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Therapeutic Drug Monitoring
Dr. Ashutosh Tiwari
PG Resident 2nd Year
Department of Pharmacology
SAIMS Indore
07/08/2014
Presentation Layout
• Introduction
• TDM: Definition, Goals & Objectives
• Criteria for TDM
• Indications
• Factors affecting TDM
• TDM process
• Analytical methods
• Samples & Timing
• Clinical interpretation
• Common Drugs requiring TDM
• Clinical usefulness
• Problems
• Limitations
• Conclusion
What is Therapeutic drug monitoring?
• TDM is measurement of drug concentrations
usually in the blood or plasma that facilitates
adjustment of dosage to produce a desired
response
Why therapeutic drug monitoring?
• Therapeutic drug monitoring can guide the
clinician to provide effective and safe drug
therapy in the individual patient using serum
drug concentration
Why should drug level be monitored?
• 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.
• Not all the patients have the same response at
similar doses
Is drug given to the patient
working?
1) Is the drug
getting to the site
of action?
• Pharmacokinetic
measures
2) Is it producing
the required
pharmacological
effect?
• Pharmacodynamic
measures
3) Is the
pharmacological
effect being
translated into
therapeutic effect?
• Therapeutic outcome
Monitoring of drug therapy
• Monitoring of drug therapy can be done by
– Therapeutic outcome using clinical end points
– Pharmacodynamic measures using surrogate
markers
– Pharmacokinetic measures using TDM
Is the pharmacological effect being
translated into therapeutic effect?
Monitoring therapeutic events in
individual
1. Anti-convulsant drug therapy: seizure
frequency
2. Drugs for angina pectoris: frequency of
attacks
3. Diuretics in the t/t of edema
Is the drug producing the required
pharmacological effect?
• In some cases it is not possible to measure
the therapeutic outcome directly.
• A pharmacodynamic effect, called surrogate
marker, is measured.
• A surrogate marker is defined as an endpoint
that is measured in place of the true end
point & that relates in someway to the end
point of primary interest.
• Surrogate markers are cheaper & easier to
measure than true end point & can be
measured more quickly
Pharmacodynamic measures
Pharmacodynamic measures of response
(surrogate markers) include :
• clinical or laboratory measurements such as
– arterial blood pressure in patients with
hypertension
– Blood glucose in patients with diabetes
– INR in patients treated with oral anticoagulants
Is the drug getting to the site of action?
• Pharmacokinetic measures of drug
response include
– measurement of drug concentrations in the
blood or plasma (serum) i.e. by TDM
TDM : Definition
• Therapeutic drug monitoring (TDM) is
generally defined as:
– the clinical laboratory measurement of a chemical
parameter that, with appropriate medical
interpretation, will directly influence drug
prescribing procedures by combining knowledge
of pharmaceutics, pharmacokinetics, and
pharmacodynamics.
Goals of TDM
– Ensure that a given drug dosage produces
• Maximal therapeutic benefit
• Minimal toxic adverse effects
– Drug must have an appropriate concentration at
site of action that produces benefits
TDM: Objectives
1. Obtaining maximum beneficial outcome of
drug therapy by appropriate dosing of drugs.
2. Providing medical advantage by reducing the
chances of drug toxicity.
3. Providing economic convenience to the
patients by shortening their hospital stay.
4. Monitoring of factors like disease state,
patient’s characteristics, drug interactions
etc., in order to reduce patient variability.
TDM: Objectives
5. Dosage adjustment in patients with pre-
existing hepatic or renal impairment and
thus preventing drug accumulation in the
body.
6. Providing an effective means of
individualization of dosing of some drugs
that have unpredictable dose-response
relationship.
Sources of variability in drug response
Large inter-individual variation between dose and response can make
individualizing drug dosage difficult
Prescribed dosing
regimen
Drug at site of
action or blood
concentration
Clinical effects or
drug effects
Pharmacokinetic variability
1. Compliance
2. Dosing or medication errors
3. Tissue and body fluid volume
4. Drug interactions
Pharmacodynamic variability
1. Drug receptor status
2. Genetic factors
3. Tolerance
4. Drug interactions
Sources of variability in drug response
Two major sources :
• Pharmacokinetic variability – variation in dose
and plasma concentration
• Pharmacodynamic variability – variation in drug
concentration at the receptor level and the
response
• The emphasis of TDM is on reduction in
variability in pharmacokinetic phase by adjusting
doses individually for patients
Pharmacokinetic variables
• Bioavailability:
– Primarily reflects and depends upon absorption of
drug
– Factors affecting bioavailability:
• Pharmaceutical characteristics of drug like molecular size, shape,
degree of ionization, Relative lipid solubility, Nature of formulation
• Route of administration: 100% with i.v.
