Comparative Pharmacokinetics and Safety of Cannabidiol in a Powder Formulation, CBtru®, vs an Oil-Based Formulation, Epidyolex®, Under Fasted and Fed Conditions in Healthy Participants: A Randomized Open-Label Cross-Over Phase I Study
Health Nutrition & Care, dsm-firmenich, Wurmisweg 576, Campus Building 245, 4303 Kaiseraugst, Switzerland
Science & Research, dsm-firmenich, Kaiseraugst, Switzerland
Nutrasource Pharmaceutical & Nutraceutical Services Inc., Guelph, ON Canada
Rhizotomos Consulting, Irvine, CA USA
Abstract
Background
Emerging evidence indicates that cannabidiol (CBD) may offer meaningful therapeutic benefits across neurological, pain, and psychiatric disorders. Cannabidiol is already approved for the treatment of pediatric epilepsy. Owing to its high lipophilicity, it is typically delivered in oil-based formulations to overcome the low oral bioavailability of pure CBD. However, pharmacokinetic (PK) and safety data remain limited across different CBD formulations. This study evaluated the PK profile, tolerability, and safety of an encapsulated powdered emulsion formulation (CBtru®) compared with a marketed oil-based formulation (Epidyolex®/Epidiolex®) under fasted and fed conditions in healthy adults.
Methods
This Phase I, single-center, open-label, randomized, 4-way crossover PK trial was conducted in healthy adults. All participants received a single 400-mg dose of CBtru® and Epidyolex® under both fasted and fed conditions, with a minimum 14-day washout between administrations. Pharmacokinetic parameters and safety were assessed throughout.
Results
Under fasted conditions, CBtru® trended to higher CBD exposure (AUC0–24) and maximum concentration in plasma (Cmax) relative to Epidyolex®. CBtru® demonstrated significantly greater metabolite exposure (7-OH-CBD, 7-COOH-CBD), along with higher active drug exposure (ADE = CBD + 7-OH-CBD) and higher total drug exposure (TDE=CBD + 7-OH-CBD + 7-COOH-CBD). Median tmax was shorter with CBtru® (3 h vs 3.5 h), indicating faster absorption. In line with previous studies, CBD exposure and concentrations were significantly higher in fed rather than in fasted conditions. Under fed conditions, median tmax was shorter with CBtru® (5 h vs 8 h), while CBD and metabolite exposure were comparable. CBtru® also showed lower interindividual variability in plasma CBD profiles, suggesting more predictable PK across both conditions. Both formulations were well tolerated, with no safety concerns reported.
Conclusion
Both formulations demonstrated distinct PK profiles under fasted and fed conditions. CBtru® showed comparable bioavailability to Epidyolex®, with faster absorption in fasted and fed conditions, higher metabolite exposure in fasted conditions, and more consistent systemic levels in the fasted condition. These findings support further development of CBtru® as a novel oral CBD formulation for clinical use in relevant indications.
ClinicalTrials.gov ID number: NCT06578455.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40263-026-01280-1.
Article notes
Untitled section
Received 2025 Oct 21; Accepted 2026 Feb 4; Issue date 2026.
Key Points
| In this first publicly reported study comparing the powder formulation, CBtru®, versus the oil-based formulation, Epidyolex® under fasted and fed conditions, CBtru® was absorbed faster and more consistently in both conditions, with higher levels of metabolites 7-OH-CBD and 7-COOH-CBD under fasted condition, suggesting more predictable and greater overall systemic exposure and effects. |
| Both formulations showed good tolerability, with mostly mild adverse events, none of them serious; the safety findings were in line with the known profile of cannabidiol (CBD), supporting further development of CBtru® as a novel oral formulation of CBD. |
Introduction
Cannabidiol (CBD) is a non-intoxicating phytocannabinoid found in the cannabis plant, where it occurs as one of the two most abundant cannabinoids, alongside Δ9-tetrahydrocannabinol (THC). In the plant, CBD is biosynthesized from cannabigerolic acid (CBGA) via the action of the enzyme CBD acid synthase, yielding cannabidiolic acid (CBDA), which is then decarboxylated to CBD through heating or aging processes [1]. The relative abundance of CBD in the plant varies widely across cannabis chemovars and breeding lines, with high-CBD cultivars typically containing 3–20% CBD by dry weight in the flowering tops [2]. In contrast to THC, CBD has little binding affinity for either of the two cannabinoid receptors (CB1 and CB2), and thus lacks CB1-dependent psychotropic effects, a feature that has contributed to its growing interest for therapeutic applications [3].
Pharmacologically, CBD has a broad spectrum of activities, potentially mediated through diverse molecular targets [1, 4, 5]. These include partial agonism or antagonism at serotonin 5-HT1A receptor, interaction with transient receptor potential (TRP) channels such as TRPV1 and G protein-coupled receptor 55 (GPR55), and modulation of endocannabinoid signaling via inhibition of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) [6]. Cannabidiol also exhibits anti-inflammatory, anxiolytic, antiseizure, and neuroprotective properties in preclinical models [7]. These pharmacodynamic effects have supported the approval of a purified, oil-based CBD formulation (Epidyolex®/Epidiolex®) for the treatment of some forms of childhood epilepsy [8], and have sparked extensive investigation into additional indications ranging from anxiety and pain to neurodegenerative disorders.
Despite its therapeutic promise, CBD presents considerable challenges in drug delivery due to its poor aqueous solubility and extensive first-pass metabolism. Oral administration of CBD leads to low and variable bioavailability, generally estimated between 6 and 14% in humans [9]. Absorption is influenced by multiple factors, including the presence of dietary fat, the formulation matrix, and interindividual metabolic differences. After absorption, CBD undergoes rapid and extensive hepatic metabolism, primarily via cytochrome P450 enzymes CYP3A4 and CYP2C19, yielding active metabolites such as 7-hydroxy-CBD (7-OH-CBD) and inactive metabolites such as 7-carboxy-CBD (7-COOH-CBD) or CBD-glucuronide [10]. This has prompted the development of alternative formulations aimed at improving the consistency, bioavailability, and PK profile of orally administered CBD [9].
