Therapeutic drug monitoring

1. THERAPEUTIC DRUG
MONITORING
DR. ADEDAYO FOLORUNSHO ASALU
CONSULTANT PHYSICIAN/ CLINICAL PHARMACOLOGIST
LECTURE DELIVERED AT THE GENERAL MEDICNE UPDATE COURSE
FACULTY OF INTERNAL MEDICINE, NPMCN
26/07/2022

2. INTRODUCTION

3. MONITORING DRUG THERAPY
• This is the broader concept
• Involves the four processes of drug therapy
✓Pharmaceutical Process
- in-vitro measures of adherence
✓Pharmacokinetic Process-
- Measurement of drug levels in appropriate body fluids
✓Pharmacodynamic Process
- Measures of appropriate physiological/pharmacological effects of
administered drugs
✓Therapeutic effect
- evaluating drug effect in relation to therapeutic effect

4. MONITORING THERAPEUTIC PROCESS
✓Anticonvulsant therapy- seizure frequency, complimentary to
measuring blood level of the drugs
✓Drugs for angina pectoris- frequency of attacks
✓Diuretics in Oedema- weight loss
✓Frequency of Hospital admissions in Patients with Chronic Heart
Failure

5. MONITORING PHARMACODYNAMIC PROCESS
• Some pharmacological effects can be measured as “surrogate
markers” of therapeutic outcome
• Surrogate markers are usually easier, cheaper and can be measured
quickly and earlier
✓Anticoagulation and PT, measure as INR
✓Insulin therapy and Blood glucose monitoring
✓Antithyroid drugs and Serum 𝑇3, 𝑇4 and TSH levels

6. MONITORING PHARMACOKINETIC PROCESS
• This is the “domain” of Therapeutic Drug Monitoring TDM
• Relevance of Pharmacokinetics and PK parameters
- what dose of drug to give
- Frequency of its administration
- When steady-state is achieved
- Need for dose alteration in certain medical conditions
- Understanding of mechanism of certain drug-drug interactions

7. Relationship between dose and effect; Pk & Pd
• Relationship between dose-effect; PK-PD
dose plasma conc site of action effect Clinical Outcome
PHARMACOKINETICS PHARMACODYNAMICS
• The concept of therapeutic range of drug concentrations

8. THERAPEUTIC DRUG MONITORING

9. • Its basically the use of drug concentration measurements in body
fluid as an aid in drug therapy. “the quantification and interpretation
of drug concentration in body fluid (usually blood/plasma) to
optimize pharmacotherapy”
• The goal is to use drug concentrations to manage a Patient’s
medication regimen and optimise outcome
• It involves the clinical laboratory measurement of drug
concentrations in biological fluid and the appropriate interpretation
of those concentrations with the intent of influencing drug therapy
• Its process is predicated on the assumption that there is a
relationship between dose and plasma or drug concentration and
between the later and pharmacodynamics effect
• Its interpretation requires knowledge of the pharmacokinetics,
sampling time, drug history and the patient’s clinical condition
• Therapeutic drug measurement + interpretation TDM

10. TDM- INDICATIONS
Limited resources require that drug assay should only be performed when
they contribute to patient’s management
1. Individualization of drug therapy
2. Assessing compliance/adherence
3. Toxicity
- Diagnosing toxicity, especially when the manifestation of toxicity and
disease state are similar (Digoxin, Theophylline)
- Avoiding toxicity (Aminoglycosides)
4. Diagnosing and investigating Treatment failure (TDM can help distinguish
between ineffective drug treatment and non-compliance)
5. Change in patient’s clinical state, especially major organ failure
6. Monitoring and detecting drug interactions
7. Guiding withdrawal of therapy

11. DRUG CRITERIA FOR TDM
• Low Therapeutic Index (NTI) or Narrow Therapeutic Window
• Significant Pharmacokinetic variability –e.g Drugs with saturable kinetics for
example Phenytoin
• Reasonable relationship between plasma conc. and clinical effects (both
therapeutic and toxic)
• Drugs for which the relationship between dose and plasma concentration is
unpredictable ..and by inference, absent relationship between dose and effect
• Drugs that are not metabolized to active metabolites.
• Drugs for which there is difficulty in measuring or interpreting the clinical
evidence of therapeutic or toxic effect
• Established target concentration range
• Availability of cost-effective analytical assays to determine drug and
metabolite concentrations

12. DRUGS THAT MEET CRITERIA FOR TDM
• Aminoglycoside Antibiotics (Gentamicin, Kanamicin, Amikacin)
• Anticonvulsants*- Phenytoin, Carbamazepine, Sodium Valproate
• Cardiac glycosides (digoxin and digitoxin)
• Antiarrhythmic drugs
• Immunosuppressants- Cyclosporin
• Anticancer drugs- Methotrexate

13. TDM- METHOD/PROCEDURE/ANALYSIS
• Procedure
- Recovery of body fluid
- Separation from the biological components
- Identification of molecules concerned
- Quantification
• The Analytical methodology employed should ideally
i. distinguish between unchanged drug and metabolite
ii. Detect small amounts
iii. Simple to use as routine assay
iv. Be unaffected by other drugs concomitantly administered

14. ✓ Spectrophotometry and Fluorimetry- not very sensitive, large
volume of samples, complex extraction procedures and interference
by other compounds
✓Thin Layer Chromatography TLC- adequate resolutions to identify
many drugs but challenges with accurate quantification, time
consuming and with inadequate sensitivity
✓High Performance Liquid Chromatography HPLC- highly specific,
precise and sensitive. Also, multiple analysis possible. Extraction steps
also required, slow, single serial analysis
✓Radio immune assay RIA
✓Enzyme Immunoassay –few advantages over RIA especially that no
radioactive tracer is required
✓Fluorescence polarization Immunoassay FPIA

15. PRACTICAL CONSIDERATIONS & USE
• Rational indication for the requests (clinical question/indication)
• Accurate and adequate patient information
✓ details to include on request form
- Time sample was collected, especially in relation to drug administration
- Time dose was given
- Dosage regimen (dose, duration, dosage form)
- Patient demographics (age/gender)
- Concomitantly administered medications, a detailed drug history
- Relevant co-morbidities (eg renal or liver disease)
- Indication for testing (eg toxicity, non-compliance)

16. • An appropriate specimen and timing of collection
✓Usually serum/plasma but whole blood required in few instances.
✓Timing of sample collection
- In most cases when SS is reached but earlier, if toxicity is suspected
-at the appropriate time in relation to the last dose: generally
measured in the elimination phase (correlates with trough conc); gives
a more reliable guide to drug dosing
- Peak conc. for some aminoglycosides
- Not during the distribution phase (no equilibrium between plasma
and tissue concentration)

17. INTERPRETATION
• Correct interpretation and appropriate response should consider the
target range and the patient. “Treat patient and not drug level”
• Potential sources of error
- Assuming patient is at steady-state
- Assuming patient is adherent to therapy
- Not knowing the sampling time in relation to dose administration
- Not considering decreased renal/hepatic function
- Not considering Drug interactions
- Using reference range as absolute values

18. • Sample Concentration lower than anticipated
- Patient non-compliance
- Error in dosage regimen
- Rapid elimination
- Poor bioavailability
- DDI
- Css not yet achieved

19. • Sample Concentration higher than anticipated
- Patient non-compliance
- Error in dosage regimen
- slow elimination
- Decreased renal/hepatic function
- DDI
- Time sampling

20. • Before making 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
- If the patient is adhered to the treatment
- If there is a DDI
- If there is a liver/kidney dysfunction
+ the individual patient without rigid adherence to a target range

21. THANK YOU