Evidence based medicine and Therapeutic drug monitoring

1. Evidence Based Medicine &
Therapeutic drug monitoring
Dr Naser Tadvi

2. Competency PH1.2
• Describe the basis of Evidence based medicine
and therapeutic drug monitoring

3. Objectives
• Identify reliable sources for research evidence
• Understand research study designs and the
hierarchy for research evidence
• Ascertain strength of evidence of treatments
• Understand the purpose of TDM
• Explain the methods in TDM
• Enlist the drugs requiring TDM

4. Reliable sources for research evidence
Credible sources
• Published within last 10
years
• Written by respected
authors
• Belong to educational or
governmental institutions
Non credible sources
• Older than last 10 years
• Written by someone
without proper credentials
• Published on commercial
websites

6. Definition of Evidence based medicine
Evidence-based medicine is the science of integrating the
best available evidence from clinical research with
Physician`s clinical expertise and patient’s unique values and
preferences
Patient
Values
Clinical
Expertise
Best
research
evidence
EBM
Straus SE, Richardson WS, Glasziou P,
Haynes RB. Evidence-based medicine: how
to practice and teach EBM 3d ed. London:
Churchill Livingstone, 2005

7. Purpose of evidence based medicine
• Assess the evidence and the risks and benefits
of ordering diagnostic tests and treatment
• To predict if treatment will do more harm than
good
• Encourages dialogue between patient &
doctor, so patients can share in decision
making and make their preferences and values
known

8. STEPS IN EVIDENCE BASED RESEARCH
Asking
answerable
questions
Finding the
best evidence
Critically
appraising the
evidence
Applying a
decision
Evaluation
Heneghan C, Badenoch D. Evidence-based medicine toolkit. 2d ed. Malden, MA: Blackwell, 2007

9. STEP 1
• Asking answerable questions – focused,
searchable, clinical
• PICO
• Patient, Problem, Population
(subjects)
• Intervention or therapy
• Comparison, Control
• Outcome (results)

10. Elements while asking question
Patient: The patient or problem being addressed
Intervention: The intervention of exposure
Comparison: Comparison Intervention
Outcome: The clinical outcome of interest

11. Can You Identify PICO?
• In children under 5 years age, is intravenous
diazepam equally effective as compared to per
rectal diazepam for treatment of status epilepticus/
convulsions
• In children under 5 years age (P), is intravenous
diazepam (I) equally effective as compared to per
rectal diazepam(C) for treatment of status
epilepticus/ convulsions (O)

12. STEP 2
• Finding the best evidence with which
to answer the question through
structured searches and
understanding the literature

13. Types of studies

14. So What Is PubMed?
PubMed is a tool to search:
• MEDLINE (1950 to present)
Produced by NCBI
• National Center for Biotechnology Information, part of NLM
Accessible worldwide on the Web at no charge

15. Accessing
PubMed
• Directly at:
http://pubmed.gov
• Or, National Library
of Medicine’s
homepage:
http://www.nlm.ni
h.gov

16. Case-control study:
A study which involves identifying
patients who have the outcome of
interest (cases) and patients without the
same outcome (controls) and looking
back to see if they had the exposure of
interest.
Cohort studies
Involves identification of two groups
(cohorts) of patients, one which received
the exposure of interest, and one which
did not, and following these cohorts
forward for the outcome of interest.
Types of studies

19. Case series
A report on a series of patients with an
outcome of interest. No control group
is involved.
Randomized control clinical trial
(RCT)
Participants are randomly allocated
into an experimental group or a
control group and followed over time
for the variables/outcomes of interest.

20. Systematic review
• Detailed, systematic
and transparent
means of gathering,
appraising and
synthesizing evidence
to answer a well
defined question
Meta-analysis
• A statistical procedure
for combining
numerical data from
multiple separate
studies.

21. Grades of strength of evidence
Grade 1 Systemic reviews/ Meta-
analysis
More reliable, may form
basis of clinical decisions
Grade II Well powered randomized
controlled trial/ more than
one trial
Reliable but may be
supported or refuted by
similar studies
Grade III Open label trials/ pilot
studies/ observational
(Cohort and case-control
studies
Less reliable, need more
rigorous testing , may
indicate further
investigation
Grade IV Case reports/ Clinical
Expericence
Least reliable: may serve
as pointers to initiate
formal studies

22. Step 3
• Appraisal of evidence
• Verifying whether the results are valid
• What are the results
• Are the results suited to your patient

23. Step 4
• Best documented critically appraised research
evidence is already with us
• Patient values to be considered while applying
evidence are
– Economical status of patient
– No contraindication for drug to be applied
– Dosage form preferred
• Integrate the evidence with clinical expertise and
patient preferences
• Evidence is applied on the patient

24. Therapeutic drug monitoring
Dr. Naser Ashraf Tadvi

25. What is therapeutic drug monitoring
(Definition)
• Therapeutic Drug Monitoring is measurement
of the plasma concentration level of a drug
and the coordination of this serum level with a
serum therapeutic range.

26. Why should drug level be monitored ?
• Some 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
patients have the same response at similar doses
• TDM can guide the clinician to provide effective
and safe drug therapy in the individual patient
using serum drug concentration .

