A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects
Morrison et al.·Clinical Pharmacology in Drug Development
CBD erhöhte die N-Desmethylclobazam-Exposition deutlich (3,4-fach) und beeinflusste Stiripentol moderat, während Valproat und CBD gegenseitig keine klinisch relevante Interaktion zeigten.
Zusammenfassung
Phase-1-DDI-Studie (gesunde Probanden): CBD (GW-Formulierung, Epidiolex) hemmt CYP3A4/2C19 — N-Desmethylclobazam-Exposition 3,4-fach erhöht bei Komedikation mit Clobazam; Stiripentol-AUC 1,6-fach erhöht; kein klinisch relevanter Effekt auf Valproat. Stiripentol senkte 7-OH-CBD-Exposition um 29 %. Keine Todesfälle, keine schwerwiegenden UAW; CBD moderat verträglich bei allen Komedikationen.
P
PopulationGesunde Probanden in einer offenen Phase-1-Studie zu Arzneimittelinteraktionen, n nicht explizit im Abstract genannt
I
InterventionHochgereinigtes CBD (orales GW-Pharmaceuticals-Präparat) in Kombination mit Clobazam, Stiripentol oder Valproat
O
OutcomeCBD hatte wenig Effekt auf Clobazam-Exposition (Cmax/AUC 1,2-fach), erhöhte N-Desmethylclobazam (3,4-fach), Stiripentol leicht (Cmax 1,3-fach, AUC 1,6-fach); kein klinisch relevanter Effekt auf Valproat. Clobazam erhöhte 7-OH-CBD (Cmax 1,7-fach, AUC 1,5-fach); Stiripentol senkte 7-OH-CBD um 29%; Valproat ohne Effekt auf CBD-Metaboliten.
Vertrauen in die Evidenz
Sehr niedrigNiedrigModeratHoch
Moderat
Dritte von vier GRADE-Stufen, die Effektschätzung ist wahrscheinlich verlässlich.
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 [C<sub>max</sub> ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (C<sub>max</sub> and AUC, 3.4-fold), stiripentol exposure increased slightly (C<sub>max</sub> , 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 (C<sub>max</sub> , 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.