• State of the GI tract ; any pathology or disease state
• Gastric emptying, GI motility
• Food and other substances
• Drug-drug interactions
• State of circulation at site of absorption
Pharmacokinetic variables
• Plasma protein binding
– Highly bound drugs: restricted to vascular compartment 
smaller volumes of distribution
– Bound fraction not available for action ; but in equilibrium
with free form
– High degree of binding; long acting, temporary storage
– Plasma conc. : free + bound form
– Displacement reactions : overall impact minimal ; the new
steady states only marginally changed
– Hypoalbuminemia : reduced binding  higher conc. of
free drug ; toxicity . E.g. phenytoin, furosemide
– Pregnancy, inflammatory diseases increased α1 acid
glycoprotein  increased binding
Pharmacokinetic variables
• Volume of distribution
– Varies widely: degrees of binding to receptors , plasma
and tissue proteins, partition coefficient in fat,
abnormal fluid accumulations
– Drugs extensively bound to plasma proteins have low
Vd, e.g. diclofenac and warfarin
– Drugs sequestrated in other tissues have high Vd e,g,
digoxin
• Clearance
– Abnormal clearance: major impairment of the kidney,
liver or heart
Pharmacodynamic varaibles
• Genetic polymorphism
– Atypical pseudocholinesterase – succinylcholine apnea
– Polymorphism of NAT 2 gene – rapid and slow acetylator status :
isoniazid, hydralazine, procainamide
– CYP2D6 abnormality : toxicity of antidepressants and antipsychotics,
Resistance to coumarin anticoagulants
• Enzyme inhibitors
– Allopurinol, Omeprazole, Erythromycin, Ketoconazole,
Ciprofloxacin, SSRI’s, Isoniazid, Cimetidine, Diltiazem,
Ritonavir etc
• Enzyme Inducers
– Anticonvulsants, Rifampicin, Glucocorticoids, Griseofulvin,
DDT etc
Pharmacodynamic varaibles
• Drug interactions
– Patient taking any concomitant medications :
Ayurvedic, homeopathic, Unnani or herbal
e.g. ‘Shankhpushpi’ causes loss of seizure control
in patients stabilized on Phenytoin
• Drug tolerance
Concept of Therapeutic range/window
• The therapeutic range/ therapeutic window is
the concentration range of drug in plasma
where the drug has been shown to be
efficacious without causing toxic effects in
most people
• Minimum Effective Concentration (MEC) –
the concentration that would set the lower
limit of therapeutic effect of the drug
• Maximum Therapeutic Concentration or
Minimum Toxic Concentration (MTC) –the
concentration at which toxic effects are seen
Therapeutic range/window
Patient studies have generated upper (MTC) and lower (MEC)
plasma concentration ranges that are deemed safe and
effective in treating disease. These concentrations are known
as the “Therapeutic range” for the drug.
Criteria for TDM
Drugs which need TDM
• Drugs having narrow therapeutic range
• Therapeutic effect cannot be readily assessed by
clinical observation
• If a direct relationship exists between the drug or drug
metabolite levels in plasma and the pharmacological or
toxic effects.
• Large inter-individual variability in plasma conc.
• Drug following non-linear kinetics
• Drugs following saturation metabolism
• Drugs used for treating life threatening conditions
Criteria for TDM
Drugs which do not need TDM
• Drugs with wide therapeutic range
• Hit and run drugs: omeprazole, MAO inhibitors
• Pharmacological effects can be clinically
quantified/monitored by clinical end points, e.g., BP,
HR, cardiac rhythm, blood sugar, blood cholesterol and
triglycerides, urine volume, body temperature,
inflammation, pain, headache, etc.
• Drugs whose serum concentrations do not correlate
with therapeutic or toxic effects.
• Drugs used to treat less complicated or non life
threatening diseases
• Drug following linear kinetics (less complicated
pharmacokinetics)
Indications for TDM
• Low therapeutic index
• Poorly defined clinical end point
• Drugs with saturable metabolism
• Drugs having wide distribution in the body
• Wide variation in the metabolism of drugs
• Major organ failure
• Prevention of adverse drug effects
• Suspected toxicity
• Inadequate therapeutic response (Therapeutic
failure)
Indications for TDM
• Compliance concerns (non compliance) e.g. in
epileptics
• Dosage change
• Change in patient’s clinical state
• Change in co-medications (quinidine decreases
digoxin clearance)
• Manifestations of toxicity and disease state are
similar (Nausea & vomiting occur in both digitalis
toxicity & congestive heart failure)
TDM Process
1. Decision to request
Any toxicity?
Lack of response
Assessment of compliance
Assessment therapy after regimen change
Potential drug interactions
Chronic administration needed.
2. Patient demographics
3. Time of sample withdrawal
4. Collection of biological sample
5. Laboratory measurement
8/7/2014 30
Patient demographics
• Patient information
• Patient age
• Address, occupation, reference
• Indication for TDM
• Precipitation factor, etiology, other illness
• Treatment past, present, other
• Investigations
8/7/2014 31
TDM : Analytical Methodology
• The fundamental procedures necessary for
the quantification of the drug in the body are:
– recovery from body fluids, tissues, and organs
– separation from the biological components
– quantification.
TDM : Analytical Methodology
• The analytical 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
Methods: Laboratory measurement
1. Colorimetry
2. UV-spectrometry
3. Fluorescence spectrometry
4. Chromatography
a) Gas chromatography
b) Mass spectrophotometry
c) HPLC
d) HPTLC
5. Capillary electrophoresis
8/7/2014 34
6. Immunoassay
– RIA: Radio immunoassy
– Enzyme Immunoassay:
– ELISA: Enzyme linked immunoassay
– EMIT: Enzyme multiplies
immunotechnique
– FPIA: Fluorescence polarization immunoassay
– NIIA: Nephelometric inhibition immunoassay
– PETINIA : Particle Enhanced Turbidimetric Inhibition
Immunoassay
7. LC-MS: Least count mass spectrometry
8/7/2014 35
TDM : Free drug monitoring
• Development of new filtration devices
(equilibrium dialysis, ultrafiltration,
ultracentrifugation) has made it possible to
measure free unbound drug levels in serum.
– Advantage: The free concentration is independent
of changes in plasma binding and is the
pharmacologically active concentration.
– Disadvantage: It is time consuming, expensive and
therapeutic ranges do not yet exist for many
drugs.
