, the use of the ED50 and TD50 doses to derive the TI may be misleading
about a drug's safety, depending on the slope of the dose-response curves for
therapeutic and toxic effects.

• To overcome this deficiency, toxicologists often use another term to denote the
safety of a drug: the Margin of Safety.

• The Margin of Safety (MOS) is usually calculated as the ratio of the toxic dose to
1% of the population (TD01) to the dose that is 99% effective to the population
(ED99).
 Dose-response relationship
• Dose-response relationship is an essential concept in toxicology.

• It correlates exposures with changes in body functions or health.

• In general, the higher the dose, the more severe the response. The dose-
response relationship is based on observed data from experimental animal,
human clinical, or cell studies.

• Knowledge of the dose-response relationship establishes:

 Causality — that the chemical has induced the observed effects.

 The threshold effect — the lowest dose where an induced effect occurs. The slope for the
dose response — the rate at which injury builds up.
Dose response relationship
 TDM process
• It is a multidisciplinary function and requires collaboration and good
communication between scientists, clinicians, nurses and pharmacologists.

• Decision to request Drug level:

 Suspected toxicity.

 Lack of response/compliance.

 To assess therapy following change in dosage.

 Change in clinical state of patient.

 Potential drug interactions due to concomitant medications

 TDM process
• After decision is made, biological sample is collected for measurement.
• Serum or plasma samples are usually collected for TDM.
• Blood sample should be collected once the drug concentration have
attained steady state (SS) (at- least 5 half lives at the current dosage
regimen).
• Levels approximating SS may be reached earlier if a loading dose has
been administered (drugs with long half lives e.g. digoxin).
• However, drugs with long half-lives should be monitored before SS is
achieved to ensure that individuals with impaired metabolism or renal
excretion are not in the risk of developing toxicity at the initial dosage
prescribed.
• If toxicity is suspected the concentration should be measured as soon as
possible.
• Usually blood samples are collected at the end of the dosage interval
(Trough).
• For antibiotics given intravenously, peak concentrations (30 minutes after
cessation of I.V infusion) are also measured.
• Usually drug concentrations are monitored in venous blood, serum or
plasma and it is important that the appropriate matrix is assayed.
• In general, serum or plasma concentrations are comparable but the blood
collecting tube used is important as the few anticoagulants used are
inappropriate to some drugs and analytical procedures.
• Whole blood must be sampled for few drugs like, Cyclosporine A, that
distributes between plasma and erythrocytes.
• In infants, capillary blood may be collected for TDM.
• Despite extensive research examined the utility of saliva measurements
other biological fluids are not routinely sampled.
• The timing of sampling is likely responsible for the greatest number of
errors in interpreting the results.

• Examples:

• Lithium: 12hr sample is most precise,

• Digoxin: Make measurements at least 6hrs after a dose to avoid

inappropriate high levels
• Carbamazepine: Its half life is as long as 48hrs following a single dose.
So a thorough concentration taken just after a dose together with a
peak level three hours later is ideal
 Laboratory measurement
• A quality drug assay should be performed within a clinically useful time frame.

• The assay procedure should be a validated one

• The assay procedure should be evaluated with an external quality assurance

program.

• Senior laboratory staff should verify the assay results in light of clinical request.

• Ideally the results of the assay should be available to the clinician before the
next dose is given
• The methodology employed should ideally:
 Distinguish between compounds of similar structure – unchanged drug
and metabolites
 Detect small amounts
 Be simple enough to use as a routine assay
 Be unaffected by other drugs administered simultaneously.
 Various analytical techniques available are;
 Spectrophotometry and Fluorimetry,

 Thin layer chromatography (TLC),

 HPLC and GLC,

 Radio Immuno assay(RIA),

 Enzyme Immuno assay,

 Fluorescence polarization Immunoassay (FPIA)

 Clinical interpretation

• Clinical interpretation can ‘add value’ and convert ‘therapeutic

measurement service’ into ‘therapeutic drug monitoring service’. • Just
relating a drug concentration to a published therapeutic range is not an
adequate interpretation.

• Concentration must always be interpreted in the light of clinical response,

individual patient demographics and dosage regimen used.

• Therapeutic ranges are available but should only be used as a guide.

 Clinical interpretation

• Important considerations;

Serum Concentrations Lower than Anticipated: (Patient compliance, error

in dosage regimen, wrong drug product, poor bioavailability).

Serum Concentrations Higher than Anticipated: (Patient compliance, error

in dosage regimen, poor metabolizer, high plasma protein bounding).

