Therapeutic Drug Monitoring

Case vignette

A 55-year-old patient, diagnosed with systemic lupus erythematosus (SLE) was admitted for monitoring after initiating tacrolimus as part of her immunosuppressive regimen. Due to its narrow therapeutic window and significant interindividual variability in pharmacokinetics, she experienced early signs of nephrotoxicity and subtherapeutic drug levels, raising concerns about both efficacy and safety. The clinical team employed therapeutic drug monitoring (TDM) to optimise her tacrolimus dose. This intervention stabilised her drug levels, improved her renal function, and enhanced treatment outcomes.

Introduction

Therapeutic drug monitoring (TDM) is a critical tool in optimising drug therapy for medications with narrow therapeutic ranges, marked variability, or high potential for toxicity. By personalising medication regimens through measurement and interpretation of drug levels, TDM maximises therapeutic benefits while minimising adverse effects.

Principles of therapeutic drug monitoring

TDM involves measuring drug concentrations in biological fluids, interpreting the results based on pharmacokinetic and pharmacodynamic principles, and adjusting doses accordingly. The key principles include:

• Therapeutic range: Drugs like vancomycin, digoxin, and tacrolimus have narrow ranges where efficacy is achieved without toxicity.
• Pharmacokinetic variability: Factors such as age, renal function, and drug interactions can significantly affect drug metabolism and clearance.
• Individualisation: TDM provides patient-specific dosing strategies to optimise outcomes.

Applications of TDM

Antibiotics

• Vancomycin TDM is used to prevent nephrotoxicity while ensuring therapeutic levels are maintained to combat severe infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA).

Immunosuppressants

• Tacrolimus and cyclosporin are monitored to prevent graft rejection in transplant patients while minimising toxicity. This is critical due to their variable pharmacokinetics and potential for severe adverse effects.

Cardioactive drugs

• Digoxin, used for heart failure and arrhythmias, requires monitoring to avoid toxicity, which can mimic symptoms of the underlying disease.

Antiepileptics

• Phenytoin and valproic acid TDM ensure seizure control while avoiding side effects related to high plasma concentrations.

Antiepileptics (Anticonvulsants) drug monitoring

• TDM is vital for ensuring effective seizure control and minimising adverse effects in epilepsy management.

Phenytoin

• Due to its narrow therapeutic index and dose-dependent, non-linear (zero-order) pharmacokinetics, phenytoin levels can vary significantly between patients.
• Small changes in dosage may lead to disproportionate changes in blood concentration, increasing the risk of toxicity or subtherapeutic levels.
• TDM is essential in critically ill patients, those with hypoalbuminaemia (affecting protein binding), and when managing complex interactions with other drugs.
• Monitoring free phenytoin levels is particularly important in cases of altered protein binding.

Valproic acid

• With its short half-life and variable pharmacokinetics, valproic acid requires close monitoring to optimise efficacy and avoid toxicity, especially in cases of breakthrough seizures or suspected overdose.

Carbamazepine

• TDM helps account for autoinduction and interindividual variability in metabolism.

Lamotrigine

• While challenging due to variable therapeutic ranges, TDM can assist in dose adjustments during pregnancy or when used with enzyme inhibitors like valproic acid.

Newer antiepileptics

• Although TDM is less commonly required, specific situations such as pregnancy, renal impairment, or polypharmacy may benefit from monitoring.
• TDM ensures that treatment remains patient-centred, accounting for pharmacokinetic variability and optimising long-term seizure control.

Integrating TDM into clinical practice

• Effective implementation of TDM involves collaboration between HCPs, pharmacists, and laboratory staff. Key steps include:
  • Timing: Blood samples should be collected at steady-state trough levels to ensure accurate measurement.
  • Interpretation: Consideration of patient-specific factors such as concurrent medications, renal function, and clinical condition is essential.
  • Communication: Prompt reporting and discussion of results between laboratories and clinicians ensure timely dose adjustments.

Challenges in TDM

Despite its advantages, barriers to TDM include limited availability of laboratory resources, delays in reporting results, and lack of standardised protocols in resource-constrained settings like South Africa. Innovations such as dried blood spot testing and point-of-care devices may improve accessibility and turnaround times.

Insights for practice

Therapeutic drug monitoring (TDM) is a critical tool for optimising drug therapy in clinical practice. HCPs should:

• Use TDM to guide dosing for drugs with narrow therapeutic windows, such as vancomycin and tacrolimus.
• Ensure timely blood sampling, preferably at trough levels, to achieve accurate measurements.
• Interpret results with consideration of patient-specific factors, including renal function, age, and drug interactions.
• Communicate promptly with laboratory teams to minimise delays in reporting and dose adjustments.
• Incorporate TDM into routine care to prevent toxicity, improve efficacy, and personalise treatment plans effectively.

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References

1. Alffenaar JC, Heysell SK, Mpagama SG. Therapeutic Drug Monitoring: The Need for Practical Guidance. Clin Infect Dis. 2019 Mar 5;68(6):1065-1066.
2. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009 Mar;24(1):1-10.
3. Xiao Y, Xu L, Qian Y, Xu Y. Identification and characterization of critical values in therapeutic drug monitoring: a retrospective analysis. Sci Rep. 2024;14:11520.
4. Selim M, Anilkumar AC, Patel P, et al. Antiepileptic Drug Monitoring. [Updated 2024 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.