Samples
• Plasma or Serum is used
for drug assays
• Whole blood: used for
drugs such as cyclosporin,
tacrolimus, sirolimus
– there are large shifts of
drug between red cells and
plasma with storage and
temperature change so
whole blood is assayed
Other Samples
• Saliva : used for phenytoin ,Lithium, amitryptyline,
alcohol
• Urine: benzodiazepines
• Sweat: cocaine & heroin
• Breath: alcohol
Use of saliva in TDM
• The concentration of a drug in saliva is a measure of
unbound drug in the plasma
• Advantage : non invasive
• Limitations :
– some substances such as lithium are actively secreted into the
saliva rather than by passive process
– Drug binding to salivary proteins may produce discrepancies in
plasma/salivary ratios, e.g. phenytoin
– Drugs may also bind to oral cell debris, e.g. propranolol
– Salivary flow may be reduced in patients taking anti cholinergic
drugs
– Preparations used to stimulate salivary flow might interfere with
drug estimation e.g. lemon flavored sweets interfere with
amitryptyline estimations.
Samples
• The drug concentration in the collected
samples are measured
• Other data such as serum creatinine and
blood urea nitrogen levels are also
measured to check the kidney function
Peak conc
Trough
Conc
Time (hours)
Conc(ug/l)
Timing of Sample Collection
Timing of Sample Collection
• The timing of blood collection is an
important part of therapeutic drug
monitoring
• Blood sample should be collected once the
drug concentration have attained steady
state (at-least 5 half lives)
• Levels approximating steady state may be
reached earlier if a loading dose has been
administered (drugs with long half lives).
Timing of Sample Collection
• Absorption is variable after oral drug
administration and blood samples should be
collected in elimination phase rather than
absorption / distribution phases
• The drug concentration changes during the
dosing interval.
• The least variable point in the dosing interval is
just before the next dose is due.
• This pre-dose or trough concentration is usually
measured.
Timing of Sample Collection
• Trough conc. :
– when a drug is administered by multiple oral doses,
commonly used for anti-convulsant drugs
– should be obtained just prior to the next dose at
steady-state conditions (i.e. just before the fifth dose)
• Peak conc. :
– useful for some antibiotics given IV
– Peak should be determined after drug absorption
(generally 2-4 hours for oral administration, 0.5-1
hour for im, sc route)
Timing of plasma sample
• Random samples :
– Peak and trough concentrations will not differ
substantially for drugs whose half-lives is much longer
than the dosing interval e.g. phenobarbitone,
– for such drugs a single sample is generally sufficient
– samples can be collected at any point in the dosage
interval after at least 4 to 5 half lives
• Correct sample timing should also take into
account absorption and distribution,
– eg for digoxin, samples are collected after 6 hours of
administration & lithium 24h after last dose
Guidelines for sampling time
• Short half life drugs:
– pre dose sampling
• Long half life drugs
– at any point in the dosing interval
• One vs Two samples
• Drugs with a short half-life: peak and trough concentrations will be very
different from one another
– both samples to be obtained
• Peak and trough concentrations will not differ substantially for drugs
whose half-life is much longer than the dosing interval
– single sample is sufficient
• For assessment of drug toxicity:
– at any time
• For purpose of adjustment of dosage or concern regarding low clearance:
– concentration just before the next dose
Guidelines for sampling time
Reasons for TDM:
• For all drugs, except aminoglycosides if
suspected –
– Toxicity : Peak level
– Failure / Non-compliance : Trough level
• For aminoglycosides if suspected –
– Toxicity : Peak & Trough level
– Failure / Non-compliance : Peak level
TDM: Clinical Interpretation
For therapeutic drug monitoring the information required
to allow interpretation of the result should include:-
• Patient -Age, weight, sex, height, smoker status
• Clinical – clinical status (renal -serum creatinine;
cardiac -cardiac output; liver function etc)
• Other drug therapy
• Relevant disease states
• time of the sample collection
• time of the last dose
• dosage regimen
• indication for drug monitoring e.g .lack of effect,
routine monitoring, suspected toxicity
Serum conc. lower than anticipated
• Patient non compliance
• Error in dosage regimen
• Rapid elimination
• Timing of sample
• Steady state not reached
• Change in hepatic blood flow
• Induction of metabolizing enzymes
• Poor bioavailability
• Increased plasma protein binding
• Enlarged apparent volume of distribution
Serum conc. higher than
anticipated
• Error in dosage regimen
• Increased bioavailability (hepatic disease)
• Slow elimination
• Inhibition of metabolizing enzymes
• Decreased plasma protein binding
• Smaller apparent volume of distribution
• Decreased renal function (important in case of
digoxin, lithium, aminoglycoside antibiotics)
• Decreased hepatic function (theophylline)
Serum concentration correct but
patient does not respond to therapy
• Altered receptor sensitivity (tolerance)
• Drug interaction at receptor site
Dose adjustment
• If these factors can not be eliminated, a
dosage adjustment is required.
• For drugs with linear kinetics the following
formulae may be used:
• New dose = Old dose X Desired drug concentration
Old drug concentration
Clinical interpretation of results
Clinical conditions requiring TDM
Collection of biological sample
Transfer to laboratory and estimation of drug concentration by suitable method
Interpretation of TDM results with reference to clinical conditions
Inadequate/Lack of Clinical response Satisfactory Clinical response/Toxicity
Below TR Within TR Above TR
Increase
dose if
required
Change or re
consider drug
therapy
If required
a small
change in
dose
should be
considered
Below TR Within TR Above TR
Other possible
reasons for signs
of toxicity should
be considered.
Laboratory
errors should be
checked
Other possible
reasons for signs
of toxicity should
be considered.
Lower dose can
be given if result
indicates the
relief of disease
Discontinue
the therapy
and restart
with a low
dose /
alternate
drug
TDM: Common drugs
1. Cardio active drugs :
– amiodarone, digoxin, digitoxin, disopyramide,
lignocaine, procainamide, propranolol and
quinidine
2. Antibiotics :
– gentamycin, amikacin and tobramycin
3. Antidepressants
– lithium and tricyclic antidepressants
TDM: Common drugs
4. Antiepileptic drugs :
– Phenytoin, phenobarbitone, benzodiazepines,
carbamazepine, Valproic acid and ethosuximide
5. Bronchodilators :
– theophylline
6. Cancer chemotherapy :
– Methotrexate
7. Immunosuppressives :
– Cyclosporine
Drugs commonly monitored
• Anticonvulsants :
– Managing non responders to a standard dose of a
drug
– Differentiate between non compliance, need for
higher dose and true drug resistance requiring change
or addition of another drug.
