Antiepileptic Drug Levels in Tuberous Sclerosis Complex Patients Taking Everolimus
Abstract number :
3.266
Submission category :
7. Antiepileptic Drugs
Year :
2015
Submission ID :
2328200
Source :
www.aesnet.org
Presentation date :
12/7/2015 12:00:00 AM
Published date :
Nov 13, 2015, 12:43 PM
Authors :
Christina Talley, Charissa Kam, Mindl Messinger, Darcy Krueger, Maxwell Mays, Angus Wilfong
Rationale: The majority of patients with Tuberous Sclerosis Complex (TSC) have seizures that are refractory to antiepileptic drugs (AEDs). Everolimus, an mTOR inhibitor, has been FDA approved for the treatment of subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs) in TSC patients. Everolimus has shown efficacy towards treating seizures in early clinical trials. It is unknown how Everolimus, a CYP3A4 substrate, affects concurrent AED metabolism. The purpose of this study is to determine the effects of Everolimus on concomitant AED serum levels.Methods: Pharmacologic data was analyzed on 20 TSC subjects who participated in an Everolimus phase I/II clinical trial. The primary endpoint was to evaluate the clinical effectiveness of Everolimus as an adjunct treatment to reduce seizure activity. Everolimus was administered at a starting dose of 5 mg/m2 once daily. During the course of the clinical trial, participant AED levels were checked before and after starting Everolimus. We examined percent changes in AED levels and the number of dose escalations required to obtain the target trough range of 5-15 ng/ mL among patients receiving concomitant CYP3A4 and P-glycoprotein inhibitors and inducers.Results: AED Levels were measured before the initiation of Everolimus, two and four weeks after beginning treatment. For AEDs metabolized via non-CYP 3A4 pathways, there was a major percent increase (22%) for mean Oxcarbazepine levels (26 to 32 ug/mL). For AEDs metabolized via CYP 3A4 pathways, there was a 16% increase in mean Felbamate levels from 52-60 ug/mL and a 15% increase in mean Zonisamide levels from 32-37 ug/mL. There were smaller differences for Valproic Acid (4% increase) and Lamotrigine (13% decrease). Levetiracetam levels decreased by 43%. For Everolimus dose increases, it was found that patients who were on Oxcarbazepine and Felbamate frequently required multiple dose increases to reach target levels of 5-15 ng/ mL.Conclusions: Everolimus appears to increase the serum levels of AEDs that are metabolized via the CYP 3A4 pathways. There are mixed results about its impact on non-CYP 3A4 AEDs. Patients who were taking Felbamate and Oxcarbazepine required additional Everolimus dose increases to obtain target levels. Patients that are on these CYP 3A4 inducers may need to start at a higher starting dose of Everolimus than 5 mg/m2 to avoid additional dose escalations and shorten time to effective dosing.
Antiepileptic Drugs