Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM) involves measuring drug levels to optimise dosing for drugs with narrow therapeutic indices, ensuring efficacy while minimising toxicity.
Key Facts
TDM is essential for drugs with a narrow therapeutic index where toxic and therapeutic levels are close Digoxin: Therapeutic range 1.0-2.0 nmol/L (0.5-1.0 ng/mL); sample at least 6 hours post-dose Lithium: Therapeutic range 0.4-1.0 mmol/L; sample 12 hours post-dose; toxicity >1.5 mmol/L Gentamicin (once-daily dosing): Trough <1 mg/L; use the Hartford nomogram for extended interval dosing Vancomycin: Target trough 15-20 mg/L for serious infections; AUC/MIC monitoring increasingly used Phenytoin: Therapeutic range 10-20 mg/L; exhibits zero-order kinetics at therapeutic doses Theophylline: Range 10-20 mg/L; levels increased by erythromycin, ciprofloxacin; decreased by smoking TDM is most useful when there is a clear concentration-effect relationship and significant pharmacokinetic variability
Overview
Key Facts
TDM uses measured drug concentrations to individualise dosing, particularly for drugs where clinical response is difficult to assess and the margin between therapeutic and toxic levels is narrow.
Epidemiology
TDM is routinely performed for approximately 20 drugs in clinical practice. In the UK, clinical pharmacology and pharmacy departments coordinate TDM services. The most commonly monitored drugs are gentamicin, vancomycin, lithium, and antiepileptics.
Aetiology
Factors necessitating TDM:
- Narrow therapeutic index: Small difference between efficacious and toxic concentrations
- Significant inter-individual variability: Due to genetic polymorphisms (CYP2D6, CYP2C19), renal/hepatic function, drug interactions
- Non-linear pharmacokinetics: Phenytoin exhibits saturation (Michaelis-Menten) kinetics
- Poor correlation between dose and clinical effect
Pathophysiology
Drug levels are determined by absorption, distribution, metabolism, and excretion (ADME). Key pharmacokinetic principles:
- First-order kinetics: Constant fraction eliminated per unit time (most drugs)
- Zero-order kinetics: Constant amount eliminated per unit time (phenytoin at therapeutic levels, ethanol)
- Steady state: Reached after approximately 4-5 half-lives
- Volume of distribution: Affects loading dose calculation
- Clearance: Affects maintenance dose calculation
Clinical Presentation
Indications for TDM
- Suspected toxicity (e.g., digoxin toxicity: nausea, visual disturbance, arrhythmias)
- Subtherapeutic response despite adequate dosing
- Changed renal or hepatic function
- Drug interactions suspected
- Compliance assessment
- Loading dose calculation
Toxicity Presentations
- Digoxin toxicity: Nausea, vomiting, xanthopsia (yellow vision), arrhythmias (any type, classically bidirectional VT)
- Lithium toxicity: Tremor, diarrhoea, ataxia, renal failure, seizures
- Phenytoin toxicity: Nystagmus (first sign), ataxia, drowsiness, diplopia
- Gentamicin toxicity: Ototoxicity (vestibular > cochlear), nephrotoxicity
- Theophylline toxicity: Nausea, vomiting, tachycardia, seizures, arrhythmias
Red Flags
- Lithium >2.0 mmol/L: Medical emergency — haemodialysis may be required
- Digoxin toxicity with hypokalaemia: Life-threatening arrhythmias
- Phenytoin toxicity: Cardiac arrhythmias at very high levels
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Drug toxicity | Symptoms correlating with supratherapeutic levels | Drug level, clinical assessment |
| Subtherapeutic dosing | Poor clinical response, levels below range | Trough drug level |
| Non-adherence | Variable drug levels, poor response | Drug levels, prescription records |