– Situations like suspected drug toxicity, dose
adjustments during pregnancy and lactation.
– Target concentration selected which will lead to
optimum seizure control.
– Therapeutic range : Phenytoin – 10-20 ug/ml
Valproic acid – 50-100 ug/ml
Drugs commonly monitored
• Phenytoin & Sod. valproate
– Sampling time:
• Immediately before next dose (trough level);
• Peak levels for confirming toxicity.
Levels should be taken : Phenytoin 3-4 hours post
dose; Valproate 1-3 hours post dose
• Range : Phenytoin 7-17 mg/L; Valproate: 40-120 mg/L
Drugs commonly monitored
• Lithium :
– Excreted unchanged by kidney, toxic conc. can
cause, damage to renal and nervous system.
– Sampling time: 12 hours after the preceding dose.
– First TDM done within 48-72 hrs.
– Subsequently done weekly for first month, then
monthly for next 6 months to once every 4-6
months.
– Therapeutic range is 0.5-0.8 mmol/l
– Level above 2 mmol - severe toxicity.
Drugs commonly monitored
• Antidepressants
– plasma conc. at a given dose may vary in excess of
40 fold
– Genetic polymorphism of metabolizing enzymes
CYP 450
Drugs commonly monitored
• Digoxin :
– For confirmation of suspected toxicity, reasons of
therapeutic failure, assessing factors like renal
dysfunction and drug interactions.
– Sample taken at least 8 hrs post dose to allow for
redistribution.
– Therapeutic range – 1.0 – 2.5 nmol/l
Drugs commonly monitored
• Aminoglycosides :
– Tissue accumulation related to nephrotoxicity and
ototoxicity.
– Peak and trough conc. measured in all pts. with
renal failure and treatment exceeding 7 days .
– Therapeutic range : Gentamicin 4-10 ug /ml
Drugs commonly monitored
• Theophylline :
– Narrow therapeutic index, variable metabolism
– Sampling time: Immediately before next dose
(trough level)
– Done 72 hrs after any change in dose
– Many drug interactions and interindividual
variability
– Therapeutic range : 5-20mg/l
Drugs commonly monitored
• Cyclosporine :
– Measured in whole bld
– Therapeutic conc. - 80-200 nmol/l
– Risk of transplant rejection in 1st 6 mon increases – when
trough conc is <80nmol/l
– Nephrotoxicity, hepatotoxicity & AE increases if conc 170-
330nmol/l
– Sampling time: just before next dose is due.
• Antitubercular drugs :
– Slow responders, drug resistant cases
– Drug interactions (esp. with concurrent HIV ) and other
associated disease states
Drugs commonly monitored
• Antiretroviral drugs :
– Useful in treatment naïve patients with wild type virus
isolates
– Athena study – better virologic outcomes and fewer
treatment discontinuations with TDM as part of
clinical care
• Anticancer drugs :
– Long term administration
– Therapy essential for patient survival
– Can produce serious side effects
– E.g. – methotrexate, 5-fluorouracil, tacrolimus
TDM : Clinical Usefulness
• Maximizing efficacy
– E.g. for Phenytoin in epilepsy, Theophylline in bronchial
asthma
• Avoiding Toxicity
– Overdose
– Differentiating adverse effects from disease effects e.g.
Digoxin toxicity & hypokalemia / ventricular arrhythmia
– Altered pharmacokinetics (Hepatic / Renal failure)
• Identifying therapeutic failure
– Non compliance
– Sub-therapeutic dose
– Drug interactions
– Decreased bioavailability / malabsorption
TDM : Clinical Usefulness
• Short hospital stay
• Better disease control
• Dose adjustment
• Dose guidelines
• Individualized dose requirement
• Avoidance of unnecessary medication
• A retrospective survey
carried out at the
Massachusetts General
Hospital showed that
• prior to the use of
digoxin monitoring
13.9% of all patients
receiving this drug
showed evidence of
intoxication
• following introduction of
monitoring this fell to
5.9%.
• A significant difference
with regard to length of
stay in the hospital
between patients on
gentamicin who were
monitored and their
dosage regulated
consequently versus
those who were not
(DeStache, 1990)
TDM : Problems
• Physicians sometimes do not understand the
principles, benefits, and the limitations of
TDM service
• Inappropriate sampling times
• Do not state the indication of TDM
• Insufficient patient’s history and other
necessary data
TDM: Limitations
• Scientific accuracy of drug assays
• Laboratory variability in reporting
• Validity of suggested target ranges.
• Limited accessibility and infrastructure
facilities
• Lack of training and skills
• Cost involved
Conclusion
• The aim of therapeutic research is to find out an effective
medication against the disease without any dangerous toxic action.
• The delicate problem is that very often the dose of drug confines
with toxicity.
• Clinicians routinely monitor drug pharmacodynamics by directly
measuring physiological indices of therapeutic response (e.g. lipid
concentration, blood glucose, BP, clotting test)
• For many drugs there is no readily available measure of effect or it
is insufficiently sensitive
• In these situations ‘Therapeutic Drug Monitoring’ becomes an
essential part of clinical management
Conclusion
• TDM is a very useful tool that uses standard
pharmacokinetic principles combined with the
measurement of drug concentrations to monitor safety
and efficacy of drugs.
