Therapeutic Drug Monitoring Techniques

Therapeutic Drug Monitoring
Dr. Rajmohan Seetharaman
1st yr Resident
Department of Pharmacology,
Lokmanya Tilak Muncipal Medical
College, Sion (w), Mumbai, 400022
1
14/12/19

Overview
2
• Case report
• Introduction & historical aspects
• Rationale & concepts of TDM
• Indications & criteria for TDM
• Sampling & analysis techniques
• Result interpretation & dose adjustment
• Drugs for which TDM is done commonly
• Estimated cost of TDM per drug
• Recent updates
• Summary
• Conclusion
• References

Case Report
3
66yr old female (suffering from Bipolar disorder)
Patient was on maintenance therapy with Lithium Carbonate 450 mg BD
(dose unchanged since many months)
Admitted to hospital with complaints of confusional state, tremors & gait abnormality
On Examination:
CNS: Coarse tremors of body & hand, gait ataxia
Mental Status: Patient was found to be anxious, agitated, fidgeting & pacing
Lithium toxicity was suspected
Serum Lithium levels: 1.69 mEq/L
Patient was commenced on I/V fluid hydration,
isotonic sodium chloride solution 1000ml/daily & Mannitol 250 ml in between for 7 days
Lithium levels decreased to 0.39 mEq/L on day 7
Arnaoudova MD. Lithium toxicity in elderly-a case report and discussion. Journal of IMAB–Annual Proceeding Scientific Papers. 2014 Jul 25;20(4):519-22.

Introduction
4
Therapeutic drug monitoring (TDM): Clinical practice of measuring
specific drugs at designated intervals to maintain a constant
concentration in a patient's bloodstream
Kang JS, Lee MH. Overview of therapeutic drug monitoring. The Korean journal of internal medicine. 2009 Mar;24(1):1.

Historical Aspects
5
1950`s: Hypothesised that drug concentrations may be a better index than dose to guide
treatment
1970`s: Studies reported more than 50% of Adverse drug reactions were at standard doses
1970`s & 80`s: Extensive Investigations on TDM & its applications
Mid 1980`s: TDM introduced in India
Extensive growth in the last 20 years
TDM currently exists in:
• Large teaching Hospitals
• Private Sector Labs
• Kang JS, Lee MH. Overview of therapeutic drug monitoring. The Korean journal of internal medicine. 2009 Mar;24(1):1.
• Gogtay NJ, Kshirsagar NA, Dalvi SS. Therapeutic drug monitoring in a developing country: an overview. British journal of clinical pharmacology. 1999 Nov;48(5):649.

Expectation
7
Administered by
the patient
Therapeutic
Concentration
Efficacy
Drug:
Prescribed & Dispensed

Reality
8
Dose Effect
Pharmacokinetics Pharmacodynamics
• Prescribed
• Dispensed
• Administered
• Absorption
• Distribution
• Metabolism
• Elimination
• Route
• Area and vascularity
of absorbing surface
• Bioavailability
• First pass metabolism
• Inhibition & Induction
• Lipid solubility
• Plasma Protien Binding
• Clearance
• t1/2
• Genetic Factors
• Pathological states.
• Drug + Receptor
• Drug Interactions
• Tolerance
• Therapeutic
• Subtherapeutic
• Toxic

Aim of TDM
9
“To optimize pharmacotherapy by maximizing
therapeutic efficacy while minimizing adverse events,
where blood concentration of drug is a better
predictor of desired effect than dose”

Types of TDM
10
Posteriori TDM
• Pharmacokinetic monitoring
• Pharmacodynamic monitoring
Priori TDM
• Pharmacogenetic information
• Demographic information
• Clinical information
Defined as “The clinical laboratory measurement of a chemical
parameter that, with appropriate medical interpretation, will directly
influence drug prescribing procedures”
• Therapeutic Drug Monitoring. Journals.lww.com. 2019 [cited 7 December 2019]. Available from: https://journals.lww.com/drug-monitoring/
pages/default.aspx

Concepts in Therapeutic Drug Monitoring
11
Peaks: Highest levels of drug in the body
Trough: Lowest levels of drug in the body

Dosing of a drug
12
Drug X has 3 dosage regimes, which one would you prefer ?
A]
B]
C]