Epidyolex®/Epidiolex® is the first approved prescription formulation of purified plant-derived CBD in Europe and the USA. It is formulated as an oral solution containing 100 mg/mL of CBD dissolved in a sesame oil-based vehicle with ethanol, strawberry flavoring, and sucralose to improve palatability [11]. This lipid-based delivery system facilitates solubilization of the lipophilic CBD molecule but exhibits limitations in absorption consistency partly due to a complex application process that requires multiple handling steps and increases the risk of dosing errors or spillage. The PK of CBD is highly sensitive to food intake: co-administration with a high-fat meal increases the area under the plasma concentration-time curve (AUC) of CBD by up to 5-fold, reflecting enhanced micellar solubilization and lymphatic transport [9]. After oral administration, peak plasma concentrations (Cmax) are typically achieved within 1.0–6.13 hours, although this can vary depending on fasting status and individual metabolism [12]. While effective in clinical use, the variability in systemic exposure and the need for precise dosing highlight the potential advantages of alternative formulations with improved PK performance.
To address these challenges, we evaluated a novel powdered emulsion-based formulation of CBD (CBtru®), selected from a panel of more than 160 solid CBD formulations that were screened in vitro for enhanced absorption. In this Phase I study, we assessed and compared the PK characteristics, tolerability and safety of CBtru® with those of Epidyolex® under fasted and fed conditions in healthy adult volunteers.
Methods
Compliance with Ethical Standards
This trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines and the ethical principles outlined in the Declaration of Helsinki. The study protocol was approved by the Advarra Institutional Review Board, 6100 Merriweather Dr., Suite 600, Columbia, Maryland 21044, (Institutional Review Board (IRB) case number Pro00080984) prior to participant screening. Written informed consent was obtained from each participant before initiation of any trial-related procedures.
Investigational Products
The investigational products included the test product (TP), CBtru®, and the reference product (RP), Epidyolex®. CBtru® (TP) is manufactured by emulsification of an inner oil phase (containing CBD) into an aqueous outer phase and subsequently spray-dried, sieved, and packed in alubags. CBtru® was then filled into hard-shell, gelatin capsules containing 66.68 mg of CBD each, along with standard excipients. Epidyolex® (RP), a commercially available CBD formulation, was sourced by dsm-firmenich (Kaiseraugst, Switzerland). It was provided as an oily oral solution containing 100 mg/mL CBD, with sesame seed oil, dehydrated alcohol, strawberry flavor, and sucralose as inactive ingredients. Both products were manufactured under Good Manufacturing Practice (GMP) conditions. Each administered dose delivered 400 mg of CBD: the TP as six capsules per dose, and the RP as 4 mL of solution per dose.
Subjects
Healthy adult male and female participants, aged 19 to 55 years, with a body mass index (BMI) between 18.0 and 29.9 kg/m2 and body weight ≥ 50 kg, were eligible for inclusion. Participants were naïve or light recreational users of oral or inhaled cannabis or hemp (averaging fewer than two uses per month). Additionally, participants were not habitual users of nicotine products, having abstained from all nicotine use for more than three months prior to the PK assessment. Female participants were either of non-childbearing potential or confirmed to be non-pregnant and non-lactating at each study visit.
Trial Design
This randomized, open-label, four-period crossover study was conducted at a single site in Canada from August 30 to December 16, 2024. The study was registered on ClinicalTrials.gov (NCT06578455). Thirty-two participants (16 males and 16 females) were randomized equally (1:1:1:1) to one of four treatment sequences involving single-dose administration of CBtru® (TP) and Epidyolex® (RP) under both fed and fasted conditions (Fig. 1). For each of the four sequences, the first two periods were conducted in the fed state, with the fasted periods administered thereafter. Participants were stratified by sex; 4 males and 4 females were assigned to every sequence.
In the fasted condition, participants began overnight fasting for at least 10.0 h prior to dosing. Water intake was permitted until 1 hour before administration. In the fed condition, participants began fasting for at least 10.5 h prior to dosing and consumed a standardized high-fat, high-calorie breakfast (800–1000 kcal, ~ 50% from fat) within 30 min before dosing. The meal included two eggs cooked in butter, two strips of bacon, two slices of toast with butter, 113 g of hash browns, and 240 mL of whole milk, as recommended by regulatory guidelines for food-effect studies. All meals and dosing events were supervised by clinical staff to ensure compliance.
Each study product was administered at a 400-mg dose on Day 1 of each treatment period. A minimum 14-day washout separated each period. Each treatment period included two in-clinic visits, i.e., one full day at the clinic and a short follow-up visit the morning after, resulting in a total of nine visits overall: Screening (Visit 1), Day 1 (Visits 2, 4, 6, 8), and Day 2 post-dose (Visits 3, 5, 7, 9). Participants received a follow-up phone call 14 to 28 days after the last dose of the study product to review any changes in health status and the use of concomitant treatments. For each participant, the timing of this call corresponded to their longest washout period plus one day during the study. The study duration for each participant was approximately 8–20 weeks.
Determination of Sample Size
The Health Canada guidance for comparative bioavailability studies recommends a minimum of 12 participants [13]. To accommodate potential sex differences and participant attrition, 32 participants (16 males, 16 females) were enrolled. Sample size estimates were guided by data from Taylor et al. [14], in which area-under-the-curve (AUC) values from 12 participants dosed with 1500 mg CBD under fed and fasted conditions were analyzed. A ~ 4:1 ratio of fed to fasted AUC was observed, with a 90% confidence interval (CI) of ± 20%. With 32 instead of 12 participants in this study, the CI was expected to narrow from ± 20% to ± 12%, whereas the 400-mg dose instead of the 1500-mg dose in this study was expected to widen the CI from ± 12% back to ± 20%.
Blood Collection and Plasma Sample Preparation
Blood samples were collected via intravenous catheter or venipuncture and centrifuged at 1200 RCF for 10 minutes at 15–20 °C. Plasma was stored at − 80°C (± 20 °C). Pharmacokinetic sampling occurred at each in-clinic visit during the four treatment periods (Visits 2–9) and included analyses of CBD, 7-OH-CBD, and 7-COOH-CBD. Fourteen samples were collected per period, including a pre-dose baseline sample (within 90 minutes prior to dosing [fasted] or prior to starting the high-fat, high-calorie breakfast [fed]). Post-dose samples were collected at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, and 24.0 hours. Actual timepoints were recorded and used for PK analyses.
