What is the role of Therapeutic Drug Monitoring (TDM) in managing childhood epilepsy?

Therapeutic Drug Monitoring in Childhood Epilepsy

Therapeutic drug monitoring (TDM) should be selectively applied in childhood epilepsy rather than routinely performed, with specific indications including establishing individual therapeutic concentrations after treatment initiation, suspected non-adherence, therapeutic failure, drug interactions, and physiological changes that affect pharmacokinetics.

Core Indications for TDM in Pediatric Epilepsy

TDM provides valuable clinical utility in childhood epilepsy when applied appropriately in specific clinical scenarios 1, 2:

• Establishing baseline individual therapeutic concentration after starting treatment to provide a reference point for future dose adjustments 2, 3
• After dosage changes, particularly for drugs with nonlinear kinetics like phenytoin where concentration changes are disproportionate to dose changes 2
• Therapeutic failure to determine whether uncontrolled seizures or side effects have a pharmacokinetic explanation 1, 2
• Suspected drug interactions, especially in polytherapy which is common in refractory pediatric epilepsy 1, 3
• Age-dependent pharmacokinetic changes since children aged 3 months to 10 years have 50% higher clearance (mL/min/kg) than adults, requiring different dosing strategies 4

Pharmacokinetic Considerations Specific to Children

Pediatric patients exhibit distinctive pharmacokinetic characteristics that make TDM particularly relevant 4:

• Neonates and infants under 2 months have markedly decreased ability to eliminate antiepileptic drugs due to immature glucuronosyltransferase and other enzyme systems 4
• Children between 3 months and 10 years demonstrate substantially higher weight-adjusted clearance rates compared to adults, necessitating higher per-kilogram doses 4
• Volume of distribution is increased in young children partly due to decreased plasma protein binding 4

Critical Concept: Individual Therapeutic Concentration vs. Reference Range

The reference range quoted by laboratories is NOT a therapeutic range 2. The emphasis must be placed on determining an individual therapeutic concentration for each child 1, 2:

• The same serum concentration may be therapeutic for one patient but inadequate or toxic for another 2
• Once seizure control is achieved at a specific concentration, that becomes the patient's individual therapeutic target 2, 3
• Subsequent dose adjustments should aim to maintain this individualized concentration 3

Practical Application Algorithm

When to Obtain TDM:

1. Initial treatment phase: After achieving steady-state (typically 5 half-lives) to establish baseline individual therapeutic concentration 2, 3

2. During treatment modifications:

   • Addition or discontinuation of concomitant medications that may cause drug interactions 1, 3
   • Change in formulation or switch between brand and generic products 2
   • Dosage adjustments, especially for drugs with nonlinear kinetics 2

3. Clinical deterioration:

   • Breakthrough seizures despite previously adequate control 1, 2
   • New or worsening adverse effects 1, 5
   • Suspected non-adherence 1, 2

4. Physiological changes:

   • Rapid growth periods in children affecting drug clearance 1
   • Intercurrent illness, particularly hepatic or renal disease 2
   • Gastrointestinal conditions affecting drug absorption 2

Sample Collection Considerations

Blood sampling remains the standard, but alternative matrices offer advantages in pediatric populations 6:

• Saliva sampling is noninvasive, preferred by children, and reflects free (pharmacologically active) drug concentrations for many antiepileptic drugs 6
• Saliva TDM is well-validated for carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide 6
• Saliva TDM is not helpful for valproic acid 6

Common Pitfalls and How to Avoid Them

Misinterpreting total drug concentrations in special circumstances 4:

• In children with hepatic disease, decreased albumin and increased free fractions mean total concentrations may appear normal while free concentrations are substantially elevated 4
• Monitor free (unbound) concentrations rather than total concentrations in patients with hypoalbuminemia or hepatic disease 4

Assuming reference ranges apply universally 2:

• Reference ranges are population-based estimates, not individual therapeutic targets 2
• Clinical response and tolerability must guide interpretation, not just whether the concentration falls within the reference range 1, 3

Timing of sample collection 3:

• Trough concentrations (immediately before next dose) provide the most reproducible and clinically useful information 3
• Samples taken at other times are difficult to interpret and should be avoided 3

Evidence Quality and Limitations

While randomized controlled trials specifically evaluating TDM effectiveness in pediatric epilepsy are limited, extensive nonrandomized investigations and decades of clinical experience support its judicious use 2. The pharmacokinetic variability of antiepileptic drugs is well-documented, with pronounced between-patient variability making individualized approaches necessary 1, 3.

TDM should not be performed routinely but rather applied strategically in the specific clinical scenarios outlined above 1, 5. This targeted approach maximizes clinical benefit while avoiding unnecessary testing and costs 2, 3.