BackgroundA formal single ascending and multiple dose pharmacokinetic (PK) trial of cannabidiol (CBD) oral solution was required to determine the safety and tolerability of CBD, the maximum tolerated dose, and to examine the effect of food on CBD PK parameters.ObjectiveThis trial assessed the safety, tolerability and PK of CBD oral solution in healthy adult volunteers, as well as the effect of food on CBD PK parameters.MethodsThe study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD [n = 6 per group]/placebo [n = 8; 2 per CBD dose group]), multiple dose (750 or 1500 mg CBD [n = 9 per group]/placebo [n = 6; 3 per CBD dose group] twice daily), and food effect (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned.ResultsCBD was generally well tolerated. Diarrhea, nausea, headache, and somnolence were the most common adverse events (AEs) across all trial arms, with an increased incidence of some gastrointestinal and nervous system disorder AEs (most notably diarrhea and headache) apparent in subjects taking CBD compared with placebo. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to maximum plasma concentration (tmax) was approximately 4–5 h. The major circulating metabolite was 7-carboxy-CBD, then parent CBD, 7-hydroxy-CBD (active metabolite), and 6-hydroxy-CBD (a relatively minor metabolite). Plasma exposure to CBD [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to time t (AUCt)] increased in a less than dose-proportional manner (Cmax slope 0.73; AUCt slope 0.64). Oral clearance of CBD was high (1111–1909 L/h) and apparent volume of distribution was large (20,963–42,849 L). CBD reached steady state after approximately 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. After 7 days, a twofold increase in CBD dose resulted in 1.6- and 1.9-fold increases in geometric mean Cmax and area under the plasma concentration-time curve over a dosing interval (AUCτ), respectively. CBD elimination was multiphasic; the terminal elimination half-life was approximately 60 h after 750 and 1500 mg CBD twice daily; and effective half-life estimates ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, respectively; there was no effect of food on tmax or terminal half-life.ConclusionCBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious. The safety and PK profile support twice-daily administration of CBD.

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.

AimsThe primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed. MethodsTwelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full 'cocktail' as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUC last (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events. ResultsOverall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone. ConclusionsThe five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically impor tant drugdrug interactions during drug development. Assessment of the interactions of five co-administered probe drugsBr J Clin Pharmacol 57:2 163

In this paper, Bayesian decision procedures are developed for dose-escalation studies based on bivariate observations of undesirable events and signs of therapeutic benefit. The methods generalize earlier approaches taking into account only the undesirable outcomes. Logistic regression models are used to model the two responses, which are both assumed to take a binary form. A prior distribution for the unknown model parameters is suggested and an optional safety constraint can be included. Gain functions to be maximized are formulated in terms of accurate estimation of the limits of a 'therapeutic window' or optimal treatment of the next cohort of subjects, although the approach could be applied to achieve any of a wide variety of objectives. The designs introduced are illustrated through simulation and retrospective implementation to a completed dose-escalation study.