Bioanalysis
A total of 1708 plasma samples were analyzed, with 35 (2.05%) identified as potentially hemolyzed. Bioanalyses were performed at the dsm-firmenich Bioanalytics lab (Kaiseraugst, Switzerland) using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Samples were diluted with buffer and spiked with internal standards (d3-CBD, d3-7-OH-CBD, d3-7-COOH-CBD) that were purchased at Sigma-Aldrich Chemie GmbH, Buchs, Switzerland, before liquid-liquid extraction using isobutanol-n-hexane and centrifugation. Samples were analyzed with no preceding β-glucuronidase hydrolysis. After evaporation of the organic phase, residues were reconstituted in methanol-water and injected into the LC-MS/MS system (Sciex 7500 TQ) equipped with an ESI (electrospray ionization) source set to negative ion mode. Detection was achieved using MRM transitions: CBD (m/z = 313 → 245), 7-OH-CBD (m/z = 329 → 268), and 7-COOH-CBD (m/z = 343 → 179). Quantification was based on external calibration. Accuracy and precision were monitored via daily analysis of control samples. The lower limit of quantification (LLOQ) was 1.00 ng/mL, 0.50 ng/mL, and 5.00 ng/mL for CBD, 7-OH-CBD, and 7-COOH-CBD, respectively.
Pharmacokinetic (PK) Assessment
Pharmacokinetic parameters were estimated using a non-compartmental model and SAS version 9.4. Evaluated parameters included:
AUC0–24: area under the plasma concentration-time curve from time 0 to 24 h.
AUCinf: area under the concentration-time curve from time zero to infinity.
Cmax: maximum concentration in plasma.
tmax: time to reach maximum (peak) plasma concentration (Cmax).
t1/2: elimination half-life.
AUC0–24/AUCinf: ratio of partial to total exposure.
CL/F: oral clearance of the drug from plasma
Vz/F: apparent volume of distribution.
MRAUC0–24: metabolite-to-parent ratios for AUC0–24.
MRCmax: metabolite-to-parent ratios for Cmax.
For summarizing PK concentrations and plotting, all concentrations below the lower limit of quantification (BLQ) were set to zero, except when a BLQ value occurred between two non-BLQ concentrations, in which case it was set to missing. When calculating AUC, BLQ values occurring before the first measurable concentration were set to zero, while all BLQ values after the first measurable concentration were set to missing.
Safety Assessments
Safety was monitored by assessing adverse events (AEs), 12-lead electrocardiograms (ECGs), vital signs, clinical laboratory parameters, and abbreviated physical examinations. Adverse events were documented from the time of informed consent through the follow-up call. Electrocardiograms were recorded pre- and post-dose during dosing visits. Vital signs (blood pressure, heart rate, respiratory rate, temperature) were measured seated at all visits. Blood samples for hematology and chemistry were collected pre-dose at Visits 1, 2, 4, 6, 8, and 12 h post-dose at Visits 2, 4, 6, and 8. Fasting samples were used where applicable. Abnormal lab values were flagged by the central lab as ‘high’ or ‘low’ based on reference ranges. A serious AE was defined as an AE that resulted in death, was life-threatening, required hospitalization, or caused significant disability. Abbreviated physical examinations were performed at key visits, and symptom-driven assessments were conducted as needed. Safety data were reviewed after each treatment period by the central medical monitor according to the study’s safety management plan.
Statistical Analyses
Statistical analyses were performed using SAS version 9.4. Descriptive statistics were calculated for continuous variables (e.g., mean, standard deviation [SD], median, minimum, maximum). For PK parameters (e.g., Cmax, AUC0–24, AUCinf, CL/F, Vz/F), geometric means and coefficients of variation (CV%) were also computed. For categorical (qualitative) variables, frequency tables showing the counts and proportions were generated. Significance level was set at 0.05.
Primary, Secondary, and Exploratory Endpoint Analysis (PK Parameters)
The PK and safety objectives were assessed under both fasted and fed conditions. The primary objective was to evaluate the AUC0–24 of CBD of the test product (TP) versus the reference product (RP), in healthy adults. The secondary objectives included the assessment of additional PK parameters AUC0–24, Cmax, tmax, t1/2, AUCinf, and AUC0–24/AUCinf for CBD and the CBD metabolites 7-OH-CBD and 7-COOH-CBD, and TDE (“total drug exposure” as sum of AUC0–24 for CBD, 7-OH-CBD, and 7-COOH-CBD) of the TP versus the RP. The exploratory objectives included the assessment of PK parameters AUC0–24, Cmax, tmax, t1/2, AUCinf, and AUC0–24/AUCinf for CBD, 7-OH-CBD, 7-COOH-CBD, and TDE of each study product between fasted and fed conditions.
Primary and secondary endpoints were centered on comparisons between TP and RP, while exploratory endpoints assessed differences between fasted and fed conditions. To compare TP and RP under each condition, an ANOVA was performed on log-transformed values of AUC0–24, AUCinf, and Cmax in line with pharmacokinetics guidance documents (e.g., FDA). The model included treatment sequence, treatment, and period as fixed effects, with subject nested within sequence as a random effect. Body weight was treated as a covariate. Treatments consisted of the following four combinations: TP-fed, TP-fasted, RP-fed, and RP-fasted.
Least-squares means (LSM), differences in adjusted treatment means, and associated standard errors (SEs) were calculated. Geometric least square mean ratios (GLSMRs) and their 90% CIs were derived for TP-fed versus RP-fed and TP-fasted versus RP-fasted. For exploratory endpoints, GLSMRs, and 90% CIs were similarly calculated for TP-fed versus TP-fasted and RP-fed versus RP-fasted using the same model. Tmax comparisons were conducted using a non-parametric Wilcoxon test.
Exploratory PK parameters MRAUC0–24, MRCmax, CL/F, and Vz/F were calculated using non-compartmental analysis. The MR assesses relative metabolite exposure, CL/F reflects drug elimination efficiency accounting for oral bioavailability, and Vz/F estimates the extent of systemic drug distribution. Additional exploratory evaluations included the active drug exposure (sum of AUC0–24 for CBD and 7-OH-CBD) of each study product, which was compared between TP and RP and between fasted and fed conditions.
Safety Analyses
The safety objective was to evaluate the tolerability of TP and RP in healthy adults. Adverse events were coded according to the contract research organization's (CRO's) medical dictionary. The safety set included all randomized participants who received at least one dose of the study product. Adverse events occurring on or after the first dosing of each period, or worsening in severity/frequency post-dosing, were considered treatment-emergent adverse events (TEAEs) and summarized by term, severity, and relationship. Each participant contributed once per TEAE incidence, regardless of the number of occurrences.
