Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD. SIGNIFICANCE STATEMENT: This review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration-approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.

Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration.

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.

"Breaking bud": the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential.

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two "major cannabinoids". However, their incorporation into clinical and nutraceutical preparations is challenging, owing to their limited bioavailability, low water solubility, and variable pharmacokinetic profiles. Understanding the organic chemistry of the major cannabinoids provides us with potential avenues to overcome these issues through derivatization. The resulting labile pro-drugs offer ready cannabinoid release in vivo, have augmented bioavailability, or demonstrate interesting pharmacological properties in their own right. This review identifies and discusses a subset of these advanced derivatization strategies for the major cannabinoids, where the starting material is the pure phytocannabinoid itself, and the final product either a cannabinoid pro-drug, or a novel pharmacoactive material.

Novel phenolate salts of bioactive agents: Cannabidiol phenolate salts.

Bioactive phenolic compounds are commonly found in medications, with examples including apomorphine, estrone, thymol, estradiol, propofol, o-phenylphenol, l-Dopa, doxorubicin, tetrahydrocannabinol (THC), and cannabidiol (CBD). This study is the first to explore the creation and assessment of metal and ammonium phenolate salts using CBD as an example. CBD is used in medicine to treat anxiety, insomnia, chronic pain, and inflammation, but its bioavailability is limited due to poor water solubility. In this study exploit a synthetic route to convert CBD into anionic CBD-salts to enhance water solubility. Various CBD-salts with metal and ammonium counterions such as lithium (Li+), sodium (Na+), potassium (K+), choline hydroxide ([(CH3)3NCH2CH2OH]+), and tetrabutylammonium ([N(C4H9)4]+) have been synthesized and characterized. These salts are obtained in high yields, ranging from 74 % to 88 %, through a straightforward dehydration reaction between CBD and alkali metal hydroxides (LiOH, NaOH, KOH) or ammonium hydroxides (choline hydroxide, tetrabutylammonium hydroxide). These reactions are conducted in either ethanol, methanol, or a methanol:water mixture, maintaining a 1:1 molar ratio between the reactants. Comprehensive characterization using Fourier-Transform Infrared Spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR) spectroscopy, and elemental (CHN) analysis confirms the formation of CBD-salts, as evidenced by the absence of aromatic hydroxyl resonances or stretching frequencies. The molecular formulas of CBD salts were determined based on CHN analysis, and CBD quantification from acid regeneration experiments. Characterization data confirms that each CBD phenolate in a specific CBD salt was electrostatically stabilized by one of the either alkali metal or ammonium ion. The CBD-salts are highly susceptible to acidic conditions, readily reverting back to the original CBD. The percentage and purity of CBD in the CBD-metal/ammonium salts have been studied using High-Performance Liquid Chromatography (HPLC) analysis. Solubility studies indicate that the conversion of CBD into CBD salts significantly enhances its solubility in water, ranging from 110 to 1606 folds greater than pure CBD. Furthermore, the pharmacokinetic evaluation of oral administration of CBD-salts compared to CBD were determined in rats.

Pharmacokinetics of cannabichromene in a medical cannabis product also containing cannabidiol and Δ9-tetrahydrocannabinol: a pilot study.

PURPOSE: Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ9-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. METHODS: Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography-tandem mass spectrometry assay. RESULTS: After a single dose and after the final dose, the Cmax of CBC increased by 1.3-1.8-fold for each twofold increase in dose; the tmax range was 1.6-4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0-t of CBD was only 6.6-9.8-fold higher than the AUC0-t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. CONCLUSIONS: CBC may have preferential absorption over CBD and THC when administered together. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019.

Promising Nanocarriers to Enhance Solubility and Bioavailability of Cannabidiol for a Plethora of Therapeutic Opportunities.

