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.
Tayo et al.·Clinical Pharmacokinetics
No benefit demonstratedGRADEModerate63 citations
Samplen = 32 Pat.
Duration48 h post-dose
ControlMatched control group with normal renal…
EndpointCmax / AUC
Blindingoffen
DesignPhase-I-Studie (offen, Parallel-Gruppe)
Cannabinoidcbd
Max. dose200.0 mg
Routeoral
”Key finding
Renal impairment has no influence on the pharmacokinetics of CBD; no dose adjustment required.
Summary
Phase I safety study (n=32; n=8 each for mild/moderate/severe renal impairment and normal function); single dose 200 mg oral CBD (Epidiolex). No statistically significant difference in Cmax, AUCt or AUC∞ between renal impairment groups and normal function (Cmax ratio GMR 0,68–1,35). 5 AEs in total, all mild; no serious AEs or discontinuations. CBD well tolerated across varying renal function; no need for dose adjustment.
P
PopulationAdults with mild, moderate or severe renal impairment as well as a control group with normal renal function, n=32 (n=8 per group each)
ControlMatched control group with normal renal function (n=8)
O
OutcomeNo statistically significant differences in Cmax, AUCt, AUC∞ or tmax between all grades of renal impairment and normal renal function; geometric mean ratios for Cmax 0,68–1,35
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
<h4>Introduction</h4>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.<h4>Methods</h4>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<sup>®</sup> 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<sub>max</sub>], oral clearance of drug from plasma [CL/F], renal clearance [CL<sub>R</sub>], area under the plasma concentration-time curve [AUC] from time zero to last measurable concentration [AUC<sub>t</sub>], and AUC from time zero to infinity [AUC<sub>∞</sub>]); descriptive analysis was used for secondary pharmacokinetic parameters (time to C<sub>max</sub> [t<sub>max</sub>], terminal [elimination] half-life [t<sub>½</sub>], cumulative amount excreted from time zero to the last quantifiable sample [Ae<sub>last</sub>], and fraction of the systemically available drug excreted into the urine [f<sub>e</sub>]).<h4>Results</h4>No statistically significant differences were observed in C<sub>max</sub>, AUC<sub>t</sub>, AUC<sub>∞</sub>, or t<sub>max</sub> 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<sub>max</sub> values ranged from 0.68 to 1.35. No differences were observed for other secondary parameters (Ae<sub>last</sub> and f<sub>e</sub>). 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.<h4>Conclusion</h4>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.<h4>Registration</h4>European Union Clinical Trials Register (EudraCT) no. 2015-002122-39.