27. Therapeutic range/ therapeutic
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.

29. Where to find information regarding
therapeutic range
• Recommended therapeutic ranges can
generally be found in the product inserts for
drugs that require monitoring.
• They are also available in books such as the
Physicians Desk Reference, and articles in the
primary medical journals.

30. Digoxin
• Plasma concentration –response relationship
– 0.5µcg/L: No therapeutic effect
– 0.7 µcg/L: some ↑ in force of contraction of heart
– 0.8- 2 µcg/L: Optimum therapeutic range
– 2 -2.5 µcg/L: ↑ risk of toxicity although tolerated
in some patients
– ˃ 2.5 µcg/L: Gastrointestinal, cardiovascular and
CNS toxicity

31. Lithium
• Plasma concentration response relationship
– ˂ 0.4 mmol/L: Little therapeutic effect
– 0.4 to 1 mmol/L: Optimum range for prophylaxis of
mania
– 0.8 to 1.2 mmol/L: Optimum range for acute mania
– 1.2 to 1.5 mmol/L: Causes possible renal impairment
– 1.5 to 3 mmol/L: Renal impairment, weakness,
drowsiness, thirst and diarrhoea
– 3 to 5 mmol/L: Confusion, spasticity, convulsions,
coma and death

32. Phenytoin
• ˂ 0.5 mg/L: No therapeutic effect
• 5 to 10 mg/L: Some anti-convulsant action
• 10 to 20 mg/L: optimum concentration for
anticonvulsant effect
• 20-30 mg/L: Nystagmus, blurred vision
• ˃30 mg/L: Ataxia, drowsiness, coma

33. Do all drugs require TDM
• No

34. Indications of TDM
• Drugs with narrow Therapeutic index
– Lithium, digoxin, phenytoin, aminoglycosides etc
• Drugs showing large interindividual variation
• To ascertain compliance
• For drugs whose toxicity is increased in presence of
renal failure
• In patients who do not respond to therapy without
any known reason

35. Clinical significance /Uses of TDM
1. Maximizes efficacy
2. Avoids toxicity
3. Identifies therapeutic failure
– Non compliance, subtherapeutic dose
4. Facilitates adjustment of dosage
New dose = Old dose X Desired Css/Old Css
5. Facilitates the therapeutic effect of drug by
achieving target drug concentration
6. Identify poisoning, drug toxicity and drug abuse

36. Examples of drugs requiring TDM
• Digoxin: 0.8 -2 µcg/L
• Theophylline:10-20
mg/L
• Gentamicin: 2-12 mg/L
• Lithium: 0.8-1.2 mmol/L
• Phenytoin: 10-20 mg/L
• Carbamazepine: 4-12
mg/L
• Ciclosporin: 100-200
ng/Ml
• Vancomycin
• Procainamide

37. The management of therapy using plasma concentration

38. REQUEST FORM OF TDM
Patient Name............................................. Date............................................... HN........................................................
Age.................................. Sex................................. Wt...................................... Ht.........................................................
Ward.............................................Ordered by....................................................... Phone No..........................................
DRUG LEVEL REQUESTED..................................................................................................................................................
REASON FOR REQUEST :
( ) Suspected toxicity ( ) Compliance
( ) Therapeutic confirmation ( ) Absence of therapeutic response
Please indicate when level is needed :
( ) within 24 h ( ) within 1-2 h ( ) stat ( ) others........................
TIME AND DATE OF LAST DOSE :
Date.................... Route : IV, IM, SC, PO, Others...........................
Time.................... Dose.......................... Freq..................................
THIS DRUG LEVEL IS FOR : SAMPLING TIME :
( ) Trough or predose level Date....................... Time.........................
( ) Peak level Date....................... Time........................
DOES THE PATIENT HAVE ORGAN-SYSTEM DAMAGE ?
( ) Renal ( ) Hepatic ( ) Cardiac ( ) GI ( ) Endocrine ( ) Others........................….
OTHER DRUG(S) PATIENT IS TAKING :.........................................................................................................……..
DRUG LEVEL & USUAL THERAPEUTIC RANGE............................................................................................…….
INTERPRETATION...............................................................................................................................................…...
.............................................................................................................................................................................…….
Date.......................... Technologist................................. Time............................…………..

39. Can drug concentration in other fluids
of body be measured
• Yes
– Urine: benzodiazepines
– Sweat: cocaine & heroin
– Saliva: marijuana, cocaine, alcohol
– Breath: alcohol

40. Therapeutic index (TI)
• It is index of safety of drug
• TI= Median lethal dose (LD50)
Median effective dose (ED50)
• Wider the value of therapeutic index safer is
the drug
• Example penicillin has a high therapeutic
index
• Digoxin, lithium, phenytoin have low TI

41. Summary
• TDM is monitoring of plasma concentration of
drug for individualization of dose in patients
• Mainly indicated for drugs having narrow
therapeutic index, or to check compliance and
titration of dose
• Most common drugs to undergo TDM are
anticonvulsants, lithium, digoxin, gentamicin