In recent years, the interest in cannabidiol (CBD) has increased because of the lack of psychoactive properties. However, CBD has low solubility and bioavailability, variable pharmacokinetics profiles, poor stability, and a pronounced presystemic metabolism. CBD nanoformulations include nanosuspensions, polymeric micelles and nanoparticles, hybrid nanoparticles jelled in cross-linked chitosan, and numerous nanosized lipid formulations, including nanostructured lipid carriers, vesicles, SNEEDS, nanoemulsions, and microemulsions. Nanoformulations have resulted in high CBD solubility, encapsulation efficiency, and stability, and sustained CBD release. Some studies assessed the increased Cmax and AUC and decreased Tmax. A rational evaluation of the studies reported in this review evidences how some of them are very preliminary and should be completed before performing clinical trials. Almost all the developed nanoparticles have simple architectures, are well-known and safe nanocarriers, or are even simple nanosuspensions. In addition, the conventional routes of administration are generally investigated. As a consequence, many of these studies are almost ready for forthcoming clinical translations. Some of the developed nanosystems are very promising for a plethora of therapeutic opportunities because of the versatility in terms of the release, the crossing of physiological barriers, and the number of possible routes of administration.

A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma.

BACKGROUND: Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM. METHODS: Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored. RESULTS: The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK. CONCLUSIONS: With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.

Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol.

Cannabidiol (CBD) is a naturally occurring nonpsychotoxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in Food and Drug Administration-approved Epidiolex (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by CYP2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared with CBD. Given the polymorphic nature of CYP2C19, we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of cytochrome P450 enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant cytochrome P450 enzymes and cytochrome P450-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7-hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD. SIGNIFICANCE STATEMENT: This study demonstrates that both CYP2C19 and CYP2C9 are involved in CBD metabolism to the active metabolite 7-OH-CBD and that CYP3A4 is a major contributor to CBD metabolism through pathways other than 7-hydroxylation. 7-OH-CBD formation was associated with human liver microsomal CYP2C19 activity, but not CYP2C19 genotype, and CYP2C9 was found to contribute significantly to 7-OH-CBD generation. These findings have implications for patients taking CBD who may be at risk for clinically important cytochrome P450-mediated drug interactions.

Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice.

Cannabidiol (CBD), a major component of cannabis, has various effects, such as antiemetic and anxiolytic activities, and has recently been marketed as a supplement. The number of people using CBD during pregnancy is increasing, and there are concerns about its effects on the fetus. In addition, the scientific evidence supporting the fetal safety of CBD use during pregnancy is insufficient. To investigate CBD transfer from the mother to the fetus, a single intravenous dose of CBD was administered to pregnant mice in this study, and fetal pharmacokinetics (distribution and elimination) was analyzed. The transfer of CBD from the maternal blood to the fetus was rapid, and the compound accumulated in the fetal brain, liver, and gastrointestinal tract. Conversely, little CBD was transferred from the mother to the amniotic fluid. We analyzed the pharmacokinetics of CBD using a two-compartment model and found that the maternal and fetal half-lives of CBD were approximately 5 and 2 hours, respectively. Furthermore, we performed a moment analysis of the pharmacokinetics of CBD, observing a mean residence time of less than 2 hours in both the mother and fetus. These results suggest that once-daily CBD intake during pregnancy is unlikely to result in CBD accumulation in the mother or fetus. SIGNIFICANCE STATEMENT: CBD is currently marketed as a supplement, and despite its increasing use during pregnancy, little information concerning its fetal effects has been reported. In the present study, CBD was administered to pregnant mice, and the pharmacokinetics in the fetus was investigated using a two-compartment model and moment analysis. The results of these analyses provide important information for estimating the risk to the fetus if CBD is mistakenly consumed during pregnancy.

Citalopram and Cannabidiol: In Vitro and In Vivo Evidence of Pharmacokinetic Interactions Relevant to the Treatment of Anxiety Disorders in Young People.

