Therapeutic Drug Monitoring Study Notes

Diploma in Pharmacy Overview

  • Institution: Cyberjaya College, Kota Kinabalu

Therapeutic Drug Monitoring (TDM) Overview

Introduction to TDM

  • Definition: Therapeutic Drug Monitoring (TDM) is the clinical assessment of a drug's pharmacokinetic properties.
  • Also referred to as clinical pharmacokinetics.
  • Clinical Pharmacokinetics Service (CPS) acts as an extension of pharmacy services, significantly contributing to patient care and therapy individualization.

Pharmacokinetics

  • Pharmacokinetics (PKs) refers to the study of the relationship between the administered dose of a drug and its concentration in the body over time.
  • Characterized by systemic input and disposition kinetic processes.
  • Key Processes:
    • Absorption
    • Distribution
    • Metabolism
    • Elimination (ADME concept).
  • Dosage adjustment is necessary due to variations in patient pharmacokinetics, which include:
    • Differences in absorption rates
    • Distribution variations
    • Metabolic rates
    • Hepatic clearance
    • Biotransformation rates
    • Excretion processes.

Importance of TDM

  • Therapeutic benefit achieved when drug concentration meets efficacy while staying below toxicity threshold (terapeutic range).
  • Main goal of clinical pharmacokinetics:
    • To optimize effectiveness of drug therapy.
    • To minimize toxic effects.

Therapeutic Range

  • Definition: Therapeutic range or index is the concentration range where a drug is effective without causing toxic effects.
  • Relationship: It is established between minimum effective concentration (MEC) and minimum toxic concentration (MTC).
  • Dosing Cycle:
    • Trough Concentration: Lowest concentration before the next dose; must remain above MEC.
    • Peak Concentration: Highest concentration during dosing cycle; must remain below MTC.

Reasons for Measuring Serum Concentration

  • To ensure the drug concentration remains within therapeutic range:

    • Example: Aminoglycosides like gentamicin require TDM to prevent nephrotoxicity and ototoxicity.
    • Adjustments needed if serum concentration is below the therapeutic range.

  • To confirm adequacy of serum drug levels:

    • Particularly when clinical response is inadequate (e.g., fitting due to inadequate dosing).

  • To assess dosing regimen appropriateness:

    • Ensuring MEC is maintained.

  • To determine if toxicity symptoms are drug-induced or due to ongoing medical conditions (e.g., PCM toxicity-related transaminitis and liver disease).

  • To study pharmacokinetics in different patient populations:

    • Understanding patient-to-patient variations.

  • To monitor patient compliance:

Situations for TDM Implementation

  • Major uses of TDM include:
    • Identifying and addressing subtherapeutic levels for dose optimization while minimizing drug toxicity.
    • Suspected toxicity due to the drug contributing to medical emergencies.

Factors Affecting Serum Drug Concentration

  1. Patient Demographics:

    • Age, sex, body weight, and ethnicity impact drug pharmacokinetics.
    • Especially critical for renally-cleared drugs (creatinine clearance calculations).

  2. Time to Sample:

    • Relies on the half-life of drugs achieving steady-state (SS) concentration.
    • Steady state is when drug administration equals drug elimination, typically reached after 4-5 half-lives.

  3. Sampling Time:

    • Serum concentration dependent on timing of blood samples relative to the last drug dose.
    • Typically, TDM samples are taken 30 minutes before the next dose.

  4. Patient Compliance:

    • Low concentrations may indicate non-compliance rather than needing a dose increase.

  5. Drug Interactions:

    • Results should be interpreted considering other concomitant medications, e.g., digoxin levels may rise unexpectedly with co-administered drugs like amiodarone.

  6. Pathological Factors:

    • Comorbid conditions affect pharmacokinetics, including:
      • Alterations in protein binding
      • Renal impairment
      • Hepatic impairment
      • Inflammatory bowel diseases
      • Conditions in critically ill patients.

  7. Alcohol and Tobacco Use:

    • Chronic alcohol use can induce hepatic enzymes, affecting clearance of certain drugs.
    • Cigarette smoking alters clearance for drugs like theophylline, leading to unexpected therapeutic outcomes.

  8. Medication and Sampling Errors:

    • Possible errors include wrong patient administration, incorrect sampling time, and discrepancies in drug records.

  9. Laboratory Errors:

    • Errors suspected should result in verification with the laboratory, either by repeating assays or resampling.

Commonly Ordered TDM Tests

  • Classes and corresponding drugs include:
    • Painkillers: Paracetamol
    • Immunosuppressants: Methotrexate, Sirolimus, Tacrolimus, Cyclosporine
    • Antiepileptics: Carbamazepine, Phenytoin, Sodium valproate, Phenobarbitone
    • Antibiotics: Vancomycin, Gentamicin, Amikacin
    • Cardiac Glycoside: Digoxin
    • Bronchodilator: Theophylline
    • Antipsychotics: Lithium

Therapeutic Ranges of Specific Drugs

  • Vancomycin:

    • Therapeutic trough levels: MSSA: 10-15 mg/L, MRSA: 10-20 mg/L.
    • Dosing varies with renal function.

  • Carbamazepine:

    • Therapeutic range: 4-12 mg/L.
    • Important to test for HLA-B* 1502 allele prior to prescribing.

  • Phenytoin:

    • Therapeutic range: 10-20 mg/L.
    • Risk of toxicity when levels exceed 20 mg/L.
    • Toxic effects include hypotension, respiratory depression.

  • Valproic Acid:

    • Therapeutic ranges: Seizures (50-100 mg/L), Psychiatric disorders (50-125 mg/L).
    • Highly protein-bound (80-90%).

  • Phenobarbital:

    • Range: 15-40 mg/L; possibly up to 70-344 mg/L for refractory status epilepticus.

  • Digoxin:

    • Typical ranges: CHF: 0.5-0.9 mcg/L, AF: 0.8-2.0 mcg/L.

Role of Pharmacists in TDM

  • Responsibilities include:
    • Suggesting appropriate drug regimens based on patient demographics and medical conditions.
    • Advising on TDM timing.
    • Interpreting TDM results.
    • Recommending dosage adjustments based on results and patient responses.
    • Identifying potential causes for unexpected TDM results, such as compliance, sampling errors, drug interactions, or pharmacogenetic variability.