Therapeutic Window
13
Drug A: 10-20 µg/mL
(Therapeutic range)
Drug B: 10-100 µg/mL
(Therapeutic range)
Standard dose:100 mg
Normally produces 10 - 12 µg/mL
One dose of 100 mg produces no effect One dose of 100 mg produces no effect
If dose is increased:
Serum levels may cross 20 µg/mL
causing toxicity
If dose is increased:
Serum levels may cross 20 µg/mL
However upper limit is 100 µg/mL
Hence no risk of toxicity
Narrow Therapeutic window Broad Therapeutic window

Therapeutic Window
14
Refers to a range of doses which optimize between efficacy and toxicity, achieving the
greatest therapeutic benefit without resulting in unacceptable adverse-effects or toxicity.
Narrow Therapeutic Window Broad Therapeutic Window
E.g. lithium, digoxin, warfarin E.g. penicillin, fluoxetine
• Brunton L, Knollmann B, Hilal-Dandan R. Goodman & Gilman's. 13th ed. New York, N.Y.: McGraw-Hill Education LLC.; 2018.
• Muller PY, Milton MN (October 2012). "The determination and interpretation of the therapeutic index in drug development". Nature Reviews. Drug Discovery. 11 (10):
751–61. doi:10.1038/nrd3801. PMID 22935759.

15
Sr
no
Condition Examples
1 The pharmacological effects can be clinically quantified Antihypertensives
2 When concentration effect relationship remains unestablished Hit and run drugs
3
Clinical outcome: unrelated either to dose or to plasma
concentration
Drugs with
irreversible action
4 Drugs with wide therapeutic range
Penicillin, β
blockers, etc.
5 Drugs activated in the body levodopa
TDM is not required when:

Criteria for TDM
16
• Drug with narrow therapeutic range.
• Direct relationship between the plasma drug levels and the
pharmacological or toxic effects.
• Drugs with large individual variability in steady state plasma
concentration.
• Drugs whose therapeutic effect cannot be readily assessed by the
clinical observation.
• Appropriate analytic techniques available: to determine the drug
concentration
• Suthakaran C, Adithan C. Chapter-7 therapeutic drug monitoring–concepts, methodology, clinical applications and limitations. Health administrator. 2006;19(1):22-6.

Major indications FOR TDM:
17
• Suthakaran C, Adithan C. Chapter-7 therapeutic drug monitoring–concepts, methodology, clinical applications and limitations. Health administrator. 2006;19(1):22-6.
Indication Example(s)
To check toxicity Digoxin
To check Efficacy Failure Antiepileptics
Drugs Showing inter-individual variation in
metabolism
Tricyclic Antidepressants
Drugs with non-linear pharmacokinetics (Zero order) Phenytoin
To check compliance
Antiepileptics,
Antidepressants
To check drug interactions
Interaction between Lithium
and thiazide diuretics
To check effect of concomitant pathological/
physiological condition on drugs
Pregnancy, organ
dysfunction
Drug with poorly defined end point   Immunosuppressant drugs

18
Steps involved
in TDM
1) Precise and reliable measurement
of the plasma concentration of a drug
3) Calculation and
proposal dose adjustment
2) Interpretation of the
obtained concentration value
Hamzah A, Ab Rahman AF. Evaluation of blood sampling times and indications for therapeutic drug monitoring services. Malaysian Journal of Pharmaceutical Sciences.
2008;6(1):1-1.

19
Measurement of plasma concentration of
a drug
Sampling Analytical Techniques
2008;6(1):1-1.

21
Type of Samples
Blood / Serum sample: Most commonly used.
• Advantages: better estimate of concentration at receptor site,
less chances of contamination.
• Disadvantages: invasive, expertise required.
• Eg: digoxin, aminoglycosides.
Whole blood used for: Cyclosporine, tacrolimus, sirolimus
2008;6(1):1-1.

22
Type of Samples (continued)
Saliva Sample:
• Advantages: simple, non invasive, no expertise required,
preferred by children and their parents, gives an estimate of
unbound drug concentration.
• Disadvantages: easily contaminated, unreliable result owing to
presence of drug residues.
• Eg: Phenytoin, Amitryptiline
2008;6(1):1-1.

