Authors :
Arjun Vijan, PharmD – Jazz Pharmaceuticals, Inc.
Hongwei Xue, MS – Jazz Pharmaceuticals, Inc.
Patricia Chandler, MD – Jazz Pharmaceuticals, Inc.
Sujith Madhavan, MS – Jazz Pharmaceuticals, Inc.
Presenting Author: Cuiping Chen, PhD – Jazz Pharmaceuticals, Inc.
Rationale:
A plant-derived highly purified pharmaceutical formulation of cannabidiol (CBD; Epidiolex®; 100 mg/mL oral solution) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. CBD and cenobamate (CNB) are newer antiseizure medications (ASMs) with limited data characterizing their concomitant use. It has been speculated that a pharmacokinetic (PK) drug-drug interaction (DDI) between CBD and CNB may result in dose-related central nervous system adverse events (AEs) when CBD and CNB are concomitantly administered.1 However, formal PK DDI between CBD and CNB had not yet been assessed. Here, we evaluated any bidirectional PK DDI between CBD and CNB.Methods:
Healthy adults (aged 18–55 years) received CBD 7.5 mg/kg twice daily (BID) from Day (D) 1–D4 followed by a morning dose only on D5. After a 7-day washout period (D6–D12), participants underwent a 12-week CNB titration according to the USPI, starting at 12.5 mg once daily (QD) on D13–D26, followed by 25 mg QD on D27–D40, 50 mg QD on D41–54, 100 mg QD on D55–D68, 150 mg QD on D69–D82, and 200 mg QD on D83–D93 (Figure). Participants received both CBD 7.5 mg/kg BID and CNB 200 mg QD for 5 days on D94–D98. Blood samples for PK assessments were collected at D5 (CBD alone as reference), D93 (CNB alone as reference), and D98 (CBD + CNB as test). AUC0-12h (CBD), AUC0-24h (CNB), and Cmax were assessed with geometric least-squares mean (GLSM) ratios and 90% confidence intervals (CIs) comparing CBD + CNB versus each ASM alone. Safety information was collected from the start of intervention until the follow-up visit and included incidence and severity of treatment-emergent AEs (TEAEs).Results:
The GLSM ratios and associated 90% CIs were within 80% to 125% for both CBD (reference n=20; test n=17; AUC0-12h: 94.3 [90% CI: 82.1–108.3]; Cmax: 98.1 [80.5–119.5]) and CNB (reference and test n=17 for both; AUC0-24h: 107.6 [104.9–110.4]; Cmax: 102.0 [98.2–106.0]). In the safety analysis set (n=20), TEAEs were reported by 4 participants receiving CBD + CNB, compared with 10 receiving CBD alone and 12 receiving CNB alone. Diarrhea (40%) and headache (25%) were the most commonly reported AEs. Two participants discontinued (1 on CBD alone, 1 on CNB alone) due to TEAEs of rash and dermatitis. No serious AEs, severe TEAEs, or deaths were reported in the study.Conclusions:
No PK effect of CBD on CNB or of CNB on CBD was observed when the two were administered concomitantly at clinically relevant dosages. Coadministration of CBD and CNB showed no evidence of increased AEs or worsening safety findings compared with either dosed alone. These PK DDI results support that coadministration of CNB with CBD does not warrant a reduction in the CBD dosage.
Reference
1. Smith MC, et al. Neurol Ther. 2022;11(4):1705-1720.
Funding:
Jazz Pharmaceuticals, Inc.