Serum Concentration Correct but Patient Does Not Respond to Therapy:

(Altered receptor sensitivity e.g., tolerance, drug interactions at receptor)
 Clinical significance
• Maximizes efficacy

• Avoids toxicity

• Identifies therapeutic failure – Non compliance, subtherapeutic dose

• Facilitates adjustment of dosage

• New dose = Old dose X Desired Css/Old Css

• Facilitates the therapeutic effect of drug by achieving target drug

concentration

• Identify poisoning, drug toxicity and drug abuse

TDM OF PHENYTOIN
 What is Phenytoin?

• Phenytoin is an anticonvulsant licensed for the management of

generalised tonic-clonic (grandmal) seizures and complex partial
(psychomotor, temporal lobe) seizures.

• It is also approved for the prevention and treatment of seizures occurring

during or after neurosurgery.

• Inhibits Na channel
 Dosage Forms
For parenteral use:
1) Phenytoin sodium, the sodium salt of phenytoin, contains (92%
phenytoin), Infusion rate <50 mg/min
2) Fosphenytoin, a water soluble phosphate ester prodrug of phenytoin,
Infusion rate <150 mg/min
For oral use:
1) Tablets and suspensions contain phenytoin (100%)
 Phenytoin tablets 50 mg chewable and
 Suspension 125 mg/5 mL.
 Capsules contain 92% phenytoin 27
 Need for monitoring

• Narrow therapeutic window

• Highly protein-bound; drug-drug interactions, drug-disease interactions
• Non-linear pharmacokinetics even within the therapeutic range
• Inter-individual variability in enzyme saturation
•Approximately 90% of phenytoin is bound to albumin. Thus, phenytoin
levels must be corrected according to albumin levels.
Disease states and conditions that alter
Phenytoin plasma protein binding
Disease states (hypoalbuminemia) Drug interaction

Liver disease Warfarin

Nephrotic syndrome Valporic acid

Pregnancy Aspirin (>2g/d)

Cystic fibrosis NSAIDs with high albumin binding

Burns

Trauma

Malnourishment

Elderly 29
 Pharmacokinetics

Absorbed slowly from the intestine and the rate of absorption varies among
dosage forms

• The time at which the concentration peaks is 3-12 hours after a single oral
dose of a capsule or tablet.

• This slow absorption and relatively slow elimination of the drug have led
to the recommendation of once daily administration.

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 Pharmacodynamics

•The usually accepted therapeutic range for plasma phenytoin

concentration is 10 to 20 mcg/ml.

•These concentrations are usually effective in controlling both seizure

disorders and cardiac arrhythmias.

•Clinical evaluation of the patient should accompany monitoring of

plasma concentration.

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 WHEN SHOULD PHENYTOIN LEVELS BE
TAKEN?
Newly Started Suspected Non-
Patient on compliance/
Phenytoin Breakthrough
Seizures
To establish an Non-compliance leading to
individual therapeutic sub-therapeutic phenytoin
concentration. The levels is common enough
reference range for that checking the phenytoin
phenytoin levels may level to ensure effective
not be applicable to all drug concentrations would
patients. be a logical first step in
patients presenting with
breakthrough seizures or
worsening epilepsy.
To guide Dose Suspected Phenytoin
Adjustment Toxicity
Factors altering the Phenytoin toxicity may be
pharmacokinetics of variable in presentation. Some
phenytoin may result dose-related adverse effects
in unpredictable may mimic symptoms of other
changes in drug levels diseases. Drug levels may
e.g. VD is higher in assist in ruling out phenytoin
obesity, implying a toxicity as a differential
need for higher diagnosis.
loading doses. Others
include Liver and
kidney disease failure,
the elderly and the
critically ill.
 Dosing
• The average half-life of oral phenytoin is 22 hours. Using normal
maintenance doses, the drug commonly reaches a steady state in 7–10
days.

• In emergency situations such as status epilepticus when phenytoin must

be initiated urgently for a patient, the use of a loading dose will help the
medication reach the necessary therapeutic levels faster.

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 Phenytoin dosing
• Phenytoin can be given intravenously or orally.

• The loading dose is 10–20 mg/kg.

• If given orally, this dose should be divided into three doses (e.g. 1000 mg given
as 400 mg initially, 300 mg two hours later and 300 mg two hours after that) to
ensure optimal oral absorption.

• If given intravenously, the full dose can be given at a maximum rate of 50

mg/min. Subsequent maintenance doses are usually in the range of 5–7
mg/kg/day (300–400 mg/day)
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HOW DO I TAKE PHENYTOIN LEVELS?
• The Importance of Taking Concurrent Albumin Levels
• Total serum phenytoin levels reflect both bound and unbound drug. In
healthy adults, approximately 90% of phenytoin is bound to albumin.
Thus, phenytoin levels must be corrected according to albumin levels.
Formula for Corrected Phenytoin

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 Sampling time
Newly Started Suspected Non- After Dose Suspected
Patient on compliance/ Adjustment Phenytoin Toxicity
Phenytoin Breakthrough
Seizures
Based on ROA of Levels can Within six to seven Immediately; second
loading dose be drawn at the point days; trough level or at phenytoin level may be
IV: one hour after of admission, least eight hours after useful to guide when to
the dose regardless of the last dose restart phenytoin.
ORAL: 24hrs after the the patient’s normal
last dose dosing time.