23
Type of Samples (continued)
Urine Sample:
• Advantages: Simple, no expertise required,
• Disadvantages: influenced by urine pH .
• Eg: Opioids, benzodiazepines
2008;6(1):1-1.

24
Sample collection for according to route of
administration
Route Sample collection timing
Intravenous dose
Peak levels: sampled 30 to 60 mins after administration
Intranasal dose Peak levels: 1-1.5 hrs
Intramuscular dose Peak levels: 2-4 hrs
Oral dose Peak levels: 3-4 hrs after dose
Trough Levels: Samples are drawn just before administration of the next
scheduled dose
• tdm-info : Therapeutic Drug Monitoring [Internet]. Questdiagnostics.com. 2019 [cited 25 November 2019]. Available from: https://www.questdiagnostics.com/
home/physicians/testing-services/condition/toxicology/tdm-info
• Hamzah A, Ab Rahman AF. Evaluation of blood sampling times and indications for therapeutic drug monitoring services. Malaysian Journal of Pharmaceutical
Sciences. 2008;6(1):1-1.

25
Timing for sample collection
• Steady State is achieved only after 4 half lives
passed
• In case of toxic drugs if sampling is delayed until
steady state is reached, damage may already be
done.
o1st sample taken after 2 half lives passed
➢if concentration >90% than the eventual
expected mean steady state, the dosage rate
is halved.
➢if concentration less then continue the
same dose.
o2nd sample taken after the next 2 half lives
➢if concentration exceeds target then dosage
halved.
2008;6(1):1-1.

26
Timing of sampling (continued)
In case of severe acute poisoning:
• Blood taken at the earliest to confirm the poisoning and to gauge its seriousness.
• It should then be repeated at intervals to monitor the progress
For checking compliance to medication:
• Even random blood sampling can be informative.
2008;6(1):1-1.

27
Drug Formulation
Route of administration
Dose regimen
Pharmacokinetic properties of the drug
Patient Age (pediatric, geriatric)
Body composition
Renal function
Hepatic function
Compliance
Factors that influence TDM Results
Ghiculesco R. Abnormal laboratory results: Therapeutic drug monitoring: which drugs, why, when and how to do it. Australian Prescriber. 2008;31(2):42-44.

28
Sample timing for some important drugs
Name Timing of sampling
Phenytoin Trough levels are measured usually
Carbamazepine Trough levels are measured usually
Digoxin Peak levels six hours after a dose or trough levels
Theophylline Trough levels are measured usually
Lithium Trough levels are measured usually
Phenobarbitone Trough levels are measured usually
Gentamicin
Peak levels 30 mins after i.v. and 1 hr after i.m.
administration.
2008;6(1):1-1.

29
Methods Of Analysis
• Chromatographic techniques:
High pessure/precision liquid chromatography (HPLC)
Gas chromatography (GC)
Thin layer chromatography (TLC)
High precision thin layer chromatography (HPTLC)
• Molecular structure identification Techniques:
Mass spectrometry (MS)
• Chromatography plus spectroscopy
Liquid chromatography–mass spectrometry (LC-MS)
Gas chromatography–mass spectrometry (GC-MS)
Boguslaski RC, Burd JF. Analytical methods for therapeutic drug monitoring. The American journal of medical technology. 1983 Aug;49(8):551-6.

30
High-performance liquid chromatography
It is a technique in analytical chemistry used to separate, identify, and quantify
each component in a mixture.
Mobile Phase: The liquid or gas that
flows through a chromatography
system, moving the materials to be
separated at different rates over the
stationary phase
Stationary Phase: solid or liquid
phase of a chromatography
system on which the materials
are to be separated or selectively
adsorbed

31

32
How are the components separated ?
On the basis of polarity
Normal Phase HPLC Reverse Phase HPLCV/s
Solvents: usually organic solvents
2-propanol in hexanes
Solvents: acetonitrile water mixtures
or methanol water mixtures
Stationary Phase: Hydroxyl groups of Silica capped with C18

33

34
Advantages:
• Highly specific, precise & sensitive
• Multiple analyses can be done
• Thermolabile compounds can be analysed
Drawbacks:
• Extraction step required
• Column degenerates with time

35
Gas chromatography
Seperation Characteristics: Volatility & Polarity
Stationary Phase: Polar
Carrier Gas: Inert Gas
More Volatile & non polar reaches fast

