A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment

• Published in: Clinical pharmacokinetics Vol. 59; no. 6; pp. 747 - 755
• Main Authors: Tayo, Bola, Taylor, Lesley, Sahebkar, Farhad, Morrison, Gilmour
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2020; Springer Nature B.V
• Subjects: Aged; Anticonvulsants; Area Under Curve; Cannabidiol; Cannabidiol - pharmacokinetics; Chromatography, Liquid; Drug dosages; Female; Humans; Internal Medicine; Kidney; Male; Medicine; Medicine & Public Health; Metabolites; Middle Aged; Original; Original Research Article; Pharmaceuticals; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Proteins; Renal Insufficiency; Tetrahydrocannabinol; THC; Urine
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-019-00841-6

Introduction As patients who receive cannabidiol (CBD) may have co-existing renal morbidities, it is important to understand whether dose adjustments are necessary to mitigate the risk of exposure-related toxicity. This study was conducted to evaluate the pharmacokinetics, safety, and tolerability of CBD in patients with renal impairment. Methods The pharmacokinetics and safety of a single oral 200 mg dose of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex ® in the USA; 100 mg/mL) were assessed in subjects with mild, moderate, or severe renal impairment ( n  = 8/group) relative to matched subjects with normal renal function ( n  = 8). Blood samples were collected until 48 h post-dose and evaluated by liquid chromatography with tandem mass spectrometry. Analysis of variance was used to compare primary pharmacokinetic parameters (maximum measured plasma concentration [ C max ], oral clearance of drug from plasma [CL/ F ], renal clearance [CL R ], area under the plasma concentration–time curve [AUC] from time zero to last measurable concentration [AUC t ], and AUC from time zero to infinity [AUC ∞ ]); descriptive analysis was used for secondary pharmacokinetic parameters (time to C max [ t max ], terminal [elimination] half-life [ t ½ ], cumulative amount excreted from time zero to the last quantifiable sample [Ae last ], and fraction of the systemically available drug excreted into the urine [ f e ]). Results No statistically significant differences were observed in C max , AUC t , AUC ∞ , or t max values between subjects with mild, moderate, or severe renal impairment and subjects with normal renal function for CBD or its major metabolites, 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD), and minor metabolite, 6-hydroxy-CBD (6-OH-CBD); geometric mean ratio for C max values ranged from 0.68 to 1.35. No differences were observed for other secondary parameters (Ae last and f e ). CBD, 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD were highly protein bound (> 90%); binding was similar in all subject groups. Urine analysis for CBD recorded no appreciable amount, and thus no urinary pharmacokinetic parameters could be derived. Adverse events (AEs) affected two subjects; all five AEs were mild in severity and resolved during the trial. There were no serious AEs or discontinuations due to AEs. Laboratory, physical examination, vital sign, and 12-lead electrocardiogram findings were not clinically significant. Conclusion Renal impairment had no effect on the metabolism of CBD after a single oral 200 mg dose. CBD was generally well tolerated in subjects with varying degrees of renal function. Registration European Union Clinical Trials Register (EudraCT) no. 2015-002122-39.