Therapeutic Drug Monitoring (TDM) is an essential tool in the management of seizure disorders. Most antiepileptic drugs (AEDs) exhibit significant interindividual variability in pharmacokinetics, narrow therapeutic index ranges, and complex drug–drug interactions. Because seizure control and drug toxicity are closely linked to plasma concentrations, TDM becomes critical for optimizing therapy and preventing adverse outcomes.
Why TDM Is Important in Seizure Disorders
Seizure medications require ongoing monitoring due to:
- Narrow therapeutic window – small difference between effective and toxic levels
- High pharmacokinetic variability – age, liver disease, pregnancy affect levels
- Risk of severe toxicity – CNS toxicity, hepatic failure, hematologic effects
- Complex drug interactions through CYP450 enzymes
- Nonlinear kinetics in some AEDs (e.g., phenytoin)
- Unpredictable clinical response – seizures may persist despite therapeutic dosing
TDM is particularly important when initiating therapy, adjusting doses, adding new drugs, or when toxicity is suspected.
Drugs Commonly Monitored in Seizure Therapy
- Phenytoin
- Carbamazepine
- Valproic acid
- Phenobarbital
- Primidone
- Newer AEDs (occasionally): levetiracetam, lamotrigine
1. Phenytoin
Phenytoin is one of the most commonly monitored seizure medications due to its nonlinear (Michaelis–Menten) kinetics.
Therapeutic Range
Total phenytoin: 10–20 µg/mL
Free phenytoin: 1–2 µg/mL (more accurate)
Reasons for Monitoring
- Narrow therapeutic index
- Highly protein-bound (90%) — free levels rise in hypoalbuminemia
- Numerous drug interactions
- Nonlinear kinetics → small dose changes cause large concentration changes
Toxicity Signs
- Nystagmus
- Ataxia
- Slurred speech
- Confusion
Sampling Time
12–24 hours after last dose for steady-state monitoring.
2. Carbamazepine
Therapeutic Range
4–12 µg/mL
Key TDM Points
- Auto-induction → levels fluctuate during first few weeks
- Metabolized by CYP3A4 → high interaction potential
- Active metabolite (carbamazepine-10,11-epoxide) may need monitoring
Toxicity Indicators
- Dizziness
- Blurred vision
- Leukopenia
- Hyponatremia
3. Valproic Acid (Valproate)
Therapeutic Range
50–100 µg/mL (may be higher in some seizure types)
Key Considerations
- Highly protein-bound
- Free levels may rise in hypoalbuminemia or uremia
- Inhibits metabolism of other AEDs
Toxicity
- Tremor
- Hepatotoxicity
- Pancreatitis (rare)
- Hyperammonemia
4. Phenobarbital
Therapeutic Range
15–40 µg/mL
Characteristics
- Long half-life (2–6 days)
- Potent enzyme inducer → reduces levels of many drugs
- Toxicity: sedation, respiratory depression
5. Primidone
Primidone is metabolized to phenobarbital; both require monitoring.
- Primidone therapeutic range: 5–12 µg/mL
- Phenobarbital (active metabolite): 15–40 µg/mL
Newer Antiepileptic Drugs (AEDs) and TDM
Many newer agents do not routinely require TDM due to predictable pharmacokinetics. However, TDM may be helpful in:
Levetiracetam
- Narrow therapeutic window not established
- Useful in renal impairment or pregnancy
Lamotrigine
- Therapeutic range: 3–14 µg/mL
- Levels significantly altered by valproate (inhibitor) and carbamazepine (inducer)
Indications for TDM in Seizure Drugs
- Suspected toxicity
- Failure of seizure control
- Starting or stopping interacting drugs
- Pregnancy (altered metabolism and volume of distribution)
- Renal or hepatic impairment
- Non-adherence suspected
- Rapid dose escalation needed
Sampling Principles in AED TDM
- Collect samples at steady state (after 4–5 half-lives)
- Trough samples are preferred (immediately before next dose)
- For phenytoin, measure free levels in hypoalbuminemia
- Always note exact dose time and formulation
Interpreting Results
TDM values must be interpreted clinically, considering:
- Patient’s seizure control
- Adverse effects
- Drug interactions
- Renal and hepatic function
- Changes in protein binding
Levels within therapeutic range do not always mean the patient is seizure-free, and levels below the range may still be effective in some individuals.
Detailed Notes:
For PDF style full-color notes, open the complete study material below:
PATH: PHARMD/ PHARMD NOTES/ PHARMD FIFTH YEAR NOTES/ CLINICAL PHARMACOKINETICS AND PHARMACOTHERAPEUTIC DRUG MONITORING (TDM)/ TDM OF SEIZURE DRUGS.