36
Gas chromatography
Advantages:
• Highly specific, precise & sensitive
• Multiple analyses can be done
Drawbacks:
• Thermolabile compounds cannot be analysed
• Extraction step required
• Column degenerates with time

37
Mass Spectrometry
Analytical technique that measures the mass-to-charge ratio of ions.
Acceleration (A) = Force (F)
————
Mass (M)
Order of Separation:
Large > Intermediate > small
Higher Mass: less acceleration
Reaches fast

38
Advantages:
• Highly Sensitive
• Low Limits of detection
• Faster run times
• Identity confirmation
Procedure:
• Introduction of sample molecules to mass
analyser by HPLC
• Ionisation of analyte molecules to charged
particles
• Separation of ions according to Mass/
charge ratio

39

40

41
Previously used analysis
techniques in TDM

42
Thin Layer Chromatography
Mobile Phase: Non Polar liquidStationary Phase: Plastic or silica
coat on top of an aluminium foil
RF: Retention Factor Value

43
Thin Layer Chromatography (Result interpretation)
Silica coated with phosphor (such as zinc sulphide): apply UV light
Dark spots are seen where zinc sulphate are absent

44
High Performance Thin Layer Chromatography
Micro syringes
Trough chamber
Densitometry measurements

45
TLC V/s HPTLC
Parameter TLC HPTLC
Technique Manual Instrumental
Efficiency Less
High (due to smaller
particle size)
Layer Lab made/ pre coated Lab made
Mean particle size 10 - 12 "m 5 - 6 "m
Stationary phase
thickness
250 "m 100 "m
Plate height 30 "m 12 "m
Shivatare RS, Nagore DH, Nipanikar SU. HPTLC’an important tool in standardization of herbal medical product: A review. Journal of Scientific and Innovative Research.
2013;2(6):1086-96.

46
Immunofluorescence
Is a technique which uses antibodies conjugated to fluorescent dyes

47
Radioimmunoassay (RIA)
• Antigen competes with
radioisotope antigen for a site on
the antibody.
• Displaced antigen contains
radioactive iodine
• Measure Radioactivity using
radioactivity meter

48
Radioimmunoassay
• Reasonably precise & sensitive
Drawbacks:
• Requires use of radio-nucleotides
• Cross reactivity with other closely reacted drugs
• It is not possible to find out optically active isomer

49
ELISA
Enzyme Linked Immunosorbent Assay

50
ELISA
• Offer advantages over RIA that no radioactive tracer is required
• Moderately precise & sensitive
Drawbacks:
• Labelling primary antibodies for each specific ELISA system is time-
consuming and expensive.
• No flexibility in choice of primary antibody label from one
experiment to another.
• Minimal signal amplification.

51
Interpretation of values
NomogramArea under the curve

52
Calculation & proposal of individual doses
Calculation formula:
Dose (new) =
Dose(Previous) X Concentration(desired)
——————————————————
Concentration (measured)

53
Therapeutic Drug Levels
Drug Therapeutic Levels Toxicity
Lithium 0.8 to 1.2 mEq/L > 1.5 mEq/L
Phenytoin 10 to 20 "g/mL > 30 "g/mL
Valproic acid 50 to 100 "g/mL > 100 "g/mL
Carbamazepine 5 to 12 "g/mL >12 "g/mL
Phenobarbital 10 to 30 "g/mL >40 "g/mL
Amikacin 15 to 25 "g/mL > 25 "g/mL
Gentamicin 5 to 10 "g/mL > 12 "g/mL
Tobramycin 5 to 10 "g/mL > 12 "g/mL
Theophylline 10 to 20 "g/mL > 20 "g/mL
Digoxin 0.8 to 2.0 ng/mL > 2.4 ng/mL
Methotrexate > 0.01 mcmol/L 10 mcmol over 24-hours

Drugs for which TDM is commonly done
54
A
Drug
Possessing
Very
Low
Therapeutic
Index
: Aminoglycosides, Anticancer drugs
: Digoxin
: Phenytoin
: Valproate
: Lithium
: TCA, Theophylline
: Immunosuppresants
]Antiepileptics