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WHAT DO I DO WITH THESE VALUES?
• The reference range for corrected phenytoin is 10– 20 mg/dL

• When it comes to TDM of anti-epileptic drugs, there is a principle which says: “Treat
the patient, not the numbers”.

• It is not recommended to increase the dose of phenytoin in patients who are seizure
free with low therapeutic levels.

• Conversely, the dose should be decreased in patients exhibiting symptoms of

phenytoin toxicity with “therapeutic” levels.

• This brings to light the importance of establishing individual therapeutic

concentrations for different patients.
37
 How Often Should I Check Phenytoin
Levels in a Stable Patient
• In the Outpatient Setting
• Phenytoin levels are generally monitored at 3 to 12 months intervals

• Generally, situations which alter phenytoin pharmacokinetics (e.g. body

weight changes, initiation of interacting drugs, changes in renal or liver
function) should prompt the physician to revisit the phenytoin regimen
and review the need to check drug levels.

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 Dose adjustment

• For plasma phenytoin concentrations less than 7 µg/ml, a

dosage increase of 100 mg/day is recommended;

• For plasma concentrations between 7 and 12 µg/ ml, the dose

may be increased by 50 mg/day;

• If the plasma concentration is greater than 12 µg/ ml, the dose

may increase by 30 mg/day

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 Dose adjustment

• Dosage increases when the plasma level is above 16 µg/ml

should only be done with caution as even a small increase may
result in toxicity.

• Dose changes should be more conservative in patients with

reduced protein binding (e.g. in hypoalbuminemia or in renal
impairment) as changes in drug concentration will be exaggerated
in these cases.
40
 Dose adjustment contd..
• Dose-related adverse effects are common during initiation of therapy, but
may improve or resolve over time, even without a change in dose.
• Titration of dosage regimen based on phenytoin levels may also help with
dose-related adverse effects, to achieve an effective drug level with
tolerable adverse effects.

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Adverse effects of Phenytoin

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 DIGOXIN TDM
History

• Extract from the purple fox glove(digitalis purpurea)

• Digitalis potency had been known since 1775.

• William Withering (scottish physician) tried out various formulations of

digitalis plant extracts on 163 patients and found that if he used the
dried powdered leaf, he got amazingly successful results.

• He introduced its use officially in 1785

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 Pharmacology of digoxin

• Digoxin is a cardiac glycoside that has inotropic effects.

MOA; binds the sodium potassium ATPase pump causing inhibition of the
sodium pump thus decreased transport of sodium out of the myocardial
cells and causes calcium entry and decreased calcium elimination hence
enhanced myocardial contractility.

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Indication of digoxin

• its used for the treatment of:

 congestive heart failure

 Atrial fibrillation.

Paroxysmal supra-ventricular tachycardia (PSVT)

Contraindications of digoxin

 Acute MI

 Myocarditis

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 Pharmacokinetics and pharmacodynamics of digoxin.
 Administration: Doses of digoxin are usually administered orally or intravenously

 Absorption: digoxin is 100% absorbed from the gut, however, Cholestyramine and
antacids decrease the intestinal absorption of digoxin.

Distribution- Vd of digoxin is large and extremely variable.

• Digoxin distributes into lean body tissue.

• Volume of distribution depends on the ideal body weight of the patient.

• Average;7 L/kg (range: 5–9 L/kg)

• In renal impairment the Vd is 4.7L/kg leading to elevation of plasma drug levels,

therefore both the initial LD and the MD must be reduced in patients with
underlying renal disease. 46
• Digoxin is approximately 25% bound to serum protein .

• Follows a 2 compartment model , and the distribution phase takes 6-

8hrs and therefore digoxin serum levels should be determined after at
least 6 hrs.

Metabolism; digoxin is metabolized in the stomach and the intestine.

Use of antibiotics such as tetracycline and erythromycin may impair GI

metabolism of digoxin leading to higher serum digoxin concentrations.

47
48
Elimination :Total clearance of digoxin is determined by both renal and
non-renal,(hepatic metabolism or biliary excretion).

• 70% of digoxin is excreted unchanged in urine, leading to prolongation of

half life in patients with renal insufficiency.

• Digoxin has a long t1/2 of at least 30 hours.

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 Therapeutic drug levels

• Therapeutic range;0.8-2ng/ml

• Toxic levels;>2 ng/ml

2-2.5ng/ml; increased risk of toxicity although tolerated by some people.

