Chapter 50: A Practical Guide to AED Pharmacology

INTRODUCTION

Almost half of the patients who initially present with epilepsy will become seizure free on their first antiepileptic drug (AED). The prognosis for the remaining half who fail initial treatment is less optimistic with response rates plummeting lower with each successive treatment failure.¹ This data underscore the importance of selecting an agent with a high probability of success early in treatment. In children, agent selection is often the foundation for successful therapy.

Pediatric therapy is confounded by the need to choose an appropriate dosage regimen and formulation that are compatible with a higher metabolic rate, heightened sensitivity to adverse drug effects, and drug–drug/drug–food compatibility issues in childhood. Achieving therapy goals is fraught with challenges as many product formulations are not pediatric-friendly. Furthermore, organogenesis complicates medication dosing by a continuum of pharmacokinetic changes that necessitate frequent monitoring and possible custom drug formulations.^2,3 Inadequate dosage regimens easily lead to treatment failure and an undeserved label of intractable epilepsy.⁴ Thus, pharmacoresistance in childhood can have complex etiologies.

EFFICACY ISSUES

Hepatic Phase I biotransformation reactions are diminished in infants during the first 6 months of life but subsequently attain and supersede adult values resulting in rapid drug elimination. This can cause ineffective drug exposure and an inadequate therapeutic response. While serum AED concentration monitoring is not typically encouraged, it remains useful to gain insight into dosing pitfalls in unresponsive children. Routine monitoring has not provided value for patient care for the second generation AEDs. Unlike the older AEDs, the newer agents lack convincing and consistent evidence of a therapeutic correlation with serum drug concentrations.^5,6

The value of routine monitoring for older AEDs has also been questioned, particularly for asymptomatic patients.⁷ Serum concentration determinations may yield useful information regarding developmental pharmacokinetic changes in childhood.⁸ Children who fail treatment despite higher than recommended doses warrant serum concentration assessments even with the second generation AEDs. In situations where serum concentrations are only slightly low, a minor dosage, dosing interval, or dosage form alteration may significantly improve response. Extremely low values, however, are suggestive of a more complicated problem.

The differential diagnoses for exceedingly low drug concentrations include: rapid drug clearance, impaired oral absorption, generic substitution problems, drug interactions (producing changes in protein binding, volume of distribution, or metabolism), dispensing errors, or medication noncompliance. Differentiating between these causative factors enables regimen changes that may improve therapeutic response.² The possibility of a diagnostic reassessment (e.g., seizure reclassification, consideration oft pseudoseizures, etc.) in unresponsive children with adequate serum AED concentrations should not be overlooked.

The distinction between poor oral absorption, rapid drug elimination, and medication noncompliance can be determined by basic drug clearance determinations. This method requires at least three serial serum AED concentrations within the same dosage interval (i.e., no drug administered between blood draws).⁹ The time interval ...