Drugs for which TDM is commonly done
55
CVS: digoxin, digitoxin, amiodarone, lidocane,
quinidine, procainamide
Antibiotics:
gentamycin, amikacin and tobramycin,
Anti-maniac & anti-depressants:
Lithium & tricyclic antidepressants
Antiepileptic drugs:
Phenytoin, phenobarbitone, benzodiazepines, carbamazepine, Valproic acid and
ethosuximide, lamotrigine, oxcarbazepine,
Bronchodilators: theophylline
Cancer chemotherapy: Methotrexate,
all anti cancer drugs
Immunosuppressives: cyclosporine, Tacrolimus, sirolimus, everolimus

WHO Priority level for TDM
56
Priority Level Criteria Drugs
High
TDM useful even for non-
critically ill patients
amikacin, gentamicin,
phenytoin, lithium
Moderate
TDM useful in patients
with co-treatments or
concomitant clinical
complications
vancomycin,
methotrexate, cyclosporin
Low
Careful clinical
assessment is enough for
most cases
digoxin, phenobarbital,
carbamazepine, valproate
[Internet]. Who.int. 2019 [cited 29 November 2019]. Available from: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/
sage-ivd-2nd-meeting/Report-on-TherapeuticDrugMonitoring-tests.pdf

57
Rationale:
• Breakthrough disease can occur if lack of efficacy
• Critical decision : to either increase dose or add another antiepileptic
Phenytoin:
• Therapeutic range : 10-20 "g/ml (Total concentration)
1-2 "g/ml (unbound concentration)
• Follows zero order kinetics after 20 "g/ml plasma concentration
• Enzyme inhibitors (disulfiram, cimetidine, isoniazid, chloramphenicol,
etc) decrease metabolism.
• Carbamazepine & phenytoin increase each others metabolism
• Unbound Indications:
Insufficient albumin concentration.
Displacement by valproic acid
Acute toxicity: Nystagmus, ataxia, CNS depression & blurred vision. If
dose very high/i.v. injection administered faster: cardiovascular collapse,
coma
Anti-epileptics
• Tripathi K. Essentials of medical pharmacology. 7th ed. New Delhi, India: Jaypee Brothers; 2013.

58
Valproate:
• Therapeutic Range: 50 – 100 "g/mL
• Clearance increased by enzyme inducers, decreased in liver diseases
• Concentration dependent side effects seen
Acute toxicity: weight gain, increase in appetite, GI distress, tremors &
reversible alopecia
Carbamazepine:
• Therapeutic Range: 4-12"g/ml
• Dose related neurotoxicity
• Auto-inducer
• Carbamazepine & phenytoin increase each others metabolism
• Erythromycin, fluoxetine & isoniazid inhibit metabolism
Acute toxicity: drowsiness, dizziness, headache, slurred speech, vertigo,
ataxia, diplopia
Other anti-epileptics

59
Lamotrigine:
• Therapeutic range: < 24 "g/mL
• Clearance increased by inducers, pregnancy and decreased by
inhibitors
Acute toxicity: dizziness, ataxia, diplopia, skin rash
Other anti-epileptics (continued)
Phenobarbitone:
• Therapeutic Range: 10-40 "g/mL
• Clearance decreased by enzyme inducers & in renal dysfunction.
• Clearance increases in alkaline pH of urine.
Acute toxicity: irritability, hyperexcitability, gait ataxia, slurred speech,
nystagmus
Others:
• Levetiracetam: Therapeutic range: 6-20 "g/ml
• Oxcarbazepine: Therapeutic range: 12-24 "g/ml
• Ethosuximide: Therapeutic Range: 40-100 "g/ml

Aminoglycosides
60
Amikacin:
• Used for MDR TB
• Therapeutic Range: Peak: 20-35 "g/mL ; Trough: 1-2 "g/mL
• Dose dependent related ototoxicity & nephrotoxicity
• Renal Failure: Over hydration - Vd increases
Under hydration - Vd decreases
Tobramycin:
• Used for LRTI, Meningitis, peritonitis, complicated & recurrent UTI
• Therapeutic Range: Peak: 4 to 8 "g/mL ; Trough <10 "g/mL
Gentamicin:
• Used for surgical prophylaxis, infective endocarditis, cystic fibrosis, PID
• Therapeutic Range: 4 and 8 µg/mL ; Trough <10 "g/mL