Results
Study Participants and Baseline Characteristics
A total of 57 healthy participants were screened for the trial. Of these, 25 were not randomized: 22 participants failed screening due to not meeting inclusion criteria and/or meeting exclusion criteria, while 3 eligible participants were not randomized due to full enrollment. Thirty-two participants were randomized and received at least one dose of the study product. Of these, 30 completed the trial per protocol. Two participants voluntarily withdrew before entering the second treatment period; both had received only RP under fed conditions during the first treatment period. All 32 randomized participants were included in the safety and PK analysis populations. A summary of participant enrollment, completion, and disposition by treatment group is presented in Fig. 1, and baseline demographic characteristics are provided in Table 1.
| Category | Before withdrawal of participants N = 32 | After withdrawal of participants N = 30 |
|---|---|---|
| Parameter | Number (percentage) | |
| Sex | ||
| Female | 16 (50.0) | 15 (50.0) |
| Male | 16 (50.0) | 15 (50.0) |
| Race | ||
| Asian Indian | 1 (3.1) | 1 (3.3) |
| Black or African American | 7 (21.9) | 7 (23.3) |
| Chinese | 1 (3.1) | 1 (3.3) |
| Not reported | 1 (3.1) | 1 (3.3) |
| Other Pacific Islander | 1 (3.1) | 1 (3.3) |
| Unknown | 1 (3.1) | 1 (3.3) |
| White | 20 (62.5) | 18 (60.0) |
| Parameter | Mean (SD) | |
| Age (y) | 40.2 (9.9) | 41.2 (9.3) |
| Weight (kg) | 71.6 (11.8) | 71.7 (12.1) |
| Height (cm) | 169.5 (8.3) | 168.80 (8.0) |
| BMI (kg/m2) | 24.8 (2.5) | 25.0 (2.4) |
Comparison of PK Between CBtru® and Epidyolex® Under Fasted and Fed Conditions
Figure 2 displays the mean plasma concentration–time profiles of CBD and its metabolites on a linear scale. For the corresponding profiles on a semi-log scale, please refer to the supplementary material (Fig. S1, in the supplementary material). Table 2 summarizes the PK parameters of CBD, 7-OH-CBD, and 7-COOH-CBD. For the descriptive statistics summary of the PK parameters of CBD, 7-OH-CBD, and 7-COOH-CBD, please refer to the supplementary material (Table S2). Table 3 presents the statistical comparisons of PK parameters following administration of 400 mg CBD (CBtru® or Epidyolex®) under fasted and fed conditions.
| Compound in plasma | PK parameter | TP fasted N = 30 | RP fasted N = 30 | TP fed N = 30 | RP fed N = 32 |
|---|---|---|---|---|---|
| CBD | AUC0–24 (h*ng/mL) | 633 (70.0) | 549 (80.8) | 1909 (35.1) | 1911 (54.4) |
| AUCinf (h*ng/mL)a | 607 (72.1) | 617 (83.9) | 1959 (33.9) | 2059 (65.0) | |
| Cmax (ng/mL) | 154.8 (73.5) | 115.0 (117.1) | 323.9 (61.4) | 255.5 (73.3) | |
| tmax (h)b | 3.0 (1.5, 6.0) | 3.5 (2.0, 23.5) | 5.0 (3.0, 12.1) | 8.0 (1.5, 23.6) | |
| t1/2 (h)c,d | 6.4 (2.1) | 7.1 (2.6) | 4.3 (0.74) | 3.8 (0.63) | |
| CL/F (L/h) | 632 (70.0) | 728 (80.8) | 210 (35.1) | 209 (54.4) | |
| Vz/F (L)e | 6153 (116.4) | 6736 (107.4) | 1275 (47.0) | 1082 (90.4) | |
| 7-OH-CBD | AUC0–24 (h*ng/mL) | 502 (52.1) | 336 (66.4) | 559 (45.6) | 524 (47.9) |
| AUCinf (h*ng/mL)f | 577 (56.2) | 441 (66.8) | 687 (40.8) | 476 (48.5) | |
| Cmax (ng/mL) | 104.3 (52.4) | 56.5 (82.7) | 63.0 (55.6) | 52.4 (56.1) | |
| tmax (h)b | 3.0 (1.5, 5.0) | 3.0 (2.0, 23.5) | 5.0 (3.0, 23.1) | 12.0 (2.0, 23.6) | |
| t1/2 (h)c,g | 10.0 (2.8) | 11.4 (3.8) | 8.6 (1.9) | 9.3 (4.2) | |
| MRAUC0–24 | 0.79 (53.2) | 0.61 (60.5) | 0.29 (48.5) | 0.27 (47.0) | |
| MRCmax | 0.67 (64.5) | 0.49 (66.0) | 0.20 (61.4) | 0.21 (59.5) | |
| 7-COOH-CBD | AUC0–24 (h*ng/mL) | 15,032 (42.0) | 9493 (65.3) | 11,067 (47.3) | 9722 (45.8) |
| Cmax (ng/mL) | 1195.6 (38.0) | 707.7 (66.5) | 734.6 (46.4) | 739.0 (49.8) | |
| tmax (h)b | 4.0 (2.0, 6.0) | 4.0 (3.0, 23.5) | 12.0 (4.0, 24.0) | 12.0 (2.0, 23.8) | |
| t1/2 (h)c,h | 27.1 (13.6) | 29.8 (17.1) | 22.4 (7.6) | 21.5 (N/A) | |
| MRAUC0–24 | 23.74 (80.4) | 17.28 (84.8) | 5.80 (58.9) | 5.09 (65.1) | |
| MRCmax | 7.72 (91.0) | 6.15 (98.7) | 2.27 (86.0) | 2.89 (98.4) |
| Compound in plasma | Comparison | AUC0–24 (h*ng/mL)a | AUCinf (h*ng/mL)a | Cmax (ng/mL)a | tmax (h)b |
|---|---|---|---|---|---|
| CBD | TP vs RP fasted | 115.3 (95.8, 138.6)p = 0.204 | 101.9 (82.8, 125.4)p = 0.880 | 134.6 (103.4, 175.3)p = 0.065 | TP: 3.0 |
| RP: 3.5 | |||||
| p = 0.015 | |||||
| TP vs RP Fed | 99.3 (82.6, 119.2)p = 0.946 | 113.8 (71.5, 181.1)p = 0.642 | 125.3 (96.5, 162.7)p = 0.155 | TP: 5.0 | |
| RP: 8.0 | |||||
| p < 0.001 | |||||
| Fed vs fasted TP | 301.4 (250.6, 362.5)p < 0.001 | 348.7 (278.0, 437.4)p < 0.001 | 209.2 (160.7, 272.4)p < 0.001 | NA | |
