Authors :
Presenting Author: Jeffrey Mensah, MS – University of Utah
Kristina Johnson, BS – 1. Contract Site of the NINDS Epilepsy Therapy Screening Program, University of Utah; Cameron Metcalf, Ph.D – Contract Site of the Epilepsy Therapy Screening Program, University of Utah; Christopher Reilly, Ph.D – Center for Human Toxicology, University of Utah; Joseph Rower, Ph.D – Center for Human Toxicology, University of Utah; Karen Wilcox, Ph.D – Contract Site of the Epilepsy Therapy Screening Program, University of Utah
Rationale:
Dravet syndrome (DS) is
a highly drug-resistant form of developmental epilepsy. Despite the advances in the search for an effective treatment strategy for DS, optimal treatment and dosing guidelines for pediatric DS patients have been based on expert opinions and often include polypharmacy. Finding an equilibrium between adequate seizure control, adverse drug effects, and avoiding the burden of polypharmacy in patients is challenging. Thus,
establishing an effective therapeutic regimen for DS is difficult. We hypothesize that pharmacokinetic (PK) information could be used to guide the development of
an optimal therapeutic regimen. As a proof-of-principle, we conducted a PK study of a second-line treatment regimen that combines clobazam (CLB) and sodium valproate (VPA) with the add-on drugs stiripentol (STP) or cannabidiol (CBD) in a mouse model of DS.
Methods:
DS (
Scn1aA1783/WT) mice were treated with either
STP (100 mg/kg, i.p), CBD (150 mg/kg, i.p), CLB (5 mg/kg; i.p), VPA (75 mg/kg; i.p), or the following combinations; CLB (5 mg/kg; i.p)+VPA (75 mg/kg; i.p), STP (100 mg/kg, i.p)+CLB (5 mg/kg; i.p)+VPA (75 mg/kg; i.p) or CBD (150 mg/kg, i.p)+CLB (5 mg/kg; i.p)+VPA (75 mg/kg; i.p). Plasma and brain samples were collected between 0.08 and 8-hour time-points. STP, CBD, CLB, CLB metabolite N-desmethylclobazam (N-CLB), and VPA concentrations in both plasma and brain matrices were quantified using liquid chromatography-tandem mass spectrometry. The mean concentrations of each analyte at each time-point were determined and used to calculate PK parameters in both plasma(p) and brain(b) using non-compartmental analysis in Phoenix WinNonLin.
Results:
CLB concentrations in the CLB+VPA+CBD
group [area under the concentration-time curve (AUC)p-2048 ng*hr/mL] were more than 3-fold greater than CLB in the CLB+VPA group [AUCp-462 ng*hr/mL] or the CLB alone group [AUCp-648 ng*hr/mL]. Additionally, N-CLB concentrations in CLB+VPA+STP
(AUC)p-7128 ng*hr/mL] were higher than CLB in CLB+VPA [AUCp-3618 ng*hr/mL] and CLB alone [AUCp-5528 ng*hr/mL]. VPA half-life (t1/2) was relatively longer in the combination therapies [ t1/2 (CLB+VPA+STP)
– 0.167 hr, t1/2 (CLB+VPA+CBD) -
0.167 hr] compared to when it was given alone [t1/2 (VPA) –
0.083. hr]. STP concentrations in CLB+VPA+STP
[AUCp-104 ng*hr/mL] were ~ 2-fold greater than STP alone [AUCp-53 ng*hr/mL]. CBD concentrations in CLB+VPA+CBD
[AUCp-6287 ng*hr/mL] were greater than CBD alone [AUCp-4207 ng*hr/mL].Conclusions:
The concurrent PK interactions between CLB, VPA, and STP or CBD may explain their potentiated efficacy in combination therapies in DS. This study also sets the stage to design a dosing regimen for a triple-drug treatment in a mouse model of DS for chronic spontaneous seizure drug screening.
Funding:
This project has been partly funded by Federal funds from the National Institute of Neurological Disorders and Stroke, Epilepsy Therapy Screening Program, National Institutes of Health, and Department of Health and Human Services, under Contract No. HHS 75N95022C00007 and the Donald R. Gehlert Fellowship (JAM).