September 22, 2018

High Incidence of Persistent Subtherapeutic Levels of the Most Common AEDs in Children with Epilepsy Receiving Polytherapy

BACKGROUND: Low levels of AEDs can be secondary drug-drug interactions or related to irregular intake due to poor treatment adherence. This latter behavior is highly suspected in ambulatory pediatric epileptic patients when controls of AEDs are subtherapeutic. However, it cannot be considered for inpatients during long periods of hospitalization. A few isolated case reports have documented persistent low levels (PLL) of AEDs in hospitalized epileptic children, but no population study has currently been reported.

OBJECTIVE: The aim of this study was to document the incidence of PLL of the most common AEDs – phenytoin (PHT), phenobarbital (PHB), valproic acid (VA), and carbamazepine (CBZ) – in pediatric epileptic in- and outpatients (PEP).

METHODS: 21,040 plasma levels of the aforementioned AEDs from 3279 PEP were retrospectively analyzed. Plasma levels of AEDs were measured by an automated method using trademarked commercial kits with their corresponding quality control programs. Randomized samples were also controlled by HPLC methods. Only cases with more than 3 controls were included in the study.

RESULTS: A high rate of PLL of PHT was detected in in- (71.7%) and outpatients (74.1%), while PLL of PHB, VA, and CBZ were detected in a lower proportion. Rates of PLL of PHT were similar in in- and outpatients. PLL of PHB was more commonly observed in outpatients while PLL of VA and CBZ were more frequently seen in inpatients. In some hospitalized patients receiving polytherapy, PLL of at least one AED were documented during a long time.

DISCUSSION: Treatment non-adherence could be present in part of the outpatients, but cannot explain the persistent low levels observed in a group of inpatients as described here. The recently described “pharmacokinetic hypothesis” of pharmaco-resistant epilepsy should be addressed in cases with antiepileptic drug persistent low levels, particularly in hospitalized cases. Perhaps, instead of stopping the subtherapeutic medication, the increasing doses of this antiepileptic drugs and/or administration of inhibitors of CYP and P-glycoprotein, could help to achieve its therapeutic range, allowing a better pharmacologic effect and avoiding the development of more severe complications, such as status epilepticus or SUDEP.

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