| Fed vs fasted RP | 350.1 (291.4, 420.5)p < 0.001 | 312.2 (196.6, 496.0)p < 0.001 | 224.8 (173.1, 292.0)p < 0.001 | NA | |
| 7-OH-CBD | TP vs RP fasted | 149.2 (132.2, 168.2)p < 0.001 | 127.2 (108.1, 149.7)p = 0.019 | 184.5 (152.6, 223.1)p < 0.001 | TP: 3.0 |
| RP: 3.0 | |||||
| p = 0.048 | |||||
| TP vs RP fed | 107.8 (95.7, 121.6)p = 0.298 | 99.8 (72.8, 136.7)p = 0.989 | 119.9 (99.3, 144.7)p = 0.113 | TP: 5.0 | |
| RP: 12.0 | |||||
| p = 0.005 | |||||
| Fed vs fasted TP | 111.4 (98.7, 125.6)p = 0.141 | 129.3 (106.8, 156.6)p = 0.031 | 60.4 (50.0, 73.1)p < 0.001 | NA | |
| Fed vs fasted RP | 154.0 (136.6, 173.6)p < 0.001 | 164.9 (119.5, 227.5)p = 0.014 | 93.0 (77.1, 112.3)p = 0.525 | NA | |
| 7-COOH-CBD | TP vs RP fasted | 158.4 (139.8–179.4)p < 0.001 | NA | 168.9 (147.9, 192.9)p < 0.001 | TP: 4.0 |
| RP: 4.0 | |||||
| p = 0.072 | |||||
| TP vs RP Fed | 114.2 (100.9–129.3)p = 0.079 | NA | 98.9 (86.6, 112.8)p = 0.884 | TP: 12.0 | |
| RP: 12.0 | |||||
| p = 0.046 | |||||
| Fed vs fasted TP | 73.6 (65.0, 83.4)p < 0.001 | NA | 61.4 (53.8, 70.2)p < 0.001 | NA | |
| Fed vs fasted RP | 102.1 (90.2, 115.6)p = 0.781 | NA | 105.0 (92.0, 119.8)p = 0.540 | NA |
Comparison of PK Between CBtru® and Epidyolex® Under Fasted Condition
For CBD, the GLSMRs of AUC0–24, Cmax, and AUCinf for TP relative to RP were 115.26% (p = 0.204), 134.60% (p = 0.065), and 101.89% (p = 0.880), respectively. Although the values were numerically higher for TP than for RP, the differences did not reach statistical significance. Notably, the geometric coefficient of variation (geometric CV) for Cmax was lower for TP (73.5%) than for RP (117.1%), indicating more consistent peak concentrations with TP.
For 7-OH-CBD, the GLSMRs of AUC0–24 and Cmax for TP relative to RP were 149.15% (p < 0.001) and 184.52% (p < 0.001), respectively. For 7-COOH-CBD, the corresponding values were 158.35% (p < 0.001) for AUC0–24 and 168.93% (p < 0.001) for Cmax. These findings demonstrated significantly higher systemic exposure with TP than with RP. The GLSMR of AUCinf for 7-OH-CBD was also significantly elevated for TP relative to RP (127.18%, p = 0.019). The AUCinf for 7-COOH-CBD, however, was not summarized or analyzed as it could not be reliably estimated in the majority of participants.
Median tmax for CBD and 7-OH-CBD occurred significantly earlier with TP compared to RP (3 h vs 3.5 h), suggesting more rapid absorption of TP (Table 3). In contrast, tmax for 7-COOH-CBD did not differ significantly between products. The mean t1/2 values for CBD (6.4 h for TP vs 7.1 h for RP), 7-OH-CBD (10.0 h vs 11.4 h), and 7-COOH-CBD (27.1 h vs 29.8 h) were comparable, indicating similar elimination profiles.
For ADE (CBD + 7-OH-CBD) and TDE (CBD + 7-OH-CBD + 7-COOH-CBD), the GLSMRs of AUC0–24 for TP relative to RP were 127.13% (90% CI 108.62–148.79%, p = 0.013) and 154.54% (90% CI 136.92–174.43%, p < 0.001), respectively, both statistically significant. The AUCinf for TDE was not calculated because it was not reliably estimable in a substantial number of participants.
Comparison of PK Between CBtru® and Epidyolex® Under Fed Condition
For CBD, 7-OH-CBD, and 7-COOH-CBD, the GLSMRs of AUC0–24 for TP relative to RP were 99.25% (p = 0.946), 107.84% (p = 0.298), and 114.18% (p = 0.079), respectively; for Cmax, the GLSMRs were 125.29% (p = 0.155), 119.85% (p = 0.113), and 98.85% (p = 0.884). None of these differences reached statistical significance. Notably, the geometric CV for Cmax of CBD under fed conditions was lower for TP than for RP (61.4% vs 73.3%), indicating more consistent peak plasma concentrations with TP. Estimation of AUCinf for CBD and 7-OH-CBD was limited by the small number of participants with reliable values in the RP arm, owing to prolonged systemic exposure under fed conditions, which also affected the estimation of t1/2. The AUCinf for 7-COOH-CBD was not summarized or statistically analyzed, as it could not be reliably estimated in the majority of the participants. Median tmax values for CBD, 7-OH-CBD, and 7-COOH-CBD were significantly earlier with TP compared to RP (5 h for TP vs 8 h for RP, 5 h vs 12 h, and 12 h vs 12 h, respectively), suggesting faster absorption of TP in the fed condition.
For ADE (CBD + 7-OH-CBD) and TDE (CBD + 7-OH-CBD + 7-COOH-CBD), the GLSMRs of AUC0–24 for TP versus RP were 100.77% (90% CI 86.18–117.82%, p = 0.936) and 110.68% (90% CI 98.13–124.84%, p = 0.165), respectively, with no statistically significant differences, indicating broadly similar overall drug exposure under fed conditions. The AUCinf for TDE was not calculated due to insufficient data across participants.