Digoxin
61
• Used for: Congestive heart failure, Atrial fibrillation
• Therapeutic Range: 0.8-2 ng/ml
• Volume of distribution and clearance both decrease with decreased renal
function.
• Heart failure decreases hepatic clearance.
• Hypokalemia, hypomagnesemia, hypercalcemia augment response
• Thyroid hormone: Hypothyroidism: eliminate slowly
Hyperthyroidism: eliminate faster
Drugs Effect
Quninidine, verapamil, diltiazem, amiodarone Decrease clearance
aluminium antacids, kaolin, pectin Oral absorption decreases
Cisapride, metoclopramide decreasing gi transit ( decrease absorption)
Tricyclic antidepressants (atropinic drugs) Increase absorption
Propantheline increases bioavailability (prolonging gi transit)

Theophylline
62
• Use: Bronchial Asthma, COPD, Apnoea in premature infant
• Therapeutic range: 10-20µg/ml
• Rationale:
Non linear pharmacokinetics.
t1/2 varies with age [Premature infant: 24-36 hrs, children: 3-5 hrs,
adults: 7-12 hrs]
Clearance increased with use of tobacco, marijuana, enzyme inducers
Concentration dependent side effects.
Acute toxicity: Dyspepsia, headache insomnia restlessness, vomiting,
palpitations agitation, tachypnoea, flushing, hypotension
extrasystoles, arrhythmias, delirium, convulsions, coma death

Cyclosporine
63
Use:
• Prevent GVHD in post hematopoetic stem cell transplant patients.
• Prevent graft rejection in solid organ transplants.
• Psoriasis, Rheumatoid arthritis.
Therapeutic range:
• Blood : 100-400 ng/ml, Plasma: 50-150 ng/ml
Rationale:
• Concentration and dose dependent nephrotoxicity.
• Drug interactions:
With other nephrotoxic drugs eg: aminoglycosides, vancomycin
Enzyme inhibitors and inducers.

Lithium
64
• Use: bipolar disorder , mania
• Therapeutic range: Acute Mania treatment :1-1.5 mEq/L
Maintenance: 0.6-1mEq/L, Old Age patients: 0.5-0.8 mEq/L
• Rationale:
• Narrow therapeutic range
• Drug interaction : Thiazide, NSAIDs, ACE inhibitors / ARBs - decrease Cl.
• Dose related toxicity
Acute toxicity:
Mild: Fine tremor, lightheadedness, weakness.
Moderate: Apathy, drowsiness, hyperreflexia, muscle twitching, slurred speech,
tinnitus.
Severe: Choreoathetoid movements, clonus, coma, confusion, muscular irritability,
seizures

Methotrexate
65
• Use: Psoriasis, rheumatoid arthritis, choriocarcinoma, non-hodgkin
lymphomas, osteosarcoma & various cancers
• Therapeutic range: <1µmol/L
• Rationale:
Displaced from protein binding sites by salicylates, sulphonamides
& dicumarol.
Tubular secretion decreased by aspirin and sulfonamides.
In high dose regimen concentration of methotrexate is monitored to
ascertain the need for leucovorin rescue.
Acute toxicity: hepatotoxicity, pulmonary toxicity, acute renal failure,
stomatitis, ulceration/erosion of the GI and pancytopenia

66
Estimated cost for TDM for various drugs
Drug Cost (in INR)
Lithium 450
Digoxin 900
Phenytoin 950
Carbamazepine 850
Valproic Acid 825
Methotrexate 3000
Cyclosporine 2600
Tacrolimus 3900
Everolimus 4600
Sirolimus 4600
Amikacin 5500
tdm-info : Therapeutic Drug Monitoring [Internet]. Questdiagnostics.com. 2019 [cited 25 November 2019]. Available from: https://www.questdiagnostics.com/
home/physicians/testing-services/condition/toxicology/tdm-info

67
Recent Advances in TDM
• TDM of Antibiotics in critically ill patients
• TDM of Antiretrovirals
• Therapeutic drug monitoring (TDM) V/s Target concentration intervention
(TCI)
• Pharmacogenomics in TDM

TDM of antibiotics in critically ill patients
68
Summary of common factors associated with altered pharmacokinetics of
antibiotics in critically ill patients:
Increased Vd Decreased Cl Increased Cl
Variable changes in
Vd and/or cl
Hypoalbuminaemia
(leading to increased
unbound drug)
Renal Hypoperfusion
Augmented renal
clearance
Renal replacement
therapy
Capillary leakage Acute Kidney Injury
Fluid resuscitation
Renal/Hepatic
dysfunction
Multi-drug resistant organisms more frequently encountered in the critically ill
also alter the dosing requirements for these patients.
Wong G, Sime FB, Lipman J, Roberts JA. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients?. BMC
infectious diseases. 2014 Dec;14(1):288.

