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

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-019-00841-6) contains supplementary material, which is available to authorized users.