Comparison of the Effects of Fed vs Fasted Conditions on the PK of CBtru® and Epidyolex®
Comparison of the Effects of Fed vs Fasted Conditions on the PK of CBtru®
For CBD, the GLSMRs of AUC0–24, AUCinf, and Cmax under fed versus fasted conditions were 301.43% (p < 0.001), 348.69% (p < 0.001), and 209.24% (p < 0.001), respectively, indicating significantly greater systemic exposure and peak plasma concentration of CBD when administered with food.
For 7-OH-CBD, the GLSMRs of AUC0–24, AUCinf, and Cmax for fed versus fasted conditions were 111.35% (p = 0.141), 129.33% (p = 0.031), and 60.43% (p < 0.001), respectively. These results suggest that food modestly increased overall exposure (AUCinf) but significantly reduced the peak concentration of 7-OH-CBD.
For 7-COOH-CBD, AUC0–24 and Cmax were significantly lower under fed conditions, with GLSMRs of 73.62% (p < 0.001) and 61.44% (p < 0.001), respectively, indicating reduced systemic levels of this metabolite with food intake.
For ADE (CBD + 7-OH-CBD), the GLSMR of AUC0–24 for fed versus fasted was 217.11% (90% CI 185.50–254.11%, p < 0.001), indicating substantially greater exposure under fed conditions. In contrast, TDE (CBD + 7-OH-CBD + 7-COOH-CBD) showed a GLSMR of 85.27% (90% CI 75.55–96.25%, p = 0.031), suggesting a modest but statistically significant reduction in total exposure under the fed condition.
Comparison of the Effects of Fed vs Fasted Conditions on the PK of Epidyolex®
For CBD, the GLSMRs of AUC0–24, AUCinf, and Cmax under fed versus fasted conditions were 350.06% (p < 0.001), 312.24% (p < 0.001), and 224.80% (p < 0.001), respectively, indicating significantly higher systemic exposure and peak concentration of CBD with food when administered as RP.
For 7-OH-CBD, the GLSMRs of AUC0–24, AUCinf, and Cmax were 154.01% (p < 0.001), 164.88% (p = 0.014), and 93.04% (p = 0.525), respectively. These findings suggest that food intake increased overall exposure to 7-OH-CBD but did not affect its peak plasma concentration.
For 7-COOH-CBD, no significant differences were observed between fed and fasted conditions, with GLSMRs of AUC0–24 and Cmax of 102.10% (p = 0.781) and 105.01% (p = 0.540), respectively.
For ADE (CBD + 7-OH-CBD), the GLSMR of AUC0–24 was 273.91% (90% CI 234.27–320.26%, p < 0.001), while for TDE (CBD + 7-OH-CBD + 7-COOH-CBD), the GLSMR was 119.06% (90% CI 105.56–134.30%, p = 0.018), indicating a significant increase in overall exposure under the fed condition compared to the fasted condition with RP.
Other PK Parameters
The metabolite ratio (MR) of 7-OH-CBD for AUC0–24 (MRAUC0–24) ranged from a minimum of 0.27 in the RP fed to a maximum of 0.79 in the TP fasted. The corresponding MR for Cmax (MRCmax) was also highest in the TP fasted (0.67) and lowest in the TP fed (0.20) (Table 2). Similarly, the MRAUC0–24 for 7-COOH-CBD ranged from a low of 5.09 in the RP fed to a high of 23.74 in the TP fasted, with MRCmax again being highest in the TP fasted (7.72) and lowest in the TP fed (2.27) condition.
Consistent with the observed increase in bioavailability under fed conditions, the apparent clearance (CL/F) of CBD was lower for both TP and RP formulations when administered with food compared to the fasted condition. A similar trend was observed for the apparent volume of distribution (Vz/F), which was reduced under fed conditions for both treatments relative to fasted conditions.
Safety of CBtru® and Epidyolex®
A single oral 400-mg dose of both TP and RP was well tolerated by healthy adult participants across all treatment periods. Overall, 14 participants (44%) reported 32 treatment-emergent adverse events (TEAEs) throughout the study (Table 4). Treatment-emergent adverse events were reported during the TP-fed, RP-fed, TP-fasted, and RP-fasted periods in 6 (20.0%), 6 (18.8%), 8 (26.7%), and 5 (16.7%) participants, respectively, corresponding to 10, 6, 11, and 5 events in each group.
| AE terms | Statistics—S (%) E | ||||
|---|---|---|---|---|---|
| TP fed (N = 30) | RP fed (N = 32) | TP fasted (N = 30) | RP fasted (N = 30) | Total (N = 32) | |
| Abdominal pain | 0 (0%) 0 | 0 (0%) 0 | 1 (3.3%) 1 | 0 (0%) 0 | 1 (3.1%) 1 |
| Anemia | 0 (0%) 0 | 1 (3.1%) 1 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.1%) 1 |
| Bloating | 0 (0%) 0 | 1 (3.1%) 1 | 2 (6.7%) 2 | 0 (0%) 0 | 2 (6.3%) 3 |
| Decreased glomerular filtration rate | 0 (0%) 0 | 0 (0%) 0 | 1 (3.3%) 1 | 0 (0%) 0 | 1 (3.1%) 1 |
| Drowsiness | 1 (3.3%) 1 | 0 (0%) 0 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.1%) 1 |
| Fatigue | 0 (0%) 0 | 1 (3.1%) 1 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.1%) 1 |
| Flu-like symptoms | 1 (3.3%) 1 | 0 (0%) 0 | 1 (3.3%) 1 | 0 (0%) 0 | 2 (6.3%) 2 |
| Food poisoning | 0 (0%) 0 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.3%) 1 | 1 (3.1%) 1 |
| Headache | 2 (6.7%) 2 | 0 (0%) 0 | 2 (6.7%) 2 | 2 (6.7%) 2 | 6 (18.8%) 6 |
| Increased fasting blood glucose | 1 (3.3%) 1 | 0 (0%) 0 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.1%) 1 |
| Loose stool | 1 (3.3%) 1 | 1 (3.1%) 1 | 2 (6.7%) 2 | 2 (6.7%) 2 | 3 (9.4%) 6 |
| Nausea | 2 (6.7%) 2 | 1 (3.1%) 1 | 1 (3.3%) 1 | 0 (0%) 0 | 3 (9.4%) 4 |
| Neck stiffness | 1 (3.3%) 1 | 0 (0%) 0 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.1%) 1 |
| Upper respiratory tract infection | 1 (3.3%) 1 | 0 (0%) 0 | 1 (3.3%) 1 | 0 (0%) 0 | 2 (6.3%) 2 |
| Upset stomach | 0 (0%) 0 | 1 (3.1%) 1 | 0 (0%) 0 | 0 (0%) 0 | 1 (3.1%) 1 |
All TEAEs were mild in severity with the exception of one, which included a participant who experienced a moderate event of drowsiness that began approximately 0.25 h after dosing in the TP-fed period and resolved within 2 h. Notably, this occurred when plasma CBD concentrations were still negligible (1.02 ng/mL at 0.25 h) and had not yet reached peak levels (5.39 ng/mL at 2 h), suggesting the event was unlikely to be related to systemic CBD exposure. No dose adjustment or treatment was required.
