Pharmacokinetic modelling of orally administered cannabidiol and implications for medication control in horses

Fabienne Eichler; Błażej Poźniak; Marc Machnik; Ina Schenk; Anke Wingender; Natalie Baudisch; Mario Thevis; Wolfgang Bäumer; Christoph Lischer; Anna Ehrle

doi:10.3389/fvets.2023.1234551

Pharmacokinetic modelling of orally administered cannabidiol and implications for medication control in horses

Front Vet Sci. 2023 Aug 9:10:1234551. doi: 10.3389/fvets.2023.1234551. eCollection 2023.

Authors

Affiliations

¹ Equine Clinic, Veterinary Hospital Freie Universität Berlin, School of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
² Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Wrocław, Poland.
³ Center for Preventive Doping Research, Institute of Biochemistry, German Sport University Cologne, Cologne, Germany.
⁴ Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.

Abstract

Cannabidiol (CBD) products gain increasing popularity amongst animal owners and veterinarians as an alternative remedy for treatment of stress, inflammation or pain in horses. Whilst the use of cannabinoids is banned in equine sports, there is limited information available concerning CBD detection times in blood or urine. The aim of this study was to determine the pharmacokinetic properties of CBD following oral administration in the horse to assist doping control laboratories with interpreting CBD analytical results. Part 1: dose escalation study: Single oral administration of three escalating doses of CBD paste (0.2 mg/kg, n = 3 horses; 1 mg/kg, n = 3; 3 mg/kg, n = 5) with >7 days wash-out periods in between. Part 2: multiple dose study: oral administration of CBD paste (3 mg/kg, n = 6) twice daily for 15 days. Multiple blood and urine samples were collected daily throughout both studies. Following study part 2, blood and urine samples were collected for 2 weeks to observe the elimination phase. Concentrations of CBD, its metabolites and further cannabinoids were evaluated using gas-chromatography/tandem-mass-spectrometry. Pharmacokinetic parameters were assessed via two approaches: population pharmacokinetic analysis using a nonlinear mixed-effects model and non-compartmental analysis. AUC_{0-12 h} and C_max were tested for dose proportionality. During the elimination phase, the CBD steady-state urine to serum concentration ratio (Rss) was calculated. Oral CBD medication was well-tolerated in horses. Based on population pharmacokinetics, a three-compartment model with zero-order absorption most accurately described the pharmacokinetic properties of CBD. High volumes of distribution into peripheral compartments and high concentrations of 7-carboxy-CBD were observed in serum. Non-compartmental analysis identified a C_max of 12.17 ± 2.08 ng/mL after single administration of CBD (dose: 3 mg/kg). AUC_{0-12 h} showed dose proportionality, increase for C_max leveled off at higher doses. Following multiple doses, the CBD terminal half-life was 161.29 ± 43.65 h in serum. Rss was 4.45 ± 1.04. CBD is extensively metabolized and shows high volumes of tissue distribution with a resulting extended elimination phase. Further investigation of the potential calming and anti-inflammatory effects of CBD are required to determine cut-off values for medication control using the calculated Rss.

Keywords: CBD; Monolix; NLME model; PK; cannabinoids; doping; drug control; equine.