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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 8/2020

01-08-2020 | Epilepsy | Original Research Article

Disposition of Oral Cannabidiol-Rich Cannabis Extracts in Children with Epilepsy

Authors: George Sam Wang, David W. A. Bourne, Jost Klawitter, Cristina Sempio, Kevin Chapman, Kelly Knupp, Michael F. Wempe, Laura Borgelt, Uwe Christians, Jan Leonard, Kennon Heard, Lalit Bajaj

Published in: Clinical Pharmacokinetics | Issue 8/2020

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Abstract

Background and Objectives

Despite limited evidence, cannabidiol-rich cannabis extracts have been popularly used in pediatrics. With increased use, it is critical to determine basic pharmacokinetic parameters of cannabidiol in these extracts in the pediatric population. The objective of this study was to determine the disposition of oral cannabidiol cannabis extracts and drug interactions in children with pediatric epilepsy.

Methods

We conducted a prospective observational study evaluating the disposition of oral cannabidiol in children (< 18 years of age) receiving cannabidiol extracts for epilepsy. Subjects underwent serial blood draws after oral cannabidiol administration. Cannabidiol and metabolites, along with anticonvulsant concentrations were determined.

Results

Twenty-nine patients had sufficient pharmacokinetic data and were included in the analysis. Mean age was 9.7 years (standard deviation 4.3) and 17 patients (59%) were male. Median peak plasma cannabidiol concentrations was 13.1 ng/mL (interquartile range 6.8–39.3 ng mL); median time to peak of 2.0 h (interquartile range 2.0–4.0 h). Mean acute elimination half-life of oral cannabidiol was 6.2 h (standard deviation 1.8 h). There was an observed half-life of degradation of 533 days noted for cannabidiol concentrations when stored for 0.6–3.1 years. There was some impact on cannabidiol pharmacokinetic parameters when cannabidiol was co-administered with zonisamide (elimination rate constant and V1) and levetiracetam (elimination rate constant).

Conclusions

In pediatric patients using oral cannabidiol-rich cannabis extract for epilepsy, the time to peak concentration of plasma cannabidiol and average acute elimination half-life were shorter than those reported for adults. Co-administration of zonisamide and levetiracetam had some impact on cannabidiol pharmacokinetic parameters. There was an observed degradation of plasma cannabidiol in long-term storage.

