Laboratory Medicine: Therapeutic Drug Monitoring for Chemotherapeutic Agents

Presented by: Jillian Shirley, Assistant Professor and Laboratory Director at Ohio State University Wexner Medical Center Hosted by: AACC and the Clinical Chemistry Trainee Council

Introduction

• Therapeutic Drug Monitoring (TDM) enhances patient management and quality of life.
• Goals of TDM: Optimizing dosage, supporting compliance, minimizing toxicity.
• Expanded by rapid sensitivity and specific analytical techniques.

Best Candidates for TDM

• Drugs meeting one or more of these criteria:
  • Narrow therapeutic index
  • Long-term therapy usage
  • Correlation between serum concentration and clinical response
  • High inter-individual or intra-individual variability in pharmacokinetics
  • Absence of biomarker associated with therapeutic outcome
  • Co-administration with potentially interacting compounds

TDM in Practice

• Common Practice: Administer drugs multiple times over days, weeks, or years.
• Steady State: Achieved when the amount of drug entering systemic circulation equals the amount being eliminated.
  • Typically requires 3-5 doses for first-order kinetics.
  • 5-7 half-lives after the last dose for 95% of the drug to be eliminated.

Administration Routes

• Intravenous Delivery: Complete dose directly into circulation.
• Oral Administration: Requires absorption from the gastrointestinal tract into the vascular system.
  • Factors Affecting Absorption: Solubility, pKa, formulation matrix, and gastrointestinal motility.

Drug Distribution

• Dependent on hydrophobicity, facilitating passage through cell membranes.
• Plasma Protein Binding:
  • Acidic drugs bind to albumin.
  • Basic drugs bind to globulins and lipoproteins.
• Free Drug: Non-bound to protein considered the active component.

Drug Metabolism

• Converts drugs to more polar products to increase water solubility.
• Metabolic Processes: Oxidation, reduction, hydrolysis, hydration, conjugation, condensation, isomerization.

Drug Excretion/Elimination

• Common Routes: Urine or stool.
• Estimated using glomerular filtration rate for urine excretion.

Monitoring Drug Concentrations

• Guides initial selection and dosing.
• Helps distinguish patients' responses and identify inadequate therapeutic ranges.
• Analytical Methods:
  • Immunoassays: Enzyme-multiplied immunoassay technique (EMIT), fluorescence polarization immunoassay (FPIA), cloned enzyme donor immunoassay (CEDIA).
  • Chromatographic Techniques: Gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), high-performance liquid chromatography-ultraviolet (HPLC-UV).

Case Study: Busulfan

• Usage: Inhibits malignant cells, used in stem cell transplant preparation and treating bone marrow disorders.
• Pharmacokinetics: Affected by age, weight, disease status, hepatic function, drug interactions.
• Therapeutic Range: 900-1350 micromolar minutes per liter for standard doses.
• Metabolism: Through cytochrome P450 isoenzymes (CYP3A4) and glutathione conjugation.
• Drug Interaction: Fluconazole inhibits CYP3A4, delaying busulfan clearance.

Case Study: Methotrexate

• Usage: Manages leukemia, carcinomas, debilitating psoriasis, rheumatoid arthritis, Crohn's disease, and more.
• Toxicity Monitoring: High dose methotrexate requires careful monitoring of serum concentrations and urine pH maintenance.
• Elimination: Primarily renal excretion, with attention to urine output and pH.

Monitoring Criteria for Toxicity

• After Single High Dose Therapy:

  • 10 micromolar/L at 24 hours

  • 1 micromolar/L at 48 hours

  • 0.1 micromolar/L at 72 hours

• Route of Elimination: Renal excretion; attention to urine alkalinity to prevent nephropathy.

Note: Low dose methotrexate is typically not monitored due to insensitivity of measurement methods and lack of correlation with disease control.

Summary

• Importance of accurate and reproducible analytical methods the key to effective TDM.
• Combination of analytical techniques ensures specific, rapid, and accurate monitoring of drug concentrations.
• TDM is crucial in managing chemotherapeutic regimens, improving patient outcomes, and minimizing adverse effects.

For more educational material: Visit traineecouncil.org.