• TDM is required for effective patient care
management
• It leads to optimizing pharmacological therapy
• Therapeutic drug monitoring is a system of quality
assurance of a drug management system, aiming that
the right drug is given to the right patient in the right
dose in order to obtain the right effect
Conclusion
• Emphasis : To use TDM in the most cost
effective and clinically effective manner.
• Important maxim is “to treat the patient and
not the level”
Therapeutic drug monitoring

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Therapeutic drug monitoring

  • 1.
  • 2. Therapeutic Drug Monitoring Dr. Ashutosh Tiwari PG Resident 2nd Year Department of Pharmacology SAIMS Indore 07/08/2014
  • 3. Presentation Layout • Introduction • TDM: Definition, Goals & Objectives • Criteria for TDM • Indications • Factors affecting TDM • TDM process • Analytical methods • Samples & Timing • Clinical interpretation • Common Drugs requiring TDM • Clinical usefulness • Problems • Limitations • Conclusion
  • 4. What is Therapeutic drug monitoring? • TDM is measurement of drug concentrations usually in the blood or plasma that facilitates adjustment of dosage to produce a desired response
  • 5. Why therapeutic drug monitoring? • Therapeutic drug monitoring can guide the clinician to provide effective and safe drug therapy in the individual patient using serum drug concentration
  • 6. Why should drug level be monitored? • 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. • Not all the patients have the same response at similar doses
  • 7. Is drug given to the patient working? 1) Is the drug getting to the site of action? • Pharmacokinetic measures 2) Is it producing the required pharmacological effect? • Pharmacodynamic measures 3) Is the pharmacological effect being translated into therapeutic effect? • Therapeutic outcome
  • 8. Monitoring of drug therapy • Monitoring of drug therapy can be done by – Therapeutic outcome using clinical end points – Pharmacodynamic measures using surrogate markers – Pharmacokinetic measures using TDM
  • 9. Is the pharmacological effect being translated into therapeutic effect? Monitoring therapeutic events in individual 1. Anti-convulsant drug therapy: seizure frequency 2. Drugs for angina pectoris: frequency of attacks 3. Diuretics in the t/t of edema
  • 10. Is the drug producing the required pharmacological effect? • In some cases it is not possible to measure the therapeutic outcome directly. • A pharmacodynamic effect, called surrogate marker, is measured. • A surrogate marker is defined as an endpoint that is measured in place of the true end point & that relates in someway to the end point of primary interest. • Surrogate markers are cheaper & easier to measure than true end point & can be measured more quickly
  • 11. Pharmacodynamic measures Pharmacodynamic measures of response (surrogate markers) include : • clinical or laboratory measurements such as – arterial blood pressure in patients with hypertension – Blood glucose in patients with diabetes – INR in patients treated with oral anticoagulants
  • 12. Is the drug getting to the site of action? • Pharmacokinetic measures of drug response include – measurement of drug concentrations in the blood or plasma (serum) i.e. by TDM
  • 13. TDM : Definition • Therapeutic drug monitoring (TDM) is generally defined as: – the clinical laboratory measurement of a chemical parameter that, with appropriate medical interpretation, will directly influence drug prescribing procedures by combining knowledge of pharmaceutics, pharmacokinetics, and pharmacodynamics.
  • 14. Goals of TDM – Ensure that a given drug dosage produces • Maximal therapeutic benefit • Minimal toxic adverse effects – Drug must have an appropriate concentration at site of action that produces benefits
  • 15. TDM: Objectives 1. Obtaining maximum beneficial outcome of drug therapy by appropriate dosing of drugs. 2. Providing medical advantage by reducing the chances of drug toxicity. 3. Providing economic convenience to the patients by shortening their hospital stay. 4. Monitoring of factors like disease state, patient’s characteristics, drug interactions etc., in order to reduce patient variability.
  • 16. TDM: Objectives 5. Dosage adjustment in patients with pre- existing hepatic or renal impairment and thus preventing drug accumulation in the body. 6. Providing an effective means of individualization of dosing of some drugs that have unpredictable dose-response relationship.
  • 17. Sources of variability in drug response Large inter-individual variation between dose and response can make individualizing drug dosage difficult Prescribed dosing regimen Drug at site of action or blood concentration Clinical effects or drug effects Pharmacokinetic variability 1. Compliance 2. Dosing or medication errors 3. Tissue and body fluid volume 4. Drug interactions Pharmacodynamic variability 1. Drug receptor status 2. Genetic factors 3. Tolerance 4. Drug interactions
  • 18. Sources of variability in drug response Two major sources : • Pharmacokinetic variability – variation in dose and plasma concentration • Pharmacodynamic variability – variation in drug concentration at the receptor level and the response • The emphasis of TDM is on reduction in variability in pharmacokinetic phase by adjusting doses individually for patients
  • 19. Pharmacokinetic variables • Bioavailability: – Primarily reflects and depends upon absorption of drug – Factors affecting bioavailability: • Pharmaceutical characteristics of drug like molecular size, shape, degree of ionization, Relative lipid solubility, Nature of formulation • Route of administration: 100% with i.v. • State of the GI tract ; any pathology or disease state • Gastric emptying, GI motility • Food and other substances • Drug-drug interactions • State of circulation at site of absorption