BACKGROUND: Cannabidiol (CBD), a major nonintoxicating constituent of cannabis, exhibits anxiolytic properties in preclinical and human studies and is of interest as a novel intervention for treating anxiety disorders. Existing first-line pharmacotherapies for these disorders include selective serotonin reuptake inhibitor and other antidepressants. Cannabidiol has well-described inhibitory action on cytochrome P450 (CYP450) drug-metabolizing enzymes and significant drug-drug interactions (DDIs) between CBD and various anticonvulsant medications (eg, clobazam) have been described in the treatment of epilepsy. Here, we examined the likelihood of DDIs when CBD is added to medications prescribed in the treatment of anxiety. METHODS: The effect of CBD on CYP450-mediated metabolism of the commonly used antidepressants fluoxetine, sertraline, citalopram, and mirtazapine were examined in vitro. Cannabidiol-citalopram interactions were also examined in vivo in patients (n = 6) with anxiety disorders on stable treatment with citalopram or escitalopram who received ascending daily doses of adjunctive CBD (200-800 mg) over 12 weeks in a recent clinical trial. RESULTS: Cannabidiol minimally affected the metabolism of sertraline, fluoxetine, and mirtazapine in vitro. However, CBD significantly inhibited CYP3A4 and CYP2C19-mediated metabolism of citalopram and its stereoisomer escitalopram at physiologically relevant concentrations, suggesting a possible in vivo DDI. In patients on citalopram or escitalopram, the addition of CBD significantly increased citalopram plasma concentrations, although it was uncertain whether this also increased selective serotonin reuptake inhibitor-mediated adverse events. CONCLUSIONS: Further pharmacokinetic examination of the interaction between CBD and citalopram/escitalopram is clearly warranted, and clinicians should be vigilant around the possibility of treatment-emergent adverse effects when CBD is introduced to patients taking these antidepressants.

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

An Ultrafast Ultrahigh-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for Cannabidiol Monitoring in Pediatric Refractory Epilepsy.

BACKGROUND: Cannabidiol (CBD) is a nonpsychoactive natural product that has been increasingly used as a promising new drug for the management of neurological conditions such as refractory epilepsy. Development of rapid and sensitive methods to quantitate CBD is essential to evaluate its pharmacokinetics in humans, particularly in children. The objective of this work was to develop and validate an ultrafast ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method for CBD quantitation that is capable of detecting major CBD and tetrahydrocannabinol (THC) metabolites in the plasma of pediatric refractory epilepsy patients. METHODS: Eight-point CBD calibration curves were prepared using 60 µL of plasma from healthy volunteers. Samples were analyzed in a Shimadzu Nexera X2 UHPLC system, which was coupled to a Sciex QTRAP 6500 mass spectrometer. Chromatography was optimized in acetonitrile (ACN)/water with a 70%-90% gradient of ACN in 2 minutes. Multiple reaction monitoring transitions of major CBD and THC metabolites were optimized in patient plasma. RESULTS: The optimized UHPLC-MS/MS method was validated for the linear range (1-300 ng/mL) of CBD (r2 = 0.996). The limit of quantification and limit of detection were 0.26 and 0.86 ng/mL, respectively. Accuracy and precision met the acceptable validation limits. CBD recovery and matrix effects were 83.9 ± 13.9% and 117.4 ± 4.5%, respectively. The method was successfully applied to quantify CBD and detect the major CBD and THC metabolites in clinical samples. 7-COOH-CBD was the most intensely detected metabolite followed by glucuronide conjugates. CONCLUSIONS: A simple and sensitive method for rapidly monitoring CBD and identifying relevant metabolites was developed. Its applicability in samples from children treated for epilepsy was demonstrated, making it an excellent alternative for performing pharmacokinetic studies.

Anticonvulsive Effects and Pharmacokinetic Profile of Cannabidiol (CBD) in the Pentylenetetrazol (PTZ) or N-Methyl-D-Aspartate (NMDA) Models of Seizures in Infantile Rats.

In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1-2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

The Effects of Food on Cannabidiol Bioaccessibility.

