Drugs that are monitored

by TDM
Sylvia Achieng Lumumba
2021/MMLS/016/PS
C.Chem
LEC: Madam Ritah

06/05/2023 1
Introduction
• TDM involves measuring drug concentrations in plasma, serum or
blood, and clinical interpretation of the result.
• This requires knowledge of the pharmacokinetics, sampling time, drug
history and the patient's clinical condition.
• The desired or adverse effects may correlate better with plasma or
blood concentrations than they do with dose.
• This information is used to individualize dosage so that drug
concentrations can be maintained within a target range.
• Other samples include saliva and ISF

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Introductions cont’d

• When an effect, such as changes in blood pressure, pain or serum cholesterol is

readily measured, the dose of a drug should be adjusted according to the response.
• TDM useful when drugs are used to prevent an adverse outcome, eg
• Graft rejection or to avoid toxicity, as with aminoglycosides.
• A drug should satisfy certain criteria to be suitable for therapeutic drug monitoring.
• The laboratory department is responsible for ensuring the accuracy and precision of
the TDM tests.
• Implementing quality control measures.
• Use internal quality control samples and external proficiency testing programs to verify the
accuracy of the TDM test results.
• Ensure that the TDM tests are performed in a timely manner.

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Terminologies used in TDM
• Therapeutic drug monitoring - A process of measuring drug concentrations in
a patient's blood or other body fluids to optimize drug therapy and minimize
toxicity.
• Pharmacokinetics - The study of how drugs are absorbed, distributed,
metabolized, and excreted by the body.
• Pharmacodynamics - The study of how drugs interact with their target
molecules or cells to produce a therapeutic effect.
• Therapeutic range - The range of drug concentrations in a patient's body that is
effective for treating a particular disease or condition.
• Half-life - The time it takes for half of the drug to be eliminated from the body.
• Clearance - The rate at which a drug is removed from the body.
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Terminologies used in TDM cont’d
• Bioavailability - The proportion of a drug that enters the systemic
circulation after administration.
• Peak concentration - The highest concentration of a drug in the
bloodstream after administration.
• Trough concentration - The lowest concentration of a drug in the
bloodstream, typically measured just before the next dose is administered.
• Loading dose - An initial higher dose of a drug to achieve therapeutic
concentrations more quickly.
• Maintenance dose - A lower dose of a drug given regularly to maintain
therapeutic concentrations.
• Toxicity - An adverse effect of a drug resulting from excessive
concentrations in the body.
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 TDM to Model‐Informed Precision Dosing for Antibiotics

Clin Pharma and Therapeutics, Volume: 109, Issue: 4, Pages: 928-941, First published: 10 February 2021, DOI: (10.1002/cpt.2202)
Criteria to be suitable for TDM
• Narrow target range
• Significant pharmacokinetic variability
• A reasonable relationship between plasma concentrations and clinical
effects
• Established target concentration range
• Availability of cost-effective drug assays.

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The drugs monitored by TDM
Drugs monitored include
• Antibiotics
• Anticonvulsants
• Immunosuppressants
• Cardiac medications
• Theophylline
• Albuteral

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 Antibiotics on TDM
• Success or failure of antibacterial therapy is driven by three
determinants which determine the required dose of an antibiotic, these
are:
• The patient,
• The bacterium, and
• The antibiotic.
• In the critically ill patients, TDM is desirable to ascertain that the
exposure of the drug is optimal.

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Under which conditions is TDM with individualized dosing of antibiotics useful?

• When the observed variability in PK/PD measures exceeds the

acceptable variability in safety and efficacy,
• i.e., if the variability in PK and response leads to therapy failure or toxicity in
a part of the population.
• When there is increased PK variability in conjunction with less
susceptible target pathogens.
• Individualized antibiotic dosing is recommended for aminoglycosides,
beta-lactams, linezolid, teicoplanin, and vancomycin in critically ill
patients.

