Single‐Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology

Atsmon, Jacob; Heffetz, Daphna; Deutsch, Lisa; Sacks, Hagit

doi:10.1002/cpdd.408

Cited by 54 publications

(56 citation statements)

References 33 publications

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“…The absorption kinetics among oral capsule studies were highly variable. The variability may be explained by the various capsule formulations that were included in our study . Feeding status may also contribute to the variability of absorption kinetics among oral capsule studies.…”

Section: Discussionmentioning

confidence: 99%

“…The variability may be explained by the various capsule formulations that were included in our study. 11,13,17,[21][22][23][24] Feeding status may also contribute to the variability of absorption kinetics among oral capsule studies. The presence of food, especially with high-fat content, may slow gastric emptying and gastrointestinal (GI) motility, and therefore delay drug absorption and reduce Cmax.…”

Section: Discussionmentioning

confidence: 99%

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Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

2020

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Introduction There is a large variation in cannabidiol (CBD) pharmacokinetics and little information on its bioavailability. This study aims to establish the CBD dose‐exposure relationship and to evaluate the effects of dosage forms, food, and doses on CBD absorption. Methods Single‐dose (range: 5–6000 mg) CBD plasma concentration‐time profiles administered as oral solution (OS), oral capsule (OC), or oromucosal spray/drop (OM) from healthy volunteers were extracted from 15 published clinical studies. A dose‐exposure proportionality assessment was performed, and a population‐based meta‐analysis of CBD pharmacokinetics and systemic bioavailability was conducted with a nonlinear mixed‐effects modeling. A three‐compartment model with a Weibull or zero‐order absorption model was used to describe CBD disposition and absorption kinetics. Dosage form, food, and dose were assessed for covariation. Results Oral solution CBD exposures increased less than proportionally with doses of 750 mg or greater, and bioavailability (6.5% at 3000 mg) decreased with increasing dose. The bioavailability of OC (5.6%) and fed‐state OM (6.2%) were similar, whereas it was lower in fasted‐state OM (0.9%). The Weibull absorption model best described OS, OC, and fed‐state OM profiles. The slowest absorption rate was observed in OS, resulting in a time of maximum concentration of 4.75 hours, followed by fed‐state OM (3.13 hrs) and OC (2.1 hrs). The absorption kinetics of fasted‐state OM was best described by a zero‐order absorption for the duration of 1.71 hours. Conclusion The effects of doses, dosage forms, and feeding status on CBD pharmacokinetics were quantified and should be taken into consideration for dose optimization.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

2020

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“…Phase 1 testing has been conducted on this product (10 to 100 mg) and found that it had significantly greater bioavailability compared to a reference product containing CBD (see Sativex® below). [85] Ananda Scientific (Israel) is producing pure CBD for medicinal purposes and reports having their Phase 1 pharmacokinetics studies underway presently in Israel, with numerous other trials planned in Israel and China. [86] In 2015, the US Food and Drug Administration (FDA) granted GW Pharmaceuticals Fast Track designation for intravenous CBD to treat Neonatal Hypoxic-Ischemic Encephalopathy (NHIE).…”

Section: Marketing Authorizations (As a Medicinal Product)mentioning

confidence: 99%

The nephrologistʼs guide to cannabis and cannabinoids

Rein

2020

Current Opinion in Nephrology and Hypertension

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“…This finding is of great interest in regard to in vivo CYP3A inhibition by CBD because this threshold range for inhibition of EM clearance in vivo was similar to the reported Ki value of CBD inhibition against CYP3A in vitro (1 lM). 13 Atsmon et al 24 developed a new formulation for CBD by embedding purified CBD in a seamless gelatin matrix and used this formulation in humans. In their study, intestinal absorption of CBD from the gelatin matrix pellets was found to be faster than that from the conventional oromucosal spray, and the resultant AUCs of CBD at the single oral doses of 10 and 100 mg were determined to be 10.31 -4.14 and 153.0 -34.7 ng$h/mL (mean -SD; n = 14), respectively, 24 indicating that the increase in dose resulted in an increase of the AUC in a greater than doseproportional manner.…”

mentioning

confidence: 99%

“…13 Atsmon et al 24 developed a new formulation for CBD by embedding purified CBD in a seamless gelatin matrix and used this formulation in humans. In their study, intestinal absorption of CBD from the gelatin matrix pellets was found to be faster than that from the conventional oromucosal spray, and the resultant AUCs of CBD at the single oral doses of 10 and 100 mg were determined to be 10.31 -4.14 and 153.0 -34.7 ng$h/mL (mean -SD; n = 14), respectively, 24 indicating that the increase in dose resulted in an increase of the AUC in a greater than doseproportional manner. Therefore, it is suggested that the pharmacokinetic nonlinearity of CBD may also be observed in humans when the absorption process does not limit its bioavailability.…”

mentioning

confidence: 99%

Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats

Nagao

Nakano

Tajima

et al. 2020

Cannabis and Cannabinoid Research

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Introduction: Cannabidiol (CBD) is known to affect the pharmacokinetics of other drugs through metabolic inhibition of CYP2C19 and CYP3A4. However, there is a lack of in vivo evidence for such drug interactions. Therefore, we investigated the saturability of CBD metabolism and CBD-drug interactions through inhibition of CYP3A in vivo. Materials and Methods: A nanoemulsion formulation of CBD (CBD-NE) was orally administered to rats at doses of 5, 10, 25, and 50 mg/kg, and plasma concentrations of CBD were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to examine the dose-dependency of CBD exposure (area under the curve [AUC]). To examine the effect of a CYP3A inhibitor on CBD pharmacokinetics, rats were orally pretreated with 50 mg/kg ketoconazole (KCZ), a strong CYP3A inhibitor, before oral administration of CBD-NE at doses of 10 and 50 mg/kg, and plasma concentrations of CBD were measured using LC-MS/MS. Moreover, 13 C-erythromycin was orally administered following administration of either NE (without CBD), as a control, or CBD-NE at 1, 10, and 50 mg/kg, and 13 C-breath response was measured by using an infrared analyzer. Results: After administration of various doses of the nanoemulsified CBD formulation to rats, the exposure of CBD (i.e., the AUC calculated from the plasma concentration-time profile) increased in a greater than doseproportional manner, especially at doses above 10 mg/kg. The AUC and maximum plasma concentration (C max) of CBD after oral administration of CBD-NE (10 mg/kg) increased approximately three times by the coadministration of KCZ. Moreover, according to the CBD-induced changes of 13 C-breath response, the metabolism of 13 C-erythromycin was shown to be inhibited by CBD at doses of 10 and 50 mg/kg, but not at 1 mg/kg. Conclusions: Nonlinear disposition and CYP-mediated drug interactions of CBD at doses exceeding 10 mg/kg were demonstrated for the first time in vivo in rats. Given the present results, it is proposed that caution for dosedependent drug interactions should be considered for CBD.

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Single‐Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology

Cited by 54 publications

References 33 publications

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

Model‐Based Analysis of Cannabidiol Dose‐Exposure Relationship and Bioavailability

The nephrologistʼs guide to cannabis and cannabinoids

Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats

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