PMID- 32350749 OWN - NLM STAT- MEDLINE DCOM- 20210805 LR - 20210805 IS - 1179-1934 (Electronic) IS - 1172-7047 (Print) IS - 1172-7047 (Linking) VI - 34 IP - 6 DP - 2020 Jun TI - A Phase II Randomized Trial to Explore the Potential for Pharmacokinetic Drug-Drug Interactions with Stiripentol or Valproate when Combined with Cannabidiol in Patients with Epilepsy. PG - 661-672 LID - 10.1007/s40263-020-00726-4 [doi] AB - BACKGROUND: In recent randomized, placebo-controlled, phase III trials, highly purified cannabidiol demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome. It is anticipated that antiepileptic drugs such as stiripentol and valproate will be administered concomitantly with cannabidiol. OBJECTIVES: This trial evaluated the effect of cannabidiol on steady-state pharmacokinetics of stiripentol or valproate in patients with epilepsy, and the safety and tolerability of cannabidiol. METHODS: This phase II, two-arm, parallel-group, double-blind, randomized, placebo-controlled trial recruited male and female patients with epilepsy aged 16-55 years. Patients receiving a stable dose of stiripentol or valproate were randomized 4:1 to receive concomitant double-blind cannabidiol or placebo. Patients received plant-derived, highly purified cannabidiol medicine (Epidiolex((R)) in the USA; Epidyolex((R)) in the EU; 100 mg/mL oral solution) at a dose of 20 mg/kg/day from day 12 to 26, following a 10-day dose-escalation period. Blood samples for pharmacokinetic evaluations were collected on days 1 and 26 before stiripentol/valproate dosing and up to 12 h postdose. Treatment-emergent adverse events (AEs) were recorded. RESULTS: In total, 35 patients were recruited to the stiripentol arm (n = 14) or the valproate arm (n = 21). Both the safety and the pharmacokinetic populations of the stiripentol arm comprised 14 patients (2 placebo; 12 cannabidiol). The safety population of the valproate arm comprised 20 patients (4 placebo; 16 cannabidiol; one withdrew before receiving treatment); the pharmacokinetic population comprised 15 patients (3 placebo; 12 cannabidiol). Concomitant cannabidiol led to a small increase in stiripentol exposure (17% increase in maximum observed plasma concentration [C(max)]; 30% increase in area under the concentration-time curve over the dosing interval [AUC(tau)]). Concomitant cannabidiol also had little effect on valproate exposure (13% decrease in C(max); 17% decrease in AUC(tau)) or its metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA) (23% decrease in C(max); 30% decrease in AUC(tau)). All changes in exposure are expressed as the dose-normalized geometric mean (CV%) day 26 to day 1 ratio. The most common AE was diarrhea; most AEs were mild. Two patients discontinued cannabidiol because of serious AEs (rash [n = 1] in the stiripentol arm; hypertransaminasemia [n = 1] in the valproate arm). A separate in vitro study investigated the bidirectional effect of cannabidiol, or its metabolite 7-carboxy-cannabidiol, on valproate plasma protein binding; no change in plasma protein binding was observed for either compound. CONCLUSIONS: The clinical relevance of the increase in stiripentol exposure is unknown; patients receiving cannabidiol and stiripentol concomitantly should be monitored for adverse reactions as individual patient responses may vary. Coadministration of cannabidiol did not affect the pharmacokinetics of valproate or its metabolite, 4-ene-VPA, in adult patients with epilepsy. Safety results were consistent with the known safety profile of cannabidiol at a dose of 20 mg/kg/day. Clinicaltrials.gov: NCT02607891. FAU - Ben-Menachem, Elinor AU - Ben-Menachem E AUID- ORCID: 0000-0001-5864-9185 AD - Department of Clinical Neuroscience at Institute of Neuroscience and Physiology, Neurologen, University of Gothenburg, Bla Straket 7, Plan 0, 41345, Gothenburg, Sweden. elinor.ben-menachem@neuro.gu.se. FAU - Gunning, Boudewijn AU - Gunning B AD - Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands. FAU - Arenas Cabrera, Carmen Maria AU - Arenas Cabrera CM AD - Hospital Universitario Virgen del Rocio, Seville, Spain. FAU - VanLandingham, Kevan AU - VanLandingham K AD - Greenwich Biosciences, Inc., Carlsbad, CA, USA. FAU - Crockett, Julie AU - Crockett J AD - GW Research Ltd, Cambridge, UK. FAU - Critchley, David AU - Critchley D AD - GW Research Ltd, Cambridge, UK. FAU - Wray, Louise AU - Wray L AD - GW Research Ltd, Cambridge, UK. FAU - Tayo, Bola AU - Tayo B AD - GW Research Ltd, Cambridge, UK. FAU - Morrison, Gilmour AU - Morrison G AD - GW Research Ltd, Cambridge, UK. FAU - Toledo, Manuel AU - Toledo M AD - Hospital Universitari Vall d'Hebron, Barcelona, Spain. LA - eng SI - ClinicalTrials.gov/NCT02607891 SI - ClinicalTrials.gov/NCT02607891 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - New Zealand TA - CNS Drugs JT - CNS drugs JID - 9431220 RN - 0 (Anticonvulsants) RN - 0 (Dioxolanes) RN - 19GBJ60SN5 (Cannabidiol) RN - 614OI1Z5WI (Valproic Acid) RN - R02XOT8V8I (stiripentol) SB - IM MH - Adolescent MH - Adult MH - Anticonvulsants/administration & dosage/adverse effects/pharmacokinetics MH - Area Under Curve MH - Cannabidiol/*administration & dosage/adverse effects/pharmacology MH - Dioxolanes/*administration & dosage/pharmacokinetics MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Drug Interactions MH - Drug Therapy, Combination MH - Epilepsy/*drug therapy MH - Female MH - Humans MH - Male MH - Middle Aged MH - Valproic Acid/*administration & dosage/pharmacokinetics MH - Young Adult PMC - PMC7275018 COIS- Elinor Ben-Menachem has received consulting honoraria from GW Pharmaceuticals companies, UCB, Sandoz, Eisai, and Bial and has been a principal investigator for GW Research Ltd. Boudewijn Gunning has received consultancy fees from GW Pharmaceuticals companies, Zogenix, and Ovid/Takeda; has been a principal investigator for GW Research Ltd, Zogenix, LivaNova, Marinus Pharmaceuticals, and UCB; and is a member of the International Speakers Bureau of LivaNova. Carmen Maria Arenas Cabrera has received consultancy fees from UCB, Eisai, Bial, and Esteve and has been a principal investigator for GW Research Ltd. Kevan VanLandingham is employed by Greenwich Biosciences, Inc. and owns shares in GW Pharmaceuticals plc. Bola Tayo and Gilmour Morrison are employed by GW Research Ltd and own shares in GW Pharmaceuticals plc. David Critchley, Louise Wray, and Julie Crockett are employed by GW Research Ltd and have share options in GW Pharmaceuticals plc. Manuel Toledo has received consulting honoraria and lecture fees from GW Pharmaceuticals companies, UCB Pharma, Eisai, Bial, Esteve, and Sanofi and has been a principal investigator for GW Research Ltd. EDAT- 2020/05/01 06:00 MHDA- 2021/08/06 06:00 PMCR- 2020/04/30 CRDT- 2020/05/01 06:00 PHST- 2020/05/01 06:00 [pubmed] PHST- 2021/08/06 06:00 [medline] PHST- 2020/05/01 06:00 [entrez] PHST- 2020/04/30 00:00 [pmc-release] AID - 10.1007/s40263-020-00726-4 [pii] AID - 726 [pii] AID - 10.1007/s40263-020-00726-4 [doi] PST - ppublish SO - CNS Drugs. 2020 Jun;34(6):661-672. doi: 10.1007/s40263-020-00726-4.