  • 20. Pharmacokinetic variables • Plasma protein binding – Highly bound drugs: restricted to vascular compartment  smaller volumes of distribution – Bound fraction not available for action ; but in equilibrium with free form – High degree of binding; long acting, temporary storage – Plasma conc. : free + bound form – Displacement reactions : overall impact minimal ; the new steady states only marginally changed – Hypoalbuminemia : reduced binding  higher conc. of free drug ; toxicity . E.g. phenytoin, furosemide – Pregnancy, inflammatory diseases increased α1 acid glycoprotein  increased binding
  • 21. Pharmacokinetic variables • Volume of distribution – Varies widely: degrees of binding to receptors , plasma and tissue proteins, partition coefficient in fat, abnormal fluid accumulations – Drugs extensively bound to plasma proteins have low Vd, e.g. diclofenac and warfarin – Drugs sequestrated in other tissues have high Vd e,g, digoxin • Clearance – Abnormal clearance: major impairment of the kidney, liver or heart
  • 22. Pharmacodynamic varaibles • Genetic polymorphism – Atypical pseudocholinesterase – succinylcholine apnea – Polymorphism of NAT 2 gene – rapid and slow acetylator status : isoniazid, hydralazine, procainamide – CYP2D6 abnormality : toxicity of antidepressants and antipsychotics, Resistance to coumarin anticoagulants • Enzyme inhibitors – Allopurinol, Omeprazole, Erythromycin, Ketoconazole, Ciprofloxacin, SSRI’s, Isoniazid, Cimetidine, Diltiazem, Ritonavir etc • Enzyme Inducers – Anticonvulsants, Rifampicin, Glucocorticoids, Griseofulvin, DDT etc
  • 23. Pharmacodynamic varaibles • Drug interactions – Patient taking any concomitant medications : Ayurvedic, homeopathic, Unnani or herbal e.g. ‘Shankhpushpi’ causes loss of seizure control in patients stabilized on Phenytoin • Drug tolerance
  • 24. Concept of Therapeutic range/window • The therapeutic range/ therapeutic window is the concentration range of drug in plasma where the drug has been shown to be efficacious without causing toxic effects in most people • Minimum Effective Concentration (MEC) – the concentration that would set the lower limit of therapeutic effect of the drug • Maximum Therapeutic Concentration or Minimum Toxic Concentration (MTC) –the concentration at which toxic effects are seen
  • 25. Therapeutic range/window Patient studies have generated upper (MTC) and lower (MEC) plasma concentration ranges that are deemed safe and effective in treating disease. These concentrations are known as the “Therapeutic range” for the drug.
  • 26. Criteria for TDM Drugs which need TDM • Drugs having narrow therapeutic range • Therapeutic effect cannot be readily assessed by clinical observation • If a direct relationship exists between the drug or drug metabolite levels in plasma and the pharmacological or toxic effects. • Large inter-individual variability in plasma conc. • Drug following non-linear kinetics • Drugs following saturation metabolism • Drugs used for treating life threatening conditions
  • 27. Criteria for TDM Drugs which do not need TDM • Drugs with wide therapeutic range • Hit and run drugs: omeprazole, MAO inhibitors • Pharmacological effects can be clinically quantified/monitored by clinical end points, e.g., BP, HR, cardiac rhythm, blood sugar, blood cholesterol and triglycerides, urine volume, body temperature, inflammation, pain, headache, etc. • Drugs whose serum concentrations do not correlate with therapeutic or toxic effects. • Drugs used to treat less complicated or non life threatening diseases • Drug following linear kinetics (less complicated pharmacokinetics)
  • 28. Indications for TDM • Low therapeutic index • Poorly defined clinical end point • Drugs with saturable metabolism • Drugs having wide distribution in the body • Wide variation in the metabolism of drugs • Major organ failure • Prevention of adverse drug effects • Suspected toxicity • Inadequate therapeutic response (Therapeutic failure)
  • 29. Indications for TDM • Compliance concerns (non compliance) e.g. in epileptics • Dosage change • Change in patient’s clinical state • Change in co-medications (quinidine decreases digoxin clearance) • Manifestations of toxicity and disease state are similar (Nausea & vomiting occur in both digitalis toxicity & congestive heart failure)
  • 30. TDM Process 1. Decision to request Any toxicity? Lack of response Assessment of compliance Assessment therapy after regimen change Potential drug interactions Chronic administration needed. 2. Patient demographics 3. Time of sample withdrawal 4. Collection of biological sample 5. Laboratory measurement 8/7/2014 30
  • 31. Patient demographics • Patient information • Patient age • Address, occupation, reference • Indication for TDM • Precipitation factor, etiology, other illness • Treatment past, present, other • Investigations 8/7/2014 31
  • 32. TDM : Analytical Methodology • The fundamental procedures necessary for the quantification of the drug in the body are: – recovery from body fluids, tissues, and organs – separation from the biological components – quantification.
  • 33. TDM : Analytical Methodology • The analytical 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
  • 34. Methods: Laboratory measurement 1. Colorimetry 2. UV-spectrometry 3. Fluorescence spectrometry 4. Chromatography a) Gas chromatography b) Mass spectrophotometry c) HPLC d) HPTLC 5. Capillary electrophoresis 8/7/2014 34
  • 35. 6. Immunoassay – RIA: Radio immunoassy – Enzyme Immunoassay: – ELISA: Enzyme linked immunoassay – EMIT: Enzyme multiplies immunotechnique – FPIA: Fluorescence polarization immunoassay – NIIA: Nephelometric inhibition immunoassay – PETINIA : Particle Enhanced Turbidimetric Inhibition Immunoassay 7. LC-MS: Least count mass spectrometry 8/7/2014 35
  • 36. TDM : Free drug monitoring • Development of new filtration devices (equilibrium dialysis, ultrafiltration, ultracentrifugation) has made it possible to measure free unbound drug levels in serum. – Advantage: The free concentration is independent of changes in plasma binding and is the pharmacologically active concentration. – Disadvantage: It is time consuming, expensive and therapeutic ranges do not yet exist for many drugs.