| Drug interaction | New drug added, changed levels | Review medications, check levels |
| Renal impairment | Rising drug levels, reduced GFR | U&Es, eGFR |
| Hepatic impairment | Altered metabolism, changed levels | LFTs, drug levels |
Diagnosis / Investigation
Bedside
- ECG: Digoxin toxicity (reverse tick ST depression, arrhythmias), phenytoin toxicity
- Clinical assessment: Nystagmus (phenytoin), tremor (lithium)
Bloods
- Drug levels: At appropriate sampling time (see below)
- U&Es: Renal function affects drug clearance
- LFTs: Hepatic function affects metabolism
- Potassium: Critical with digoxin (hypokalaemia potentiates toxicity)
- Calcium: Hypercalcaemia potentiates digoxin toxicity
Timing of Samples
- Digoxin: ≥6 hours post-dose (distribution phase)
- Lithium: 12 hours post-dose
- Phenytoin: Trough level (pre-dose)
- Gentamicin (extended interval): Pre-dose trough
- Vancomycin: Pre-dose trough; increasingly AUC-guided monitoring
- Theophylline: 4-6 hours post-dose (oral), or 24 hours after starting IV
Special Tests
- Free (unbound) phenytoin levels: In hypoalbuminaemia (use Winter-Tozer equation)
- Pharmacogenomic testing: CYP2D6, CYP2C19, TPMT, DPYD where relevant
Management
Non-pharmacological
- Patient education about importance of regular monitoring
- Medication adherence support
- Alert cards (e.g., lithium, anticoagulant)
Pharmacological
Dosing adjustments:
- Adjust based on drug levels, clinical response, and renal/hepatic function
- For phenytoin: Small dose changes can cause large level changes (zero-order kinetics)
- For aminoglycosides: Hartford nomogram for extended interval dosing
Toxicity management:
- Digoxin toxicity: Digoxin-specific antibody fragments (DigiFab) for life-threatening toxicity; correct hypokalaemia
- Lithium toxicity: IV normal saline, haemodialysis if severe (>2.0 mmol/L with symptoms)
- Phenytoin toxicity: Withhold drug, supportive care, monitor levels
- Theophylline toxicity: Activated charcoal if within 1 hour, beta-blockers for tachyarrhythmias
Referral Criteria
- Clinical pharmacology advice for complex TDM interpretation
- Toxicology referral for severe drug toxicity
- Nephrology for haemodialysis in lithium/theophylline toxicity
Prognosis
- Appropriate TDM reduces adverse drug reactions by approximately 50% for monitored drugs
- Gentamicin nephrotoxicity occurs in 10-25% of patients without proper monitoring
- Lithium-associated chronic kidney disease develops in approximately 15-20% of long-term users
- Phenytoin has complex kinetics — small dose adjustments of 25-50mg can cause significant level changes
- Digoxin toxicity mortality reduced from >20% to <5% with availability of DigiFab
Other Relevant Information
TDM Summary Table
| Drug | Therapeutic Range | Sampling Time | Key Interactions |
|---|---|---|---|
| Digoxin | 1.0-2.0 nmol/L | ≥6h post-dose | Amiodarone, verapamil, renal impairment |
| Lithium | 0.4-1.0 mmol/L | 12h post-dose | NSAIDs, ACEi, diuretics, dehydration |
| Phenytoin | 10-20 mg/L | Trough (pre-dose) | Enzyme inducers/inhibitors, albumin |
| Carbamazepine | 4-12 mg/L | Trough | Auto-induction, enzyme interactions |
| Sodium valproate | 50-100 mg/L | Trough | Protein binding displacement |
| Gentamicin | Trough <1 mg/L | Pre-dose | Renal impairment, loop diuretics |
| Vancomycin | Trough 15-20 mg/L | Pre-dose | Renal impairment |
| Theophylline | 10-20 mg/L | 4-6h post-dose | CYP1A2 inhibitors, smoking |
Winter-Tozer Equation for Phenytoin
Adjusted phenytoin = Measured phenytoin / (0.2 × albumin [g/L] / 40 + 0.1) Used when albumin <30 g/L to estimate free phenytoin levels.