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The TDM process of antibiotics in the lab
• Collect blood sample from the patient, for analysis of antibiotics and biomarkers.
• Extract the antibiotic from the sample and measure its concentration.
• Compare the concentration of the antibiotic to the therapeutic range for the
specific antibiotic.
• Interpret the TDM results and communicate them to the caregiver .
• If the concentration falls outside of the therapeutic range, the dose of the antibiotic may
need to be adjusted.
• Generate a report that includes
• Measured antibiotic concentration
• Therapeutic range,
• Recommended dosage adjustments

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Biomarkers: quantitative treatment
response and toxicity
• Biomarkers are used to;
• identify the onset of an infection,
• evaluate the response
• define when to stop treatment
• Repeated measurements of endogenous substances, potentially guide
individual dose adjustments more precisely than drug concentrations.
• Biomarkers for antibiotics measurement include; CRP, interleukins (IL6, α-
TNF), procalcitonin
• In myelosuppressive chemo, IL-6 peaks occurred ~ 2 days before the CRP
peak, coinciding with the dx of febrile neutropenia. while α-TNF peaks
even earlier
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Biomarkers: quantitative treatment
response and toxicity
• Procalcitonin reflects disease progression fairly well; i.e.,
• Studies have shown that antibiotic treatment efficiency is proportional
to the decrease in procalcitonin concentrations
• This nay be an indicator for stoppage of treatment.
• Other biomarkers that may used to guide treatment include immune
cell response, IL-8, IL-10.
• Quantification of bacterial DNA or RNA indicate the disease state and
can guide precision dosing.

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Vancomycin
• Vancomycin treats gram-positive bacteria infections.
• TDM ensure that the drug is being administered at the appropriate
dose and to prevent toxic side effects.
• The therapeutic range is typically between 15 and 20 mg/L.
• TDM of vancomycin has been shown to improve clinical outcomes by
reducing the incidence of nephrotoxicity and treatment failure.

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Aminoglycosides
• Aminoglycosides, such as gentamicin and amikacin, are used to treat
infections caused by gram-negative bacteria.
• TDM reduce the risk of toxic side effects, such as nephrotoxicity and
ototoxicity.
• The therapeutic range is typically between 5 and 10 mg/L.
• TDM of aminoglycosides has been shown to improve clinical
outcomes by reducing the incidence of toxicity and improving
bacterial clearance.

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Linezolid
• Linezolid is used to treat infections caused by gram-positive bacteria,
including methicillin-resistant Staphylococcus aureus (MRSA).
• TDM of linezolid is used to prevent toxic side effects, such as
myelosuppression and peripheral neuropathy.
• The therapeutic range for linezolid is typically between 2 and 15
mg/L.
• TDM of linezolid has been shown to improve clinical outcomes by
reducing the incidence of toxicity and improving bacterial clearance.

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TDM OF Anticonvulsants

• TDM of anticonvulsants is a test that measures the concentration of

anticonvulsant drugs in a patient's blood
• Anticonvulsants are a class of medications used to treat
• Seizures
• Bipolar disorder
• Neuropathic pain.
• The TDM of anticonvulsants helps healthcare providers to adjust the
dose of the medication and optimize the therapeutic outcomes.

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Phenytoin
• Phenytoin is a widely used anticonvulsant medication for treating
seizures.
• The therapeutic range for phenytoin is typically between 10 and 20
µg/mL.
• The laboratory technician will extract the drug from the blood sample
and analyze it using a method such as high-performance liquid
chromatography (HPLC).
• The results of the TDM are then reported to the healthcare provider,
who may adjust the dose of the medication based on the TDM results.

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Valproic acid
• Valproic acid is another commonly used anticonvulsant medication
that is used to treat seizures.
• TDM of valproic acid is typically performed to ensure that therapeutic
levels are maintained and to prevent toxicity.
• The therapeutic range for valproic acid is typically between 50 and
100 µg/mL.
• The TDM process for valproic acid is similar to that for phenytoin,
involving the measurement of the concentration of the drug in the
patient's blood and comparison to the therapeutic range.

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Carbamazepine
• Carbamazepine is used to treat seizures and neuropathic pain.
• TDM of carbamazepine is typically performed to ensure that
therapeutic levels are maintained and to prevent toxicity.
• The therapeutic range for carbamazepine is typically between 4 and 12
µg/mL.
• The TDM process for carbamazepine involves measuring the
concentration of the drug in the patient's blood and comparing it to the
therapeutic range.
• The laboratory technician will extract the drug from the blood sample
and analyze it using a method such as HPLC.
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TDM of immunosuppresants
• Immunosuppressants are drugs that suppress the immune system to
prevent transplant rejection and to treat autoimmune diseases.
• They are highly variable in their PK, i.e the way the drug is absorbed,
distributed, metabolized, and eliminated from the body can vary
significantly between patients.
• This variability can make it difficult to achieve optimal drug
concentrations and can increase the risk of adverse drug reactions.

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Tacrolimus & Cyclosporine
• These are calcineurin inhibitors that are commonly used in solid organ
transplantation autoimmune diseases to prevent rejection.
• TDM of tacrolimus is essential to ensure that therapeutic levels are
maintained and to prevent toxicity.
• The therapeutic range for tacrolimus is typically between 5 and 20
ng/mL while that of cyclosporine is 100 and 400 ng/mL in whole
blood.
• TDM method used include liquid chromatography-tandem mass
spectrometry (LC-MS/MS).

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TDM of cardiac medications
• Therapeutic drug monitoring (TDM) is used for some cardiac
medications to ensure that patients are receiving optimal doses and to
prevent toxicity.
• Examples of cardiac medications for which TDM is commonly
performed include:

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Warfarin
• Warfarin is an anticoagulant that is used to prevent blood clots in
patients with conditions such as atrial fibrillation and deep vein
thrombosis.
• The therapeutic range is narrow, and both under dosing and
overdosing can lead to serious complications.
• The therapeutic range for warfarin is expressed as an international
normalized ratio (INR) between 2.0 and 3.0 for most indications.
• TDM of warfarin involves measuring the patient's INR using point-of-
care testing or laboratory-based methods and adjusting the dose of
warfarin based on the INR.
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Digoxin
• Digoxin is a cardiac glycoside that is used to treat heart failure and
arrhythmias.
• TDM of digoxin is important because the therapeutic range is narrow,
and toxicity can occur even at therapeutic levels.
• The therapeutic range for digoxin is typically between 0.5 and 2
ng/mL in serum or plasma.
• TDM of digoxin involves measuring the concentration of the drug in
the patient's blood using a method such as immunoassay or high-
performance liquid chromatography (HPLC) and comparing it to the
therapeutic range.
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Amiodarone
• Amiodarone is an antiarrhythmic medication that is used to treat
ventricular and supraventricular arrhythmias.
• TDM of amiodarone is important because the drug has a long half-life
and can accumulate in the body, leading to toxicity.
• The therapeutic range for amiodarone is not well defined, but serum
concentrations between 1.0 and 2.5 mg/L are generally considered to be
therapeutic.
• TDM of amiodarone involves measuring the concentration of the drug
in the patient's blood using a method such as HPLC or LC-MS/MS and
adjusting the dose of amiodarone based on the measured concentration.
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TDM of Theophylline

• Theophylline is a bronchodilator medication used to treat asthma and

chronic obstructive pulmonary disease (COPD).
• Theophylline has a narrow therapeutic range,
• TDM is necessary to ensure that the patient is receiving a safe and
effective dose
• Theophylline is primarily metabolized by the liver, and the rate is
affected by age, smoking and other medications,

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TDM of Theophylline
• The therapeutic range for theophylline varies depending on the
indication for use.
• between 5 and 15 mcg/mL for asthma,
• between 8 and 20 mcg/mL for COPD.
• Some patients may experience therapeutic effects at concentrations
below the lower end of the therapeutic range, while others may
experience toxicity at concentrations within the therapeutic range.
• TDM of theophylline uses method such as immunoassay or high-
performance liquid chromatography (HPLC).

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Albuterol
• Albuterol treats bronchospasm in conditions such as asthma and
chronic obstructive pulmonary disease (COPD).
• Albuterol does not require TDM because it has a wide therapeutic
index.
• In some cases, TDM may be used to monitor albuterol levels.
• This is done in research settings or in cases where the patient is
experiencing unexpected side effects or poor response to treatment
• Consider age, weight, and renal function

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Albuterol
• In renal disease, the clearance of albuterol may be reduced, leading to
higher drug concentrations and an increased risk of side effects.
• A patient is using albuterol too frequently, will have higher
concentration of the drug than expected, indicating that they may need
to adjust their dosing regimen or use a different medication.

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Indications for drug monitoring
Toxicity
• Dx undifferentiated clinical syndrome (unexplained nausea in a patient taking
digoxin)
• Avoiding toxicity (aminoglycosides, cyclosporin)
Dosing
• After dose adjustment (usually after reaching a steady state)
• Assessment of adequate loading dose (after starting phenytoin treatment)
• Dose forecasting to help predict a patient's dose requirements1 (aminoglycosides)

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Indications for drug monitoring cont’d
Monitoring
• Assessing compliance (anticonvulsant concentrations in seizure patients)
• Dx of under treatment (important for prophylactic drugs such as
anticonvulsants, immunosuppressants)
• Dx of failed therapy (to distinguish between ineffective drug treatment,
non-compliance and adverse effects mimicking underlying disease).
• The target concentration may depend on the indication. (the recommended
concentration for digoxin depends on whether it is being used to treat
atrial fibrillation or congestive heart failure)

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Timing of the plasma sample

• Samples should be taken at steady state within 4-5 half-lives after starting therapy
• At steady state, plasma concentration is usually proportional to receptor
concentration.
• Howeverr Some drugs are monitored before steady state,
• Perhexiline, TDM is done after the first few doses due to its very long half-life in patients who
are 'poor metabolisers’
• Phenytoin TDM can give a preliminary indication of adequate dosing.
• The drug concentration changes during the dosing interval and the least variable
point is just before the next dose is due.
• This pre-dose or trough concentration is what is usually measured.