Greater than or equal to 2.5ng/ml: GI, CVS,CNS Effects.

50
 Factors that must be considered in selecting
a dose of digoxin
The body weight of the patient..

The patient’s renal function, preferably evaluated on the basis of

estimated creatinine clearance.

The patient’s age

Concomitant disease states, concurrent medications, or other

factors likely to alter the pharmacokinetic or pharmacodynamic profile
of digoxin.
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 Initiation of Digoxin therapy

 Divided into;

Rapid loading: for ventricular rate control in Atrial fibrillation

Slow loading, followed by the maintenance digoxin dose.

Slow digoxin loading; preferred for most patients,

can be achieved by starting a maintenance dose of 0.125 to 0.25 mg daily.

A steady state will be achieved after approximately 7 to 10 days in the

average subject.
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• Rapid digoxin loading — Rapid intravenous and oral loading

• The total loading dose with digoxin varies from patient to patient but is
usually between 0.75 to 1.5 mg with intravenous administration and 1 to
1.5 mg with oral administration.

• Digoxin loading dose 10-15 mcg/kg PO or 8-12 mcg/kg IV, divided into 3
doses and given as 50% initially then 25% the next 2 doses q6hrs.

53
Loading dose adjustments

Patients who are hypokalemic, hypomagnesemic, hypercalcemic, hypoxic,

or with hypothyroidism are more sensitive to the effects of digoxin .an
initial loading dose in the lower range (eg, 0.75 mg or less) should be
considered.

Renal impairment : a reduced loading dose of 3 to 5 mcg/kg (0.25 to

0.375 mg) is recommended, followed by a maintenance dose of 0.0625 mg
every 48 hours.

Reduce the total dose by 50%

54
LD = Vd x Css/F where Css is the desired digoxin steady-state
concentration in μg/L which is equivalent to ng/mL, V is the digoxin volume
of distribution, and F is the bioavailability fraction

Maintenance dose

For most patients, the maintenance dose is be between 0.125 mg and 0.25
mg daily.

MD = Cl x Css/F

55
 Appropriate sampling time

• Blood samples should be obtained at least 6 hours, but optimally 12

hours, after administration of digoxin to ensure completion of distribution
from the blood to the tissues.

• In patients with advanced kidney disease or who are on hemodialysis,

the digoxin level should be checked at least 12 to 24 hours after the
prior dose.

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Example:
MJ has a steady state concentration of 1.2 μg/L . volume of distribution V
= 7 L/kg ⋅ 70 kg = 490 L,F=1
• LD = (Css ⋅ V) / F = (1.2 μg/L ⋅ 490 L) / 1
= 588 μg rounded to 500 μg

• When digoxin loading doses are administered, they are usually given in
divided doses separated by 6 hours (50% of dose at first, followed by two
additional doses of 25%). In this case, an initial intravenous dose of 250 μg
would be given initially, followed by two additional intravenous doses of
125 μg each.

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Adverse effects of digoxin

GIT: Nausea, vomiting, diarrhea, anorexia, abdominal pain, or constipation

CNS: headache, fatigue, insomnia, Confusion, blurred vision and changes

in color vision

• CVS: palpitations , second or third degree atrioventricular block,

atrioventricular dissociation, bradycardia, premature ventricular
contractions, or ventricular tachycardia.

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Toxicity reversal

• Digibind or digoxin immune fab can be used to rapidly reverse the

adverse symptoms.

• MOA: bind digoxin and digitoxin molecules, facilitating removal from the
body.

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• Qn. HY is a 72-year-old, 80-kg (5 ft 7 in ) male who has
accidently been taking twice his prescribed dose of digoxin
tablets. The admitting digoxin serum concentration is 4.1 ng/mL.
Compute an appropriate dose of Digibind for this patient.

• Ans. Digibind dose (in vials) = (digoxin concentration in ng/mL)

(body weight in kg)/100 =(4.1 ng/mL ⋅ 80 kg)/100 = 3.3 vials,
rounded up to 4 vials

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 Conclusion
• Slow oral loading of digoxin, generally preferred for most patients, can
be achieved by starting a maintenance dose of 0.125 to 0.25 mg daily.

• Given the relatively narrow therapeutic window of digoxin, patients

taking digoxin require monitoring of the serum digoxin concentration.

• Monitoring the serum digoxin level is particularly important in persons

with chronic renal dysfunction, rapidly changing renal function, or
electrolyte disturbance.
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 Conclusion

• TDM can be useful for establishing initial dosing and monitoring certain
medications.

• TDM can not compensate for error in diagnosis, poor choice of drugs,
errors in dispensing and dosages, errors in sampling, non compliance etc.

• However, when used in combination with good clinical observation, it can

lead to optimal drug therapy with minimal side effects.