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.
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 between the first and third specimen should be equivalent or longer than the half-life of the AED. It is frequently necessary to delay the next scheduled dose to allow an appropriate time lapse between specimens.
A bolus dose may be necessary if baseline serum concentrations are extremely low. This boost facilitates a sufficiently high serum concentration to demonstrate a suitable decline between specimens with a measurable value on the last sample. It is also important that the first specimen be obtained after the drug absorption phase, so that all specimens are drawn only on the elimination side of the serum concentration time curve. The first blood draw can usually be obtained 2 hours after drug administration as this is typically sufficient for completion of the absorption phase of most immediate release formulations.
For extended release (ER) formulations, the absorption phase may be as long as 6–8 hours after the dose. Serial testing with these products requires the elimination of a dose to allow both completion of the absorption phase and an acceptable time (one half-life) between the first and last specimen. The procedure and formulas for drug elimination calculations are reviewed elsewhere.9
Rapid AED clearance is likely when serum drug concentrations drop rapidly (>50%) between serial blood specimens. There are three primary methods to overcome hypermetabolism and maintain an effective drug exposure: (1) increasing dosing frequency and drug dose (e.g., from bid to tid dosing) to accommodate the high elimination rate, (2) use a sustained release formulation, (3) change to an AED with a longer drug half-life or renal excretion.
ER formulations retard drug release and are popular to maintain stable serum concentrations. Sustained release products release drug continuously into the system protecting the total dose from immediate metabolism. Even ER products require more frequent dosing in children compared to adults (e.g., every 8 hours vs. every 12 hours). However, they maintain more consistent serum concentrations and avoid large peak-to-trough variation.
Children also may exhibit erratic and unpredictable drug absorption. Predisposing factors include: delayed gastric emptying time in infants, diminished intestinal transit times (limits absorption of ER formulations), reduced absorptive surface area, intestinal disorders (e.g., acute diarrhea), and drug interactions with milk and infant formulas.2,3 Absorption problems lead to low or erratic serum concentrations and a poor therapeutic response. Impaired oral absorption should be suspected if peak concentrations are much lower than expected and either decline normally between specimens or fail to show expected peak and trough variations.
Coadministered medications, food and liquids should be reviewed for interactions producing malabsorption.2,9 Some solid dosage forms are poorly absorbed in children due to shorter transit time through the gastrointestinal tract. Solid formulations recovered from the stool contain significant amounts of drug and are particularly problematic with some AEDs.10,11 Inconsistent generic substitution or generic brand switching is another cause of erratic serum concentration in generic products.12
Lastly, medication noncompliance is prevalent in children with chronic illnesses. Compliance issues are a primary cause of low or widely fluctuating serum concentrations and inadequate drug exposure. Noncompliance rates may reach 30%–40% in pediatric patients and increase proportionately to the number of medications.13 Serial drug concentrations may appear normal when taken after an observed dose. However, the clinical assessment does not correlate with levels obtained at home.
Compliance can also be evaluated with serial trough serum concentrations at the same time of the day—several days to a week apart. The values should not vary by more than 10% with full compliance and the same testing laboratory. Pill counts and prescription refill records can also be used to check compliance. Counseling is sometimes effective but a change to a less frequently administered medication may be necessary.2
Determining the cause of incomplete treatment response in children can be frustrating and time consuming. Figure 50–1 represents a cognitive algorithm for inadequate treatment response that may prove useful in sorting out drug therapy issues.
ADVERSE DRUG EFFECTS
In pediatric epilepsy, drug safety and tolerability are equally if not more important than efficacy. Efficacy of the approved AEDs is fairly equal for epilepsy types and syndromes but the adverse effect (AE) profile often determines AED selection.14 An individualized treatment approach will take into account the patient’s seizure type or syndrome, family history, and AED safety and efficacy profile. It is important to carefully balance AED morbidity with efficacy profile and potential consequences of recurrent seizures.
Approximately 33%–61% of patients on AED therapy will experience at least one AE during the course of their treatment.15,16 For the purpose of prescription drug labeling, the FDA defines adverse reaction as an undesirable effect, reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse events during drug usage, only those for which there is some basis to ascribe a causal relationship between the drug and adverse event occurrence.17 These effects are further characterized by body system, reaction severity, incidence of occurrence, or by a combination. Updated safety requirements further separate adverse reactions from clinical trials and postmarketing spontaneous reports.