No TEAEs were deemed related to the study product by the investigator. Nearly half of the TEAEs (reported by eight participants, 25.0%) were considered unrelated, while the remaining events (reported by 11 participants, 34.4%) were classified as “suspected to be related.” These included loose stools, headache, nausea, bloating, drowsiness, fatigue, and abdominal pain, and were distributed relatively evenly across the four treatment periods. Headaches were the most frequently reported TEAE, occurring in six participants (18.8%).
Weight and BMI were monitored throughout the study. One participant exhibited noticeable weight gain (≥ 5%) from baseline during treatment periods 2–4, but this was not considered clinically significant by the investigator. No other participants showed notable changes in weight or BMI.
There were no severe or serious adverse events (SAEs), deaths, or early withdrawals due to AEs. Two participants voluntarily withdrew after Visit 3 each having completed only treatment period 1 (both assigned to RP-fed). These withdrawals were deemed unrelated to the study treatment or procedures.
Three AEs were associated with safety laboratory assessments: anemia, decreased estimated glomerular filtration rate (eGFR), and increased fasting blood glucose. All were mild in severity and deemed unrelated to the study product. No consistent trends were observed in liver enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or gamma-glutamyl transferase [GGT]). Additionally, no AEs were reported based on vital signs or ECG findings. Table 4 presents TEAEs by AE term. For a summary of TEAEs, please refer to the supplementary material (Table S1).
Discussion
This clinical trial in healthy participants evaluated and compared the PK profile, safety, and tolerability of CBtru® powder and Epidyolex® oil under both fed and fasted conditions.
Comparison of the PK Parameters Between CBtru® and Epidyolex® Under Fasted and Fed Conditions
Under fasted conditions, CBtru® resulted in numerically higher CBD exposure compared to Epidyolex®, with a 15% higher AUC0–24 (p = 0.204) and a 35% higher Cmax (p = 0.065). Cannabidiol reached its peak concentration statistically significantly earlier with CBtru® (median tmax = 3 h) than with Epidyolex® (3.5 h; p = 0.015), indicating somewhat faster absorption with CBtru®. Exposure to CBD metabolites was significantly greater with CBtru® than with Epidyolex®. Specifically, AUC0–24 values were 49% higher for 7-OH-CBD (p < 0.001), 58% higher for 7-COOH-CBD (p < 0.001), 27% higher for ADE (p = 0.013), and 55% higher for TDE (p < 0.001). The significantly greater AUC0–24 for ADE, which includes CBD and 7-OH-CBD (the latter being a major first-pass metabolite of CBD [10, 15]) suggests a higher systemic availability of pharmacologically active components with CBtru®. These findings suggest that CBtru® may provide a more efficient systemic delivery of CBD than Epidyolex®, potentially resulting in enhanced clinical effectiveness.
Under fed conditions, AUC0–24 values for CBD, 7-OH-CBD, 7-COOH-CBD, ADE, and TDE were similar between CBtru® and Epidyolex®, with relative exposures of 0.99-fold (p = 0.946), 1.08-fold (p = 0.298), 1.14-fold (p = 0.079), 1.01-fold (p = 0.936), and 1.11-fold (p = 0.165), respectively. These findings indicate comparable overall systemic exposure to CBD and its metabolites for both formulations. However, the median tmax for CBD was significantly earlier with CBtru® (5 h) than with Epidyolex® (8 h; p < 0.001), suggesting faster absorption following a high-fat, high-calorie meal.
The similarity in AUC0–24 between the two formulations may be attributed to the standardized fed-state conditions. Notably, prior studies have reported a double-peak phenomenon in CBD plasma concentration profiles under fed conditions, with peaks occurring at approximately 5 and 10 hours post-dose [16]. This pattern that was less evident in the fasted state has been linked to lymphatic transport, enterohepatic recirculation, and/or the influence of a secondary meal, and may also explain the PK profiles observed in the present study. Importantly, CBD plasma levels during the first 8 hours post-dose appeared more consistent across participants receiving CBtru® compared to those receiving Epidyolex®, suggesting lower interindividual variability with CBtru® under fed conditions.
Pharmacokinetic variability was lower with CBtru® compared to Epidyolex®, particularly under fed conditions (geometric CV for AUC0–24: 35.1% instead of 54.4%), but also in the fasted state (70.0% instead of 80.8%). This observation is consistent with prior findings. Izgelov et al. compared the PK profile of CBD in sesame oil (similar to Epidyolex®) with a capsule-based self-emulsifying drug delivery system (SNEDDS) [17]. Despite similar overall exposure between formulations, the SNEDDS-based CBD showed a more uniform early absorption profile, whereas the sesame oil-based formulation exhibited variable absorption patterns both early and delayed across participants. A similar heterogeneity in absorption was observed in the current study, especially under fasted conditions, as reflected by the high geometric coefficients of variation (CVs) in PK parameters (Table 2) and individual concentration-time profiles (data not shown).
High interindividual variability in the PK of oral CBD is well documented. A recent population PK study reported CVs as high as 60%, which could not be explained by evaluated covariates [18]. In the present study, the reduced variability observed with CBtru® may be attributed to differences in ways in which the two formulations interact with the gastrointestinal environment. CBtru®, an emulsion-based solid powder formulation, likely disperses more rapidly, thus reduces the impact of gastric emptying. Additionally, the effective dissolution and the high surface area of the nano-sized emulsion droplets ensure an efficient interaction with solubilizing agents such as bile salts and phospholipids in the intestine. This facilitates the formation of mixed micelles, promoting faster and more uniform absorption. By contrast, Epidyolex®, a bulk oil-based formulation, may produce larger lipid droplets upon digestion, leading to less efficient and more variable emulsification. This droplet size heterogeneity can render CBD absorption more dependent on individual physiological variables such as bile flow, lipase activity, and gastric motility, contributing to the greater variability observed with Epidyolex®.
