A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects

Gilmour Morrison, Julie Crockett, Graham Blakey, Kenneth Sommerville, Gilmour Morrison, Julie Crockett, Graham Blakey, Kenneth Sommerville

Abstract

GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (Cmax and AUC, 3.4-fold), stiripentol exposure increased slightly (Cmax , 1.3-fold; AUC, 1.6-fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with cannabidiol increased 7-OH-CBD exposure (Cmax , 1.7-fold; AUC, 1.5-fold), without notable 7-COOH-CBD or cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.

Keywords: cannabidiol; clobazam; drug-drug interaction; pharmacokinetics; stiripentol; valproate.

Conflict of interest statement

G.B. has consulted for, conducted studies funded by, or received honoraria from GW Research Ltd; K.S. is a consultant of Greenwich Biosciences, Inc; and J.C. and G.M. are employees of GW Research Ltd. Greenwich Biosciences, Inc is the US affiliate of GW Research Ltd.

© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Disposition of subjects. Period 1, victim drug alone; period 2, victim and perpetrator drugs in combination.
Figure 2
Figure 2
Treatment schema for DDI clobazam, DDI stiripentol, and DDI valproate. Period 1, victim drug alone; period 2, victim and perpetrator drugs in combination. DDI, drug‐drug interaction.
Figure 3
Figure 3
(A) DDI clobazam. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) clobazam and (ii) N‐desmethylclobazam (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (B) The effect of concomitant administration of 5 mg of clobazam bid on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (C) DDI stiripentol. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) stiripentol (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (D) The effect of concomitant administration of 750 mg of stiripentol bid on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (E) DDI valproate. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) valproate (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (F) The effect of concomitant administration of 750 mg of valproate, on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). 7‐OH‐CBD, 7‐hydroxy‐cannabidiol; 7‐COOH‐CBD, 7‐carboxy‐cannabidiol; CI, confidence interval; DDI, drug‐drug interaction; SD, standard deviation.
Figure 3
Figure 3
(A) DDI clobazam. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) clobazam and (ii) N‐desmethylclobazam (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (B) The effect of concomitant administration of 5 mg of clobazam bid on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (C) DDI stiripentol. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) stiripentol (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (D) The effect of concomitant administration of 750 mg of stiripentol bid on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (E) DDI valproate. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) valproate (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (F) The effect of concomitant administration of 750 mg of valproate, on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). 7‐OH‐CBD, 7‐hydroxy‐cannabidiol; 7‐COOH‐CBD, 7‐carboxy‐cannabidiol; CI, confidence interval; DDI, drug‐drug interaction; SD, standard deviation.
Figure 3
Figure 3
(A) DDI clobazam. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) clobazam and (ii) N‐desmethylclobazam (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (B) The effect of concomitant administration of 5 mg of clobazam bid on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (C) DDI stiripentol. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) stiripentol (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (D) The effect of concomitant administration of 750 mg of stiripentol bid on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (E) DDI valproate. The effect of concomitant administration of 750 mg of cannabidiol bid on plasma concentrations of (i) valproate (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). (F) The effect of concomitant administration of 750 mg of valproate, on plasma concentrations of (i) cannabidiol, (ii) 7‐OH‐CBD, and (iii) 7‐COOH‐CBD (arithmetic mean ± SD [lower tail is not shown if greater than mean value]). 7‐OH‐CBD, 7‐hydroxy‐cannabidiol; 7‐COOH‐CBD, 7‐carboxy‐cannabidiol; CI, confidence interval; DDI, drug‐drug interaction; SD, standard deviation.
Figure 4
Figure 4
(A) DDI clobazam. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90% confidence intervals [CIs]) to clobazam and N‐CLB. (ii) The effect of concomitant administration of 5 mg of clobazam bid, on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. (B) DDI stiripentol. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to stiripentol. (ii) The effect of concomitant administration of 750 mg of stiripentol bid, on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. (C) DDI valproate. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to valproate. (ii) The effect of concomitant administration of 750 mg of valproate bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. 7‐OH‐CBD, 7‐hydroxy‐cannabidiol; 7‐COOH‐CBD, 7‐carboxy‐cannabidiol; AUCtau, area under the plasma concentration–time curve over a dosing interval, where tau is the dosing interval; CI, confidence interval; Cmax, maximum concentration; DDI, drug‐drug interaction; N‐CLB, N‐desmethylclobazam; SD, standard deviation.
Figure 4
Figure 4
(A) DDI clobazam. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90% confidence intervals [CIs]) to clobazam and N‐CLB. (ii) The effect of concomitant administration of 5 mg of clobazam bid, on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. (B) DDI stiripentol. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to stiripentol. (ii) The effect of concomitant administration of 750 mg of stiripentol bid, on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. (C) DDI valproate. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to valproate. (ii) The effect of concomitant administration of 750 mg of valproate bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. 7‐OH‐CBD, 7‐hydroxy‐cannabidiol; 7‐COOH‐CBD, 7‐carboxy‐cannabidiol; AUCtau, area under the plasma concentration–time curve over a dosing interval, where tau is the dosing interval; CI, confidence interval; Cmax, maximum concentration; DDI, drug‐drug interaction; N‐CLB, N‐desmethylclobazam; SD, standard deviation.
Figure 4
Figure 4
(A) DDI clobazam. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90% confidence intervals [CIs]) to clobazam and N‐CLB. (ii) The effect of concomitant administration of 5 mg of clobazam bid, on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. (B) DDI stiripentol. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to stiripentol. (ii) The effect of concomitant administration of 750 mg of stiripentol bid, on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. (C) DDI valproate. (i) The effect of concomitant administration of 750 mg of cannabidiol bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to valproate. (ii) The effect of concomitant administration of 750 mg of valproate bid on individual and geometric mean steady‐state exposure (top panel: Cmax; middle panel: AUCtau; bottom panel: treatment ratios with 90%CI) to cannabidiol, 7‐OH‐CBD, and 7‐COOH‐CBD. 7‐OH‐CBD, 7‐hydroxy‐cannabidiol; 7‐COOH‐CBD, 7‐carboxy‐cannabidiol; AUCtau, area under the plasma concentration–time curve over a dosing interval, where tau is the dosing interval; CI, confidence interval; Cmax, maximum concentration; DDI, drug‐drug interaction; N‐CLB, N‐desmethylclobazam; SD, standard deviation.

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