Specialist and Therapeutic Drug Monitoring Notes

Intended Learning Outcomes

• Understanding TDM: Comprehend the concept of Therapeutic Drug Monitoring (TDM) and its significance in clinical practice.

• Understanding Relationships: Describe how therapeutic window correlates with narrow therapeutic index and target concentration strategies.

• Clinical Indications: Recognize when TDM is clinically warranted and the methods for conducting it.

• TDM Principles Application: Apply TDM principles in clinical practice, especially with examples like IV antibiotics.

• Emerging Trends: Summarize new trends and technologies in personalized medicine that are reshaping TDM strategies.

Therapeutic Drug Monitoring (TDM)

• Definition: TDM involves the clinical practice of measuring specific drug concentrations in the bloodstream at designated intervals to maintain an optimal concentration and customize doses for individual patients.

• Therapeutic Range Factors: The therapeutic range is influenced by various factors, including the patient's physiology and the drug's pharmacokinetics (discussed in Dr Ogunbenro’s lectures).

Importance of TDM in Clinical Practice

• Optimized Therapeutic Efficacy: Ensures effective disease management for chronic conditions.

  • Examples: Phenytoin for epilepsy, theophylline for acute asthma.

• Personalized Dosing: Adjusts medication based on genetic differences in drug metabolism.

  • Example: 5-FU to limit genetic variability.

• Medication Safety: Enhances the safe use of medications by minimizing adverse drug reactions (ADRs) and toxicities.

  • Examples: Warfarin for atrial fibrillation (AF), Digoxin for heart failure (HF).

• Managing Drug Interactions: Addresses potential toxicity risks from concomitant therapies (e.g., NSAIDs and methotrexate).

• Adaptation to Health Changes: Modifies antibiotic use in conditions like renal impairment or during pregnancy.

Therapeutic Windows, Indices, and Target Concentration Strategies

• Pharmacokinetics: Understanding the processes of Absorption, Distribution, Metabolism, and Excretion (ADME), and their variations across individuals (age, health status).

• Pharmacodynamics: Examining the correlation between drug concentration, action, and outcome.

• Therapeutic Window: Defined as the range between Minimum Effective Concentration (MEC) and Minimum Toxic Concentration (MTC).

• Narrow Therapeutic Index Drugs: Examples include Digoxin, Lithium, Phenytoin, Theophylline, and Vancomycin.

• Target Concentration Strategy: Utilizing TDM to reach and maintain target concentrations of drugs.

Clinical Indications for TDM

• When to Implement TDM:

  • Narrow Therapeutic Index Drugs

  • Variability in Drug Response

  • Management of Acute and Chronic Conditions

  • Monitoring for Adverse Drug Reactions (ADRs)

  • Drug Interactions (DDIs)

• Testing Methodologies:

  • Measurement Techniques: immunoassays, HPLC, mass spectrometry.

  • Collection Strategies: peak vs trough sampling and their timing considerations.

• Factors Affecting Drug Concentration: Patient hydration, food intake, and timing can substantially influence drug levels.

Applying TDM Principles to Clinical Practice

• Clinical Decision Making:

  • Dose Adjustment: Modifying drug dosages based on test results.

  • Therapeutic Ranges: Comparing levels against expected concentrations to determine therapeutic effectiveness.

  • Monitoring Schedules: Adjusting monitoring frequency based on individual patient contexts.

  • Interpreting Results: Understanding high levels (toxicity risk) and low levels (risk of inadequate efficacy).

  • Actions for Out-of-Range Levels: Adjusting dosage, checking for interactions, and assessing patient compliance.

Inter-Patient Variability and Compliance Issues

• Variability in ADME: Individual differences in how drugs are absorbed, distributed, metabolized, and eliminated can complicate TDM.

• Compliance Challenges: Poor adherence by patients can significantly impact drug efficacy.

• Drug Interactions: The complexity introduced by concurrent medications necessitates careful adjustment in TDM strategies.

• Analytical Variability: Reliability of TDM results can be affected by lab errors, specimen handling, and assay sensitivity.

Specific Case Studies in TDM with IV Antibiotics

Vancomycin

• Metabolism and Excretion: Not metabolized; 90% excreted in urine.

• Elimination Half-Life: Normal function: 6-8 hours; increased in patients with renal impairment.

• Administration Considerations:

  • Intermittent Infusion: Requires timely administration for optimal levels.

  • Continuous Infusion: Provides more stable plasma concentrations to achieve Minimum Inhibitory Concentration (MIC).

Gentamicin

• Absorption: Poor GI absorption; 70-85% plasma albumin binding.

• Excretion: 90% unchanged in urine.

• Ototoxicity and Nephrotoxicity Risks: Must monitor levels closely.

• Half-Life Adjustments: Normal function: 2-3 hours; prolonged in renal impairment.

• Dosing Strategies:

  • “Once-daily” dosing preferred; Measures trough (<2mg/L) and peak (5-10mg/L) levels.

Emerging Trends and Technologies in TDM

• Personalized Medicine: The rise of pharmacogenomics allows for tailored drug therapies based on genetic makeup.

• Point-of-Care Testing: Advancements in testing equipment and methods for rapid decision-making.

• Artificial Intelligence Utilization:

  • Pharmacokinetic modelling to optimize treatments.

  • Simulation trials and genetic profile analysis for better predictions of drug interactions and efficacy.

Summary

• Concept Understanding: Comprehension of TDM's concept and its clinical application.

• Application of TDM: Ability to apply TDM principles using IV antibiotics as case examples.

• Awareness of Trends: Knowledge of current advancements in personalized medicine affecting TDM practices.

Useful Resources

• University of Manchester articles on gentamicin dosing and monitoring.

• Articles on adjustments of antimicrobial doses in renal impairment and the future of precise antibiotic dosing as informed by recent studies.