Cannabidiol (CBD) is a hydrophobic non-psychoactive compound with therapeutic characteristics. Animal and human studies have shown its poor oral bioavailability in vivo, and the impact of consuming lipid-soluble CBD with and without food on gut bioaccessibility has not been explored. The purpose of this research was to study the bioaccessibility of CBD after a three-phase upper digestion experiment with and without food, and to test lipase activity with different substrate concentrations. Our results showed that lipase enzyme activity and fatty acid absorption increased in the presence of bile salts, which may also contribute to an increase in CBD bioaccessibility. The food matrix used was a mixture of olive oil and baby food. Overall, the fed-state digestion revealed significantly higher micellarization efficiency for CBD (14.15 ± 0.6% for 10 mg and 22.67 ± 2.1% for 100 mg CBD ingested) than the fasted state digestion of CBD (0.65 ± 0.7% for 10 mg and 0.14 ± 0.1% for 100 mg CBD ingested). The increase in bioaccessibility of CBD with food could be explained by the fact that micelle formation from hydrolyzed lipids aid in bioaccessibility of hydrophobic molecules. In conclusion, the bioaccessibility of CBD depends on the food matrix and the presence of lipase and bile salts.

A pilot safety, tolerability and pharmacokinetic study of an oro-buccal administered cannabidiol-dominant anti-inflammatory formulation in healthy individuals: a randomized placebo-controlled single-blinded study.

BACKGROUND: The cannabis plant presents a complex biochemical unit of over 500 constituents of which 70 or more molecules have been classified as cannabinoids binding to cannabinoid receptors. The study aimed to investigate the safety, tolerability, and preliminary pharmacokinetics of a nanoparticle CBD formulation. METHODS: The cannabis-based medicine was elaborated with a micellular technology, to produce a water-soluble nanoparticle CBD-dominant anti-inflammatory cannabis medicine (MDCNB-02). On day one, 12 participants administered 2 sprays and on day 2 administered 6 sprays to alternating right and left cheeks [18 mg of CBD and 0.72 mg of THC]. Four other participants administered 2 and 6 sprays on days 1 and 2, respectively of a nanoparticle placebo. RESULTS: The study met the primary outcomes of safety, tolerability, and preliminary pharmacokinetics of a standardized CBD-dominant anti-inflammatory extract for oro-buccal administration. Bioavailability of a 6 mg and 18 mg dose of CBD (median IQR) was 0.87 and 8.9 ng h mL-1, respectively. The maximum concentration of CBD for the low and high doses administered once per day occurred at 60 min for both concentrations. The median half-life of the 6 mg and 18 mg CBD dose was 1.23 and 5.45 h, respectively. The apparent clearance of CBD was 115 and 34 L min-1 for a 6 mg and 18 mg dose, respectively. CONCLUSION: The oro-buccal nanoparticle formulation achieved plasma concentrations that were largely comparable to other commercial and investigated formulations relative to the concentrations administered. Moreover, there were no reports of adverse effects associated with unfavorable inflammatory sequalae.

Predicting the Potential for Cannabinoids to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation of Major Cytochromes P450.

Cannabis is used for both recreational and medicinal purposes. The most abundant constituents are the cannabinoids - cannabidiol (CBD, nonpsychoactive) and (-)-trans-Δ9-tetrahydrocannabinol (THC, psychoactive). Both have been reported to reversibly inhibit or inactivate cytochrome P450 (CYPs) enzymes. However, the low aqueous solubility, microsomal protein binding, and nonspecific binding to labware were not considered, potentially leading to an underestimation of CYPs inhibition potency. Therefore, the binding-corrected reversible (IC50,u) and irreversible (K I,u ) inhibition potency of each cannabinoid toward major CYPs were determined. The fraction unbound of CBD and THC in the incubation mixture was 0.12 ± 0.04 and 0.05 ± 0.02, respectively. The IC50,u for CBD toward CYP1A2, 2C9, 2C19, 2D6, and 3A was 0.45 ± 0.17, 0.17 ± 0.03, 0.30 ± 0.06, 0.95 ± 0.50, and 0.38 ± 0.11 µM, respectively; the IC50,u for THC was 0.06 ± 0.02, 0.012 ± 0.001, 0.57 ± 0.22, 1.28 ± 0.25, and 1.30 ± 0.34 µM, respectively. Only CBD showed time-dependent inactivation (TDI) of CYP1A2, 2C19, and CYP3A, with inactivation efficiencies (k inact/K I,u) of 0.70 ± 0.34, 0.11 ± 0.06, and 0.14 ± 0.04 minutes-1 µM-1, respectively. A combined (reversible inhibition and TDI) mechanistic static model populated with these data predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2/2C9/2C19/2D6/3A and between orally administered THC and drugs extensively metabolized by CYP1A2/2C9/3A. These predictions will be extended to a dynamic model using physiologically based pharmacokinetic modeling and simulation and verified with a well-designed clinical cannabinoid-drug interaction study. SIGNIFICANCE STATEMENT: This study is the first to consider the impact of limited aqueous solubility, nonspecific binding to labware, or extensive binding to incubation protein shown by cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) on their true cytochrome P450 inhibitory potency. A combined mechanistic static model predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2, 2C9, 2C19, 2D6, or 3A and between orally administered THC and drugs extensively metabolized by CYP1A2, 2C9, or 3A.