  • 37. Samples • Plasma or Serum is used for drug assays • Whole blood: used for drugs such as cyclosporin, tacrolimus, sirolimus – there are large shifts of drug between red cells and plasma with storage and temperature change so whole blood is assayed
  • 38. Other Samples • Saliva : used for phenytoin ,Lithium, amitryptyline, alcohol • Urine: benzodiazepines • Sweat: cocaine & heroin • Breath: alcohol
  • 39. Use of saliva in TDM • The concentration of a drug in saliva is a measure of unbound drug in the plasma • Advantage : non invasive • Limitations : – some substances such as lithium are actively secreted into the saliva rather than by passive process – Drug binding to salivary proteins may produce discrepancies in plasma/salivary ratios, e.g. phenytoin – Drugs may also bind to oral cell debris, e.g. propranolol – Salivary flow may be reduced in patients taking anti cholinergic drugs – Preparations used to stimulate salivary flow might interfere with drug estimation e.g. lemon flavored sweets interfere with amitryptyline estimations.
  • 40. Samples • The drug concentration in the collected samples are measured • Other data such as serum creatinine and blood urea nitrogen levels are also measured to check the kidney function
  • 42. Timing of Sample Collection • The timing of blood collection is an important part of therapeutic drug monitoring • Blood sample should be collected once the drug concentration have attained steady state (at-least 5 half lives) • Levels approximating steady state may be reached earlier if a loading dose has been administered (drugs with long half lives).
  • 43.
  • 44. Timing of Sample Collection • Absorption is variable after oral drug administration and blood samples should be collected in elimination phase rather than absorption / distribution phases • The drug concentration changes during the dosing interval. • The least variable point in the dosing interval is just before the next dose is due. • This pre-dose or trough concentration is usually measured.
  • 45. Timing of Sample Collection • Trough conc. : – when a drug is administered by multiple oral doses, commonly used for anti-convulsant drugs – should be obtained just prior to the next dose at steady-state conditions (i.e. just before the fifth dose) • Peak conc. : – useful for some antibiotics given IV – Peak should be determined after drug absorption (generally 2-4 hours for oral administration, 0.5-1 hour for im, sc route)
  • 46. Timing of plasma sample • Random samples : – Peak and trough concentrations will not differ substantially for drugs whose half-lives is much longer than the dosing interval e.g. phenobarbitone, – for such drugs a single sample is generally sufficient – samples can be collected at any point in the dosage interval after at least 4 to 5 half lives • Correct sample timing should also take into account absorption and distribution, – eg for digoxin, samples are collected after 6 hours of administration & lithium 24h after last dose
  • 47. Guidelines for sampling time • Short half life drugs: – pre dose sampling • Long half life drugs – at any point in the dosing interval • One vs Two samples • Drugs with a short half-life: peak and trough concentrations will be very different from one another – both samples to be obtained • Peak and trough concentrations will not differ substantially for drugs whose half-life is much longer than the dosing interval – single sample is sufficient • For assessment of drug toxicity: – at any time • For purpose of adjustment of dosage or concern regarding low clearance: – concentration just before the next dose
  • 48. Guidelines for sampling time Reasons for TDM: • For all drugs, except aminoglycosides if suspected – – Toxicity : Peak level – Failure / Non-compliance : Trough level • For aminoglycosides if suspected – – Toxicity : Peak & Trough level – Failure / Non-compliance : Peak level
  • 49. TDM: Clinical Interpretation For therapeutic drug monitoring the information required to allow interpretation of the result should include:- • Patient -Age, weight, sex, height, smoker status • Clinical – clinical status (renal -serum creatinine; cardiac -cardiac output; liver function etc) • Other drug therapy • Relevant disease states • time of the sample collection • time of the last dose • dosage regimen • indication for drug monitoring e.g .lack of effect, routine monitoring, suspected toxicity
  • 50. Serum conc. lower than anticipated • Patient non compliance • Error in dosage regimen • Rapid elimination • Timing of sample • Steady state not reached • Change in hepatic blood flow • Induction of metabolizing enzymes • Poor bioavailability • Increased plasma protein binding • Enlarged apparent volume of distribution
  • 51. Serum conc. higher than anticipated • Error in dosage regimen • Increased bioavailability (hepatic disease) • Slow elimination • Inhibition of metabolizing enzymes • Decreased plasma protein binding • Smaller apparent volume of distribution • Decreased renal function (important in case of digoxin, lithium, aminoglycoside antibiotics) • Decreased hepatic function (theophylline)
  • 52. Serum concentration correct but patient does not respond to therapy • Altered receptor sensitivity (tolerance) • Drug interaction at receptor site
  • 53. Dose adjustment • If these factors can not be eliminated, a dosage adjustment is required. • For drugs with linear kinetics the following formulae may be used: • New dose = Old dose X Desired drug concentration Old drug concentration
  • 54. Clinical interpretation of results Clinical conditions requiring TDM Collection of biological sample Transfer to laboratory and estimation of drug concentration by suitable method Interpretation of TDM results with reference to clinical conditions Inadequate/Lack of Clinical response Satisfactory Clinical response/Toxicity Below TR Within TR Above TR Increase dose if required Change or re consider drug therapy If required a small change in dose should be considered Below TR Within TR Above TR Other possible reasons for signs of toxicity should be considered. Laboratory errors should be checked Other possible reasons for signs of toxicity should be considered. Lower dose can be given if result indicates the relief of disease Discontinue the therapy and restart with a low dose / alternate drug
  • 55. TDM: Common drugs 1. Cardio active drugs : – amiodarone, digoxin, digitoxin, disopyramide, lignocaine, procainamide, propranolol and quinidine 2. Antibiotics : – gentamycin, amikacin and tobramycin 3. Antidepressants – lithium and tricyclic antidepressants
  • 56. TDM: Common drugs 4. Antiepileptic drugs : – Phenytoin, phenobarbitone, benzodiazepines, carbamazepine, Valproic acid and ethosuximide 5. Bronchodilators : – theophylline 6. Cancer chemotherapy : – Methotrexate 7. Immunosuppressives : – Cyclosporine
  • 57. Drugs commonly monitored • Anticonvulsants : – Managing non responders to a standard dose of a drug – Differentiate between non compliance, need for higher dose and true drug resistance requiring change or addition of another drug. – Situations like suspected drug toxicity, dose adjustments during pregnancy and lactation. – Target concentration selected which will lead to optimum seizure control. – Therapeutic range : Phenytoin – 10-20 ug/ml Valproic acid – 50-100 ug/ml
  • 58. Drugs commonly monitored • Phenytoin & Sod. valproate – Sampling time: • Immediately before next dose (trough level); • Peak levels for confirming toxicity. Levels should be taken : Phenytoin 3-4 hours post dose; Valproate 1-3 hours post dose • Range : Phenytoin 7-17 mg/L; Valproate: 40-120 mg/L
  • 59. Drugs commonly monitored • Lithium : – Excreted unchanged by kidney, toxic conc. can cause, damage to renal and nervous system. – Sampling time: 12 hours after the preceding dose. – First TDM done within 48-72 hrs. – Subsequently done weekly for first month, then monthly for next 6 months to once every 4-6 months. – Therapeutic range is 0.5-0.8 mmol/l – Level above 2 mmol - severe toxicity.