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Timing of the plasma sample
• Long half-life drugs such as phenobarbitone and amiodarone, collect samples at
any point in the dosage interval.
• Correct sample timing should also take into account absorption and distribution.
• eg digoxin monitoring should not be performed within six hours of a dose,
• Occasionally, sampling at the time of specific symptoms may detect toxicity
related to peak concentrations (carbamazepine and lithium).
• Aminoglycosides OD, is collected 6-14 hours post-dose when a nomogram is
used, or twice within the dosing interval to calculate the area under the
concentration-time curve.
• When aminoglycosides are prescribed in multiple daily doses to treat,
enterococcal endocarditis, trough samples are measured
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Therapeutic drug monitoring request
• Drug assays are usually requested for TDM or for clinical toxicology
purposes.
For TDM the information required;
• Time of the sample collection,
• Time of the last dose,
• Dosage regimen and
• Indication for drug monitoring

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 Interpretation
• Drug concentrations is interpreted in the context of the individual
patient without rigid adherence to a target range.
• For dose adjustments, consider ;
• if the sample was taken at the correct time with respect to the last dose,
• if a steady state has been reached and whether the patient has adhered to their
treatment.
• Hypokalaemia should be noted when interpreting digoxin concentrations.
• Unbound fractions may be affected by
• serum albumin concentration,
• Displacement by an interacting drug and
• Renal failure.

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 Measuring and monitoring

• Drug concentrations are measured within a clinically useful timeframe

• Concentrations are reported in mass or molar units. conversion
formulas attached to assist with interpretation of results
• Validated target ranges should accompany results to assist clinicians
with safe and effective prescribing.
• The lab may provide drug monitoring and interpretive services which
may help to improve the safety, efficacy and cost-effectiveness of
clinical services.

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Limitations of TDM
• Most drugs are not amenable to TDM in local set ups also;
• there are inherent limitations, including
• the scientific accuracy of the drug assays,
• laboratory variability in reporting,
• limited accessibility
• the validity of suggested target ranges
• The target range for most drugs is not well described and is often
based on a very limited number of data points.
• Active metabolites (for example carbamazepine-10,11-epoxide) may
contribute to the therapeutic response though not routinely measured.
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References
• Krasowski MD, McMillin GA. Advances in Anti-Epileptic Drug Testing. Clin
Lab Med. 2012;32(2):313-329. doi:10.1016/j.cll.2012.03.005
• Dasgupta A. Therapeutic drug monitoring of cardiovascular drugs. Clin Chem.
2003;49(5):730-734. doi:10.1373/49.5.730
• Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. Enterohepatic
Circulation: Physiological, Pharmacokinetic and Clinical Implications. Clin
Pharmacokinet. 2002;41(10):751-790. doi:10.2165/00003088-200241100-00002
• Pichini S, Pacifici R, Busardo FP. The Role of Therapeutic Drug Monitoring in
the Treatment of Drug Addiction. Ther Drug Monit. 2015;37(6):710-719.
doi:10.1097/FTD.0000000000000213
• eTG complete. Therapeutic Guidelines Ltd. 2007 Nov.

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Therapeutic drug monitoring (TDM) Case Studies

Case 1:
• A patient with congestive heart failure has been successfully treated with digoxin for several years.
Laboratory records indicate semiannual peak digoxin levels have all been in the therapeutic range. This
patient recently developed renal failure, and admission testing was performed. Selected serum or blood
laboratory results from this specimen are shown below. Although digoxin is high, the physician
indicates the patient is not exhibiting signs or symptoms of toxicity.
• LABORATORY RESULTS
• TEST RESULT REFERENCE RANGE
• Sodium 129 135–145 mEq/L
• Potassium 5.5 3.5–5
• Chloride 113 97–107 mEq/L
• Blood pH 7.25 7.35–7.45
• TCO2 16 21–31 mmol/L
• Urea nitrogen 180 5–20 mg/dL
• Creatinine 4.5 0.6–1 mg/dL
• Osmolality 275 282–300 mOsm/kg
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• Digoxin 2.5 0.9–2 ng/ml
Questions for case 1

1. If these results were derived from a random specimen, how may the time since the
last dose affect the interpretation of the digoxin results?
• The peak level of digoxin is evaluated about 8 hours after an oral dose. Levels measured
prior to this may present with a concentration greater than the upper limit of the
therapeutic range and yet not reflect the tissue concentration associated with toxic
effects
2. Other than time, what additional factors should be taken into consideration when
interpreting the digoxin results?
• The therapeutic actions of digoxin may be influenced by serum electrolyte
concentration. High serum potassium may attenuate digoxin actions; therefore, the
patient may not be displaying digoxin toxicity
3. What additional laboratory test would aid in the interpretation of this case?
• Digoxin-like immunoreactive factors may be observed in uremic patients. The measured
digoxin in this case may not truly reflect the circulating concentration of drug present 41
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Therapeutic drug monitoring (TDM) Case
Studies
Case 2:
A patient is receiving procainamide for treatment of cardiac arrhythmia. An IV loading dose resulted in a serum
concentration of 6.0 ug/mL. The therapeutic range for procainamide is 4–8 ug/mL, and its half-life is 4 hours.
Four hours after the initial loadingdose, another equivalent dose was given as an IV bolus. This resulted in a
serum concentration of 7.5 ug/mL.
1. Does the serum concentration after the second dose seem appropriate? If not, what would be the
predicted serum concentration at this time?
After one half-life has passed, the predicted serum concentration should have fallen to half of its initial
concentration. After one half-life, the predicted serum concentration of procainamide would be 3 μg/mL. The
serum concentration after the second dose should be the sum of what remains from the first dose plus what is
being added. The first dose resulted in a serum concentration of 6 μg/mL. Therefore, the second dose should
have resulted in a serum concentration of 9 μg/mL. A disparity exists between the predicted and observed
concentration after the second dose. Procainamide is eliminated by hepatic metabolism. A plausible explanation
for these results is that this patient is metabolizing procainamide at about twice the normal rate (half-life = 2
hours). If this is the case, 4 hours after the initial dose, the predicted serum concentration would be 1.5 μg/mL.
The predicted serum concentration after the second dose would then be 7.5 μg/mL

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2. What factors would influence the rate of elimination of this
drug?
The rate of hepatic metabolism may be influenced by various factors.
Procainamide is eliminated by acetylation. There is a range of activity
of the enzyme responsible for this reaction in the population.
Individuals who are fast acetylators are relatively common

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Therapeutic drug monitoring (TDM) Case
Studies
Case Study 3
• A child, who has been successfully treated for seizure disorders with
oral phenytoin for several years, has had severe diarrhea for the past 2
weeks. After this, the patient had a seizure. Evaluation of serum
phenytoin at the time of the seizure revealed a low value. The dose
was increased until serum concentrations were within the therapeutic
range. The diarrhea was resolved. Several days after this, the patient
had another seizure.

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Questions for case 3
1. What is the most probable cause of the initial low serum
phenytoin?
Gastrointestinal absorption of phenytoin, like most drugs, occurs by
passive diffusion. Many factors may influence the degree of absorption.
In this case, a key element may be time. In diarrhea associated with
hypermotility, there may not be sufficient time for absorption to occur.
Because phenytoin is eliminated according to zero-order kinetics, small
changes in absorption can effect large changes in serum concentration

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2. Would determination of free serum phenytoin aid in resolving the
cause of the initial seizure?
Determination of free phenytoin would probably not provide
information beneficial to patient care in this situation. The low total
phenytoin, in conjunction with seizure onset, is probably sufficient to
assume the free fraction is also low. No further seizures occurred when
the dose was increased to the therapeutic range, which supports the
determination that free drug is not needed

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3. What assays other than the determination of serum phenytoin would
aid in this situation?
Severe diarrhea is associated with changes in various serum analytes, many of
which may affect the binding characteristics of phenytoin. Possibilities
include serum total protein, serum albumin, blood pH, or the presence of
other substances that maycompete for the phenytoin binding site
4. What is the most probable cause of the seizure after the diarrhea has
been resolved?
In the presence of excessive loss due to diarrhea, the dosage was increased.
After diarrhea has stopped, the dosage of phenytoin needs to be readjusted to
reflect the changes in degree of absorption
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