Clinical registration

ClinicalTrials.gov Identifer no. NCT02447198.
Appendix
Available only for authorised users
Literature
1.
2.
Izquierdo I, Oshinger OA, Berardi AC. Effect of cannabidiol and of other cannabis sativa compounds on hippocampal seizure discharges. Psychopharmacologia. 1973;28(1):95–102.CrossRefPubMed
3.
Carlini EA, Leite JR, Tennhauser M, Berardi AC. Letter: cannabidiol and cannabis sativa extract protect mice and rats against convulsive agents. J Pharm Pharmacol. 1973;25(8):664–5.CrossRefPubMed
4.
Consroe P, Wolkin A. Cannabidiol-antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther. 1977;201(1):26–32.PubMed
5.
Turkanis SA, Smiley KA, Borys HK, Olsen DM, Karler R. An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia. 1979;20(4):351–63.CrossRefPubMed
6.
Turkanis SA, Karler R. Electrophysiology properties of the cannabinoids. J Clin Pharmacol. 1981;21(S1):449S–63S.CrossRefPubMed
7.
Karler R, Turkanis SA. The cannabinoids as potential antiepileptics. J Clin Pharmacol. 1981;21(S1):437S–48S.CrossRefPubMed
8.
Consore P, Benedito MA, Leite JR, Carlini EA, Mechoulam R. Effects of cannabidiol on behavorial seizures cause by convulsant drugs or current in mice. Eur J Pharmacol. 1982;83(3–4):293–8.CrossRef
9.
Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332(2):569–77.CrossRefPubMedPubMedCentral
10.
Hill TD, Cascio MG, Romano B, et al. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol. 2013;170(3):679–92.CrossRefPubMedPubMedCentral
11.
Jones NA, Glyn SE, Aliyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21(5):344–52.CrossRefPubMed
12.
Colasanti BK, Lindamood C 3rd, Craig CR. Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats. Pharmacol Biochem Behav. 1982;16(4):573–8.CrossRefPubMed
13.
Martin AR, Consroe P, Kane VV, et al. Structure-anticonvulsant activity relationship of cannabidiol analogs. NIDA Res Monogr. 1987;79:48–58.PubMed
14.
Usami N, Okuda T, Yoshia H, et al. Synthesis and pharmacological evaluation in mice of halogenated cannabidiol derivatives. Chem Pharm Bull (Tokyo). 1999;47(11):1641–5.CrossRefPubMed
15.
Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;3:CD009270.
16.
Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C. Chronic administration of cannabidiol to health volunteers and epileptic patients. Pharmacology. 1980;21(3):175–85.CrossRefPubMed
17.
Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981;21(S1):417S–27S.CrossRefPubMed
18.
Ames FR, Cridland S. Anticonvulsant effect of cannabidiol. S Afr Med J. 1985;69:14.
19.
Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Naturwissenschaften. 1978;65:14–9.CrossRef
20.
Trembly B, Sherman M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. In: Marijuana ’90 International Conference on Cannabis and Cannabinoids; 8–11 July 1990; Kolympari; International Association for Cannabinoid Medicines, 1990;Section 2, p. 5.
21.
Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29(3):574–7.CrossRefPubMedPubMedCentral
22.
23.
24.
25.
26.
27.
28.
29.
Campbell CT, Phillips MS, Manasco K. Cannabinoids in pediatrics. J Pediatr Pharmcol Ther. 2017;22(3):176–85.
30.
Agurell S, Halldin M, Lingren JE, et al. Pharmacokinetics and metabolism of delta 9-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38:21–42.PubMed
31.
Harvey DJ, Mechoulam R. Metabolites of cannabidiol identified in human urine. Xenobiotica. 1990;20:303–20.CrossRefPubMed
32.
Ohhsson A, Lindgren JE, Andersson S, Agurell S, Gillespie H, Hollister LE. Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. Biomed Environ Mass Spectrom. 1986;13:77–83.CrossRef
33.
Guy GW, Whitte BA, Robson P. The medicinal uses of cannabis and cannabinoids. Cornwall: TJ International; 2004.
34.
Yamori S, Oakamoto Y, Yamamoto I, Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP 2D6. Drug Metab Dispos. 2011;39(11):2049–56.CrossRef
35.
36.
Klawitter J, Sempio C, Mörlein S, et al. An atmospheric pressure chemical ionization MS/MS assay using online extraction for the analysis of 11 cannabinoids and metabolites in human plasma and urine. Ther Drug Monit. 2017;39(5):556–64.CrossRefPubMedPubMedCentral
37.
Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit. 2012;34(4):467–76.CrossRefPubMedPubMedCentral
38.
39.
40.
41.
42.
43.
44.
45.
Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–51.CrossRefPubMed
46.
Wang GS, Bourne DW, Klawitter J, et al. Disposition of oral delta-9 tetrahydrocannabinol (THC) in children receiving cannabis extracts for epilepsy. Clin Toxicol (Phila). 2020;58(2):124–8.CrossRefPubMed
47.
Karchner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA. Plasma cannabinoid pharmacokinetics following controlled oral Δ9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011;57(1):66–75.CrossRef
48.
Nahler G, Grotenhermen F, Zuardi AW, Crippa JAS. A conversion of oral cannabidiol to delta9-tetrahydrocannabinol seems not to occur in humans. Cannabis Cannabinoid Res. 2017;2(1):81–6.CrossRefPubMedPubMedCentral
49.
Nadulski T, Pragst F, Weinberg G, et al. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit. 2005;27(6):799–810.CrossRefPubMed
50.
Scheidweiler KB, Schwope DM, Karchner EL, Desrosier NA, Gorelick DA, Huestis MA. In vitro stability of free and glucuronidated cannabinoids in blood and plasma following controlled smoked cannabis. Clin Chem. 2013;59(7):1108–17.CrossRefPubMed
51.
Taylor L, Crockett J, Tayo B, Morrison G. A phase 1, open-label, parallel-group, single-dose trial of the pharmacokinetics and safety of cannabidiol (CBD) in subjects with mild to severe hepatic impairment. J Clin Pharmacol. 2019;59(8):1110–9.CrossRefPubMedPubMedCentral
52.
Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018;32(11):1053–67.CrossRefPubMedPubMedCentral
Metadata
Title
Disposition of Oral Cannabidiol-Rich Cannabis Extracts in Children with Epilepsy
Authors
George Sam Wang
David W. A. Bourne
Jost Klawitter
Cristina Sempio
Kevin Chapman
Kelly Knupp
Michael F. Wempe
Laura Borgelt
Uwe Christians
Jan Leonard
Kennon Heard
Lalit Bajaj
Publication date
01-08-2020
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 8/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-020-00869-z

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