Stefanie Hamacher (1), F. Markus Leweke (2, 3), Martin Hellmich (1), Christian Queckenberg (4), Uwe Fuhr (4), Max Taubert (4)
(1) Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany, (2) Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, (3) Brain and Mind Centre, University of Sydney, Sydney, Australia, (4) Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Objectives: Cannabidiol (CBD) is a lipophilic and non-psychoactive compound from hemp plant Cannabis sativa [1]. It inhibits cellular uptake and hydrolysis of endocannabinoids in the central nervous system [2]. Endocannabinoids play a role in patients with psychiatric disorders and therefore there is a promising therapeutic potential for CBD as possible medication [3,4]. Because information on the pharmacokinetic (PK) characteristics of CBD applied orally as a pure substance is limited, the objective of this project was to describe the PK of a single CBD dose using a population PK model.
Methods: Twenty-four healthy subjects (14 (58.3%) male, mean ± SD age 29.1 ± 8.2 years, height 174.9 ± 9.2 cm, body weight 72.1 ± 14.3 kg, BMI 23.4 ± 3.0 kg/m2) received a single oral dose of 200 mg immediate release CBD formulated as CBD powder in a rapidly dissolving capsule. The volunteers fasted from 10 hours prior to dosing until 4.333 hours thereafter when a standardized meal was provided. PK blood samples were taken at baseline and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 24 hours after CBD administration. 238 plasma concentrations were included in development of a population pharmacokinetic model and the investigation of possible demographic covariates using NONMEM 7.4.1. The bootstrap resampling method was used to assess bias and precision of parameter estimates. Since the bioavailability (F) of CBD for oral administration is not known, it was fixed to 1.
Results: Individual concentration vs. time-profiles showed a high variability, observed maximal concentrations have a variation coefficient of 234%. Additionally, there were double peaks with varying height ratios in most of the subjects. Second peaks appeared about 3 hours after the first peak and 4.5 hours after dosing, i.e. when lunch was served. One zero-order absorption process each, starting (with a lag time) just after dosing for one (estimated) fraction of the dose and being delayed until lunch for the remaining fraction of the dose, together with a two-compartment model, linear elimination and a proportional error model was most suitable to describe the data. Demographic covariates sex, age, weight and BMI had no significant influence on clearance (CL) and central volume of distribution (Vc) and were not included in the model. PK parameters were estimated as follows: % dose splitting ratio (1st fraction : 2nd fraction)= 81.7 [78.9 – 90.0] : 18.3 [10.0 – 21.1] (median [95% CI] from bootstrap), CL/F = 4125 [2867 – 5570] l/h, Vc/F = 60007 [40990 – 73558] l, peripheral volume of distribution (Vp)/F = 142178 [125477 – 193536] l, inter-compartmental clearance (Q)/F = 8530 [6707 – 11087] l/h, 1st absorption lag time (ALAG1) = 0.48 [0.36 – 0.61] h, 2nd absorption lag time (ALAG2) = 4.333 h (fixed), duration of 1st zero-order absorption (D1) = 1.20 [0.86 – 1.71] h and duration of 2nd zero-order absorption (D2) = 0.112 [UF1] [sh2] [0.107 – 0.117] h. High inter-individual variability was associated with F (157%), dose splitting ratio (561%), CL (83%), Vc (67%), ALAG1 (50%) and D1 (90%).
Conclusions: A population PK model was developed successfully to describe the highly variable concentration vs. time profiles of oral CBD taken in the fasted state. Systemic exposure was low, suggesting a bioavailability which is considerably lower than the value of 6% reported for CBD in a different setting [5]. Moreover, the model is compatible with an effect of food intake on CBD absorption.
Acknowledgment: The Stanley Medical Research Institute (non-profit organization) provided financial support for the clinical trial.
References:
[1] Adams R et al. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp I. J Am Chem Soc 1940;62: 196-200.
[2] Leweke FM et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl psychiatry. 2012;2:e94.
[3] Devinsky O et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802.
[4] Leweke FM et al. Therapeutic Potential of Cannabinoids in Psychosis. Biol Psychiatry. 2016;79(7):604–612.
[5] Ohlsson A et al. Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. Biomed Environ Mass Spectrom. 1986;13(2):77-83.
Reference: PAGE 28 (2019) Abstr 8943 [www.page-meeting.org/?abstract=8943]
Poster: Drug/Disease Modelling - Other Topics