Comparison of the Effects of Fed vs Fasted Conditions on the PK of CBtru® and Epidyolex®
The AUC0–24 of CBD was substantially higher under fed than under fasted conditions for both CBtru® and Epidyolex®: 3.01-fold (p < 0.001) and 3.50-fold (p < 0.001), respectively, consistent with prior reports demonstrating enhanced CBD bioavailability when administered with food [14, 19]. However, for CBtru®, AUC0–24 values for 7-COOH-CBD and TDE were significantly lower in the fed condition than in the fasted condition, by 26% (0.74-fold; p < 0.001) and 15% (0.85-fold; p = 0.031), respectively. Given that 7-COOH-CBD is the predominant circulating metabolite of CBD [20–22] TDE largely reflects this compound.
The observation of reduced 7-COOH-CBD levels for CBtru® under fed conditions, despite higher CBD exposure, is unexpected and has not been reported in previous studies. One plausible explanation is that elevated CBD plasma concentrations with food may alter or saturate metabolic enzyme activity, particularly cytochrome P450 (CYP) isoforms, thereby slowing down metabolism or redirecting it towards alternative, unmeasured pathways. This hypothesis is supported by findings from Taylor who reported that in patients with hepatic impairment, CBD exposure increases while 7-COOH-CBD levels decrease, suggesting that a compromised or altered metabolism can lead to decreased levels of this metabolite [23]. Additionally, Tayo found that renal impairment modifies the elimination of CBD and its metabolites, though without significant accumulation of 7-COOH-CBD, further underscoring the complexity and interindividual variability of CBD metabolism and clearance [24]. Another possible explanation for low 7-COOH-CBD exposure is that the sampling protocol possibly did not cover the actual exposure in the fed condition in the 12- to 24-h period. In the fed condition, a delay in response (plasma 7-COOH-CBD) is observed, and a concentration increase after 12 h might have been missed in a number of participants (Fig. 2).
For both CBtru® and Epidyolex®, exposure to CBD and its active metabolite 7-OH-CBD increased under fed conditions, with the most pronounced increase observed for parent CBD. This pattern was supported by reductions in metabolic ratios (MRAUC0–24 and MRCmax), suggesting that food intake affected the metabolic conversion of CBD. Notably, the peak concentration of 7-OH-CBD was significantly reduced, despite an increase in overall exposure, in contrast to previous studies, which reported increases in both Cmax and AUC under fed conditions. Slower and more prolonged absorption of CBD in the current study may have delayed the onset and extended the duration of 7-OH-CBD formation, producing a flatter concentration-time profile with reduced Cmax while maintaining overall exposure. Although food generally slows absorption, the magnitude and timing of this effect in the present study may have been sufficient to alter early metabolite formation, resulting in this unique PK pattern. Clinically, such a profile could reduce peak concentration-related AEs while preserving therapeutic exposure. These findings highlight the need for further investigation into the mechanisms driving the reduced peak of 7-OH-CBD under fed conditions and its impact on overall PK.
Recent evidence also highlights the influence of sex and body weight on the PK of CBD. In a study by Zhang et al. [22], females exhibited a 2.25-fold higher Cmax and a 1.97-fold higher AUC for 7-COOH-CBD compared to males, independent of body weight. A linear relationship between body weight and 7-OH-CBD AUC was observed in females but not in males. However, the study’s small sample size (n = 6 per sex) limits the generalizability of its conclusions. In the current study, body weight was included as a covariate in ANCOVA models, and participants were stratified to ensure an equal distribution of females and males. Pharmacokinetic profiles for CBtru® and Epidyolex® were evaluated by sex subgroup, revealing consistent findings across groups. Specifically, in the fasted condition, levels of CBD metabolites were higher with CBtru® than with Epidyolex® in both sexes. A post hoc exploratory analysis assessed potential sex effects on CBD and its metabolite exposure. In contrast to Zhang findings [22], sex did not significantly influence exposure to CBD or its metabolites, although females exhibited slightly higher levels overall, likely attributable to differences in body weight.
Safety of CBtru® and Epidyolex®
CBtru® and Epidyolex® were both well tolerated. Most AEs were mild, with only one moderate AE (drowsiness) and no serious or severe AEs reported (Table 4). The most frequent AEs were loose stools, headaches, and nausea. No clinically significant findings emerged from laboratory tests, ECGs, vital signs, or physical exams. Three lab-related AEs (anemia, decreased GFR, and increased fasting glucose) were all mild and deemed unrelated to study treatment.
Trial Limitations
A potential limitation of this study is that it was conducted in healthy adults rather than in patients. This approach, however, allowed for a controlled evaluation of PK and safety. While the sample size for an initial PK study was appropriate, it is acknowledged that it was small. Another consideration is that PK sampling was restricted to 24 h post-dose. While this period captured the majority of systemic exposure, it did not permit full characterization of the terminal elimination phase for some analytes—future studies will extend the sampling period. In addition, the study assessed only a single-dose level and employed a single-dose design. These choices provided clear insights into the initial PK profile and safety; nonetheless, future studies incorporating multiple-dose levels and repeated dosing will be important to confirm dose proportionality, steady-state kinetics, and potential accumulation. The between-subject variability of CBD absorption is considerable. Therefore, with a larger sample size, the ratio between PK parameters of the two formulations or gender or weight differences could be estimated more precisely and the probability of detecting rare TEAEs would be higher.
Conclusion
CBtru® demonstrated similar CBD bioavailability to Epidyolex® under fasted conditions, with more consistent absorption. However, the significantly higher exposure to the metabolites 7-OH-CBD and 7-COOH-CBD achieved with CBtru® is suggestive of greater overall bioavailability. Under fed conditions, systemic exposure was comparable between the two products, although CBtru® reached peak CBD concentrations more rapidly and with lower interindividual variability. These advantages may reflect differences in formulation and dispersion characteristics. Both products were well tolerated, with no safety concerns identified. