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.