TDM of antibiotics in critically ill patients
69
Antibiotics for which TDM is done
Antibiotics Toxicity & Indications
Vancomycin
20 - 40 "g/ml
Efficacy: Trough concentrations >27 "g/ml
Vancomycin induced Nephrotoxicity
Linezolid
2 - 20 "g/ml
Efficacy: Trough concentrations: 7 "g/ml
Linezolid induced pancytopenia, & liver dysfunction
Aminoglycosides Aminoglycoside induced ototoxicity & nephrotoxicity
Fluoroquinolones
2.8 to 5.2 "g/ml
To avoid treatment failure as well as minimise the emergence of
resistance
Beta-lactams To maximise efficacy & avoid subtherapeutic exposures
Wong G, Sime FB, Lipman J, Roberts JA. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients?. BMC
infectious diseases. 2014 Dec;14(1):288.

Antiretroviral drugs TDM
70
TDM is not recommended for routine use in but may be considered in selected clinical
scenarios:
• Suspected Drug-Drug or Drug-Food interaction.
• Pathophysiological states impairing G/I, hepatic or renal function
• Heavily pretreated patients with reduced susceptibility to ARV
• Lack of response in adherent patients
• Concentration dependent toxicities
• Use of medication with limited PK data & therapeutic experience in children.
DHHS (Department of Health & Human Services) guidelines
Therapeutic Drug Monitoring Management of the Treatment-Experienced Patient Adult and Adolescent ARV [Internet]. AIDSinfo. 2019 [cited 8 December 2019].
Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/17/therapeutic-drug-monitoring

Antiretroviral drugs TDM (continued)
71
Drug Concentration (ng/mL)
Efavirenz 1000
Darunavir 550
Indinavir 100
Lopinavir 1000
Atazanavir 150
Nevirapine 3000
Saquinavir 100-250
Nelfinavir 800
Fosamprenavir 400
Minimum target trough concentrations:
Therapeutic Drug Monitoring Management of the Treatment-Experienced Patient Adult and Adolescent ARV [Internet]. AIDSinfo. 2019 [cited 8 December 2019].
Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/17/therapeutic-drug-monitoring

Therapeutic drug monitoring (TDM) V/s
Target concentration intervention (TCI)
72
The therapeutic range concept suffers from two strategic deficiencies.  
• Idea of a range introduces uncertainty into exactly how to prescribe the
desired dose.
• Implicit assumption that all concentrations within the range are equally
desirable.
• Holford NH. Target concentration intervention: beyond Y2K. British journal of clinical pharmacology. 1999 Jul;48(1):9-13.
• Holford NHG, Tett S. Therapeutic Drug Monitoring. The strategy of target concentration intervention. In: Speight T, Holford NHG, editors. Avery’s Drug Treatment. 4.
Auckland: Adis Intl; 1997. pp. 225–259.

Target concentration intervention (TCI)
73
• Target concentration intervention (TCI) is proposed as an alternative
conceptual strategy to therapeutic drug monitoring (TDM).
• Target concentration (TC) is directly linked to a specific target concentration
for an individual - not a range of concentrations

Steps involved in target concentration strategy
74
Select a target concentration
Predict Dosing of the drug
Pharmacokinetic parameters and individual characteristics
Administer the doses and measure drug concentrations
Check for the deficit or excess in concentration
Revise further doses accordingly
During Follow-ups:
Revise the target concentration for the individual based on clinical assessment

Important Genetic polymorphisms
76
Gene Drug(s)
TMPT 6-mercaptopurines
UGT1A1*28 irinotecan
VKORC1 warfarin
HLA-B5701 abacavir
HLA-B1502 Phenytoin, carbamazepine
G6PD Defeciency
rasburicase, dapsone, primaquine,
chloroquine
MDR1 Protease inhibitors
NAT Sulfonamides, hydralazine, INH
Pseudocholinesterase deficiency Succinylcholine
Hiratsuka M, Mizugaki M. Genetic polymorphisms in drug-metabolizing enzymes and drug targets. Molecular genetics and metabolism. 2001 Aug 1;73(4):298-305.

