Dataset Information

Human Pharmacokinetic Parameters of Orally Administered ?9-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences.

ABSTRACT: Background: There is variability in the reported ?9-tetrahydrocannabinol (THC) and 11-hydroxy-tetrahydrocannabinol (11-OH-THC) pharmacokinetic (PK) and pharmacodynamic (PD) parameters between studies and there is limited investigation into how the presence of food or sex affect these parameters. In this study, we examined the PK and PD parameters of an encapsulated THC extract and its major active metabolite, 11-OH-THC, under different fed states. Methods: The study was a single-dose, randomized, double-blinded, four-way crossover investigation. THC capsules (1 or 2×5?mg) were administered to 28 healthy adults (13 females: 15 males) under a fasted condition or after a high-fat meal. Blood samples were collected and PK parameters were determined through noncompartmental analysis. Adverse events (AEs), cognitive function (through completion of digit symbol substitution tests), blood pressure, and heart rate were also recorded. Results: The presence of high-fat food significantly enhanced time to peak plasma concentration (T max) and area under the curve (AUC0-24) for both THC and 11-OH-THC and reduced THC's apparent volume of distribution (V z/F) and apparent clearance (Cl/F). Females had a significantly greater peak plasma concentration (C max) compared with males after 5?mg THC in a fasted state. No cardiovascular or cognitive effects and only mild AEs (somnolence, fatigue, and euphoric mood) were reported. Conclusion: These findings may help to inform the guidelines provided by governing health bodies on the effects of cannabis, such as time to onset and duration of action, and aid health care practitioners in their prescribing practices. Furthermore, the doses used in this study are safe to consider for future interventional studies in disease conditions where THC has been shown to have therapeutic efficacy.

SUBMITTER: Lunn S

PROVIDER: S-EPMC6922062 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Human Pharmacokinetic Parameters of Orally Administered Δ9-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences.

Lunn Stephanie S Diaz Patrick P O'Hearn Shannon S Cahill Shaina P SP Blake Alexia A Narine Kelly K Dyck Jason R B JRB

Cannabis and cannabinoid research 20191206 4

Background: There is variability in the reported Δ9-tetrahydrocannabinol (THC) and 11-hydroxy-tetrahydrocannabinol (11-OH-THC) pharmacokinetic (PK) and pharmacodynamic (PD) parameters between studies and there is limited investigation into how the presence of food or sex affect these parameters. In this study, we examined the PK and PD parameters of an encapsulated THC extract and its major active metabolite, 11-OH-THC, under different fed states. Methods: The study was ...[more]

PMID: 31872060

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Project description:ImportanceControlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations.ObjectiveTo compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg).Design, setting, and participantsThis randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week.InterventionsBrownies containing (1) no cannabis extract (ie, placebo); (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam.Main outcomes and measuresChange-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined.ResultsThe participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + Δ9-THC and CYP cocktail + placebo.Conclusions and relevanceIn this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products.Trial registrationclinicaltrials.gov Identifier: NCT04201197.

Project description:Cannabidiol (CBD) products gain increasing popularity amongst animal owners and veterinarians as an alternative remedy for treatment of stress, inflammation or pain in horses. Whilst the use of cannabinoids is banned in equine sports, there is limited information available concerning CBD detection times in blood or urine. The aim of this study was to determine the pharmacokinetic properties of CBD following oral administration in the horse to assist doping control laboratories with interpreting CBD analytical results. Part 1: dose escalation study: Single oral administration of three escalating doses of CBD paste (0.2 mg/kg, n = 3 horses; 1 mg/kg, n = 3; 3 mg/kg, n = 5) with >7 days wash-out periods in between. Part 2: multiple dose study: oral administration of CBD paste (3 mg/kg, n = 6) twice daily for 15 days. Multiple blood and urine samples were collected daily throughout both studies. Following study part 2, blood and urine samples were collected for 2 weeks to observe the elimination phase. Concentrations of CBD, its metabolites and further cannabinoids were evaluated using gas-chromatography/tandem-mass-spectrometry. Pharmacokinetic parameters were assessed via two approaches: population pharmacokinetic analysis using a nonlinear mixed-effects model and non-compartmental analysis. AUC0-12 h and Cmax were tested for dose proportionality. During the elimination phase, the CBD steady-state urine to serum concentration ratio (Rss) was calculated. Oral CBD medication was well-tolerated in horses. Based on population pharmacokinetics, a three-compartment model with zero-order absorption most accurately described the pharmacokinetic properties of CBD. High volumes of distribution into peripheral compartments and high concentrations of 7-carboxy-CBD were observed in serum. Non-compartmental analysis identified a Cmax of 12.17 ± 2.08 ng/mL after single administration of CBD (dose: 3 mg/kg). AUC0-12 h showed dose proportionality, increase for Cmax leveled off at higher doses. Following multiple doses, the CBD terminal half-life was 161.29 ± 43.65 h in serum. Rss was 4.45 ± 1.04. CBD is extensively metabolized and shows high volumes of tissue distribution with a resulting extended elimination phase. Further investigation of the potential calming and anti-inflammatory effects of CBD are required to determine cut-off values for medication control using the calculated Rss.

Project description:In vivo drug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study was to evaluate the in vivo drug dissolution and systemic absorption of the BCS class IIa drug ibuprofen under fed and fasted conditions by direct sampling of stomach and small intestinal luminal content. Expanding current knowledge of drug dissolution in vivo will help to establish physiologically relevant in vitro models predictive of drug dissolution. A multilumen GI catheter was orally inserted into the GI tract of healthy human subjects. Subjects received a single oral dose of ibuprofen (800 mg tablet) with 250 mL of water under fasting and fed conditions. The GI catheter facilitated collection of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen concentration in GI fluid supernatant and plasma was determined by LC-MS/MS. A total of 23 subjects completed the study, with 11 subjects returning for an additional study visit (a total of 34 completed study visits). The subjects were primarily white (61%) and male (65%) with an average age of 30 years. The subjects had a median [min, max] weight of 79 [52, 123] kg and body mass index of 25.7 [19.4, 37.7] kg/m2. Ibuprofen plasma levels were higher under fasted conditions and remained detectable for 28 h under both conditions. The AUC0-24 and Cmax were lower in fed subjects vs fasted subjects, and Tmax was delayed in fed subjects vs fasted subjects. Ibuprofen was detected immediately after ingestion in the stomach under fasting and fed conditions until 7 h after dosing. Higher levels of ibuprofen were detected in the small intestine soon after dosing in fasted subjects compared to fed. In contrast to plasma drug concentration, overall gastric concentrations remained higher under fed conditions due to increased gastric pH vs fasting condition. The gastric pH increased to near neutrality after feedingbefore decreasing to acidic levels after 7 h. Induction of the fed state reduced systemic levels but increased gastric levels of ibuprofen, which suggest that slow gastric emptying and transit dominate the effect for plasma drug concentration. The finding of high levels of ibuprofen in stomach and small intestine 7 h post dosing was unexpected. Future work is needed to better understand the role of various GI parameters, such as motility and gastric emptying, on systemic ibuprofen levels in order to improve in vitro predictive models.

Dataset Information

Human Pharmacokinetic Parameters of Orally Administered ?9-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences.

Publications

Human Pharmacokinetic Parameters of Orally Administered Δ<sup>9</sup>-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences.

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