A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects.

OBJECTIVE: The pharmacokinetics (PK) and safety of single oral 750-mg doses of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the USA and Epidyolex in Europe; 100-mg/mL oral solution) were assessed in healthy adults following a high-fat/calorie meal (n = 15), a low-fat/calorie meal (n = 14), whole milk (n = 15), or alcohol (n = 14), relative to the fasted state (n = 29). METHODS: Blood samples were collected until 96 hours postdose in each period and evaluated by liquid chromatography and tandem mass spectrometry. PK parameters (maximum observed plasma concentration [Cmax ], area under the plasma concentration-time curve from time zero to the last observed quantifiable concentration, area under the concentration-time curve from time zero to infinity [AUC0-∞ ], and time to maximum plasma concentration [tmax ]) of CBD and its major metabolites were derived using noncompartmental analysis. RESULTS: CBD exposure increased by 3.8-fold for AUC0-∞ and 5.2-fold for Cmax when CBD was administered with a high-fat/calorie meal versus fasted. To a lesser extent, a low-fat/calorie meal enhanced CBD exposure versus fasted with a 2.7-fold increase in AUC0-∞ and a 3.8-fold increase in Cmax . Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4-fold for AUC0-∞ and 3.1-fold for Cmax . Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6-fold for AUC0-∞ and 1.9-fold for Cmax . No clinically relevant effect of any test condition on CBD tmax or t½ versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7-carboxy-cannabidiol tmax was considerably longer when CBD was administered with alcohol (14 vs 4 hours fasted). Inter- and intrasubject variability in PK parameters was moderate to high during the trial. SIGNIFICANCE: CBD and metabolite exposures were most affected by a high-fat/calorie meal. CBD exposures also increased with a low-fat/calorie meal, whole milk, or alcohol, but to a lesser extent. CBD was tolerated, and there were no severe or serious adverse events during the trial.

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Using the Absorption Cocktail Approach to Assess Differential Absorption Kinetics of Cannabidiol Administered in Lipid-Based Vehicles in Rats.

Lipid-based drug delivery systems have been vastly investigated as a pharmaceutical method to enhance oral absorption of lipophilic drugs. However, these vehicles not only affect drug bioavailability but may also have an impact on gastric emptying, drug disposition, lymphatic absorption and be affected by lipid digestion mechanisms. The work presented here compared the pharmacokinetic (PK) behavior of the non-intoxicating cannabinoid cannabidiol (CBD) in sesame oil vs. a self-nano emulsifying drug delivery system (SNEDDS). This investigation was conducted with a unique tool termed the "absorption cocktail approach". In this concept, selected molecules: metoprolol, THC, and ibuprofen, were coadministered with CBD in the SNEDDS and sesame oil. This method was used to shed light on the complex absorption process of poorly soluble drugs in vivo, specifically assessing the absorption kinetics of CBD. It was found that the concentration vs. time curve following CBD-sesame oil oral administration showed extended input of the drug with a delayed Tmax compared to CBD-SNEDDS. Using the "cocktail" approach, a unique finding was observed when the less lipophilic compounds (metoprolol and ibuprofen) exited the stomach much earlier than the lipophilic cannabinoids in sesame oil, proving differential absorption kinetics. Findings of the absorption cocktail approach reflected the physiological process of the GI, e.g., gastric retention, stomach content separation, lipid digestion, drug precipitation and more, demonstrating its utility. Nonetheless, the search for more compounds as suitable probes is underway.