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Monitoring of phenytoin in epileptic children: value of the single morning sample
A S Naglo1, A Nergårdh, L O Boréus
1Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Insights
Intra-individual phenytoin levels in children show significant variation, suggesting the commonly used 40 mumol/l threshold for seizure control may need reevaluation. Routine single morning samples are adequate for monitoring well-controlled children on monotherapy.
Area of Science:
- Pharmacokinetics
- Clinical Pharmacy
- Pediatric Neurology
Background:
- Phenytoin is a widely used antiepileptic drug.
- Accurate therapeutic drug monitoring is crucial for optimizing seizure control and minimizing toxicity.
- Understanding intra-individual variability in drug concentrations is essential for effective patient management.
Purpose of the Study:
- To assess the intra-individual variation in plasma phenytoin concentrations in children on monotherapy.
- To evaluate the adequacy of single pre-dose samples for routine monitoring.
- To examine the shape of concentration-time curves and protein binding.
Main Methods:
- Ten clinically well-controlled children on phenytoin monotherapy were studied.
- Plasma phenytoin concentrations were measured in routine pre-dose samples over 3-5 mornings.
- Concentration-time profiles and unbound/total drug ratios were determined on two occasions.
Main Results:
- Morning phenytoin concentrations varied significantly within individuals (7.5-40 mumol/l range).
- Half of morning concentrations were below 40 mumol/l, questioning its utility as a sole indicator of seizure control.
- Concentration-time curves showed considerable inter-individual differences, precluding prediction.
- Unbound to total drug ratio was stable at 9.4%.
Conclusions:
- Single morning phenytoin samples are sufficient for routine monitoring in well-controlled pediatric patients on monotherapy.
- For complex cases or combination therapy, extensive monitoring including dose-interval curves and protein binding is recommended.
- The 40 mumol/l threshold for good seizure control warrants reconsideration in pediatric phenytoin therapy.
Abstract:
The intra-individual variation in plasma concentration of phenytoin was studied in ten clinically well controlled children on monotherapy. The drug concentration was determined in routine pre-dose samples taken on three to five different mornings. On two of these occasions, plasma phenytoin was also determined at 0.5, 1, 2, 3, 5 and 7 h after the dose. The difference between the highest and lowest morning concentrations in a patient varied between 7.5 and 40 mumol/l (mean 20.1 mumol/l). Half of all morning concentration values were lower than 40 mumol/l. This often-recommended lower limit for good seizure control should therefore be reconsidered. The two concentration versus time curves in each patient during 7 h after administration differed considerably in shape, and the first curve could not be used for prediction of the second curve. The ratio between unbound and total drug was very stable and amounted to 9.4, SD 0.94% (n = 168). It is concluded that the conventional single morning sample is satisfactory for routine monitoring in well-controlled children on monotherapy with phenytoin. In problem patients, and during combination therapy, however, more extensive investigation will be necessary, including repeated morning samples as well as determination of dose-interval curves and protein binding.