Genetic polymorphism of CYP450 enzymes
77
Enzyme Drugs
CYP2D6
Metabolism of approximately 20-25% of marketing drugs. Beta-
blockers, antidepressants, antiarrhythmic, antipsychotics
CYP2C9 Phenytoin, Warfarin, Glipizide. Tolbutamide
CYP2C19 Diazepam, Omeprazole, Phenytoin
Hiratsuka M, Mizugaki M. Genetic polymorphisms in drug-metabolizing enzymes and drug targets. Molecular genetics and metabolism. 2001 Aug 1;73(4):298-305.

Summary
78
Risky Drugs Vulnerable Patients
Drugs that demonstrate dose dependent toxicity:
e.g. digoxin, lithium, aminoglycosides,
methotrexate
Patients with unstable disease: E.g. epileptics,
cardiac arrhythmia
Drugs where loss of effect leads to breakthrough
of disease: e.g. Antiepileptics,
immunomodulators
Impaired Pharmacokinetics: E.g. Renal
dysfunction, Liver disease, Pregnancy
Drugs having a saturable kinetics: e.g.
phenytoin, theophylline
Patients depending on drug treatment for
survival: e.g. Transplant recepients
Patient Related: E.g Polypharmacy, having more
than one prescribing doctor
• Monitoring of certain drugs lithium, theophylline, phenytoin, valproic acid is
associated with increased efficacy & decreased incidences of adverse drug reactions.
• The process of TDM is based on the assumption that there is a definable relationship
between dose and plasma drug concentration, and between concentration and
therapeutic effects.

Conclusion
79
• TDM has helped to individualise drug therapy for patients.
• It provides an opportunity for clinical pharmacologists to excel in
therapeutic challenges & to work as a vital segment of the healthcare
team.
• Increased availability of laboratories preforming TDM in Indian
metropolitan cities.
• Indian clinicians need more convincing about the benefits of TDM.
• Cost of TDM is still not feasible for Indian patients.

References
80
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McGraw-Hill Education LLC.; 2018.
• Sharma H, Sharma K. Sharma & Sharma's principles of pharmacology. 3rd ed. Hyderabad: Paras
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applications and limitations. Health administrator. 2006;19(1):22-6.
• Arnaoudova MD. Lithium toxicity in elderly-a case report and discussion. Journal of IMAB–
Annual Proceeding Scientific Papers. 2014 Jul 25;20(4):519-22.
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overview. British journal of clinical pharmacology. 1999 Nov;48(5):649.
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References
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• Ghiculesco R. Abnormal laboratory results: Therapeutic drug monitoring: which drugs, why, when
and how to do it. Australian Prescriber. 2008;31(2):42-44.
• Boguslaski RC, Burd JF. Analytical methods for therapeutic drug monitoring. The American
journal of medical technology. 1983 Aug;49(8):551-6.
• Wong G, Sime FB, Lipman J, Roberts JA. How do we use therapeutic drug monitoring to improve
outcomes from severe infections in critically ill patients?. BMC infectious diseases. 2014 Dec;14(1):
288.
• Therapeutic Drug Monitoring Management of the Treatment-Experienced Patient Adult and
Adolescent ARV. AIDSinfo. 2019 [cited 8 December 2019]. Available from: https://
aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/17/therapeutic-drug-monitoring
• Holford NH. Target concentration intervention: beyond Y2K. British journal of clinical
pharmacology. 1999 Jul;48(1):9-13.
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intervention. In: Speight T, Holford NHG, editors. Avery’s Drug Treatment. 4. Auckland: Adis Intl;
1997. pp. 225–259.
• Hiratsuka M, Mizugaki M. Genetic polymorphisms in drug-metabolizing enzymes and drug
targets. Molecular genetics and metabolism. 2001 Aug 1;73(4):298-305.

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