  • 60. Drugs commonly monitored • Antidepressants – plasma conc. at a given dose may vary in excess of 40 fold – Genetic polymorphism of metabolizing enzymes CYP 450
  • 61. Drugs commonly monitored • Digoxin : – For confirmation of suspected toxicity, reasons of therapeutic failure, assessing factors like renal dysfunction and drug interactions. – Sample taken at least 8 hrs post dose to allow for redistribution. – Therapeutic range – 1.0 – 2.5 nmol/l
  • 62. Drugs commonly monitored • Aminoglycosides : – Tissue accumulation related to nephrotoxicity and ototoxicity. – Peak and trough conc. measured in all pts. with renal failure and treatment exceeding 7 days . – Therapeutic range : Gentamicin 4-10 ug /ml
  • 63. Drugs commonly monitored • Theophylline : – Narrow therapeutic index, variable metabolism – Sampling time: Immediately before next dose (trough level) – Done 72 hrs after any change in dose – Many drug interactions and interindividual variability – Therapeutic range : 5-20mg/l
  • 64. Drugs commonly monitored • Cyclosporine : – Measured in whole bld – Therapeutic conc. - 80-200 nmol/l – Risk of transplant rejection in 1st 6 mon increases – when trough conc is <80nmol/l – Nephrotoxicity, hepatotoxicity & AE increases if conc 170- 330nmol/l – Sampling time: just before next dose is due. • Antitubercular drugs : – Slow responders, drug resistant cases – Drug interactions (esp. with concurrent HIV ) and other associated disease states
  • 65. Drugs commonly monitored • Antiretroviral drugs : – Useful in treatment naïve patients with wild type virus isolates – Athena study – better virologic outcomes and fewer treatment discontinuations with TDM as part of clinical care • Anticancer drugs : – Long term administration – Therapy essential for patient survival – Can produce serious side effects – E.g. – methotrexate, 5-fluorouracil, tacrolimus
  • 66. TDM : Clinical Usefulness • Maximizing efficacy – E.g. for Phenytoin in epilepsy, Theophylline in bronchial asthma • Avoiding Toxicity – Overdose – Differentiating adverse effects from disease effects e.g. Digoxin toxicity & hypokalemia / ventricular arrhythmia – Altered pharmacokinetics (Hepatic / Renal failure) • Identifying therapeutic failure – Non compliance – Sub-therapeutic dose – Drug interactions – Decreased bioavailability / malabsorption
  • 67. TDM : Clinical Usefulness • Short hospital stay • Better disease control • Dose adjustment • Dose guidelines • Individualized dose requirement • Avoidance of unnecessary medication
  • 68. • A retrospective survey carried out at the Massachusetts General Hospital showed that • prior to the use of digoxin monitoring 13.9% of all patients receiving this drug showed evidence of intoxication • following introduction of monitoring this fell to 5.9%.
  • 69. • A significant difference with regard to length of stay in the hospital between patients on gentamicin who were monitored and their dosage regulated consequently versus those who were not (DeStache, 1990)
  • 70. TDM : Problems • Physicians sometimes do not understand the principles, benefits, and the limitations of TDM service • Inappropriate sampling times • Do not state the indication of TDM • Insufficient patient’s history and other necessary data
  • 71. TDM: Limitations • Scientific accuracy of drug assays • Laboratory variability in reporting • Validity of suggested target ranges. • Limited accessibility and infrastructure facilities • Lack of training and skills • Cost involved
  • 72. Conclusion • The aim of therapeutic research is to find out an effective medication against the disease without any dangerous toxic action. • The delicate problem is that very often the dose of drug confines with toxicity. • Clinicians routinely monitor drug pharmacodynamics by directly measuring physiological indices of therapeutic response (e.g. lipid concentration, blood glucose, BP, clotting test) • For many drugs there is no readily available measure of effect or it is insufficiently sensitive • In these situations ‘Therapeutic Drug Monitoring’ becomes an essential part of clinical management
  • 73. Conclusion • TDM is a very useful tool that uses standard pharmacokinetic principles combined with the measurement of drug concentrations to monitor safety and efficacy of drugs. • TDM is required for effective patient care management • It leads to optimizing pharmacological therapy • Therapeutic drug monitoring is a system of quality assurance of a drug management system, aiming that the right drug is given to the right patient in the right dose in order to obtain the right effect
  • 74. Conclusion • Emphasis : To use TDM in the most cost effective and clinically effective manner. • Important maxim is “to treat the patient and not the level”

Editor's Notes

  1. CL = rate of elimination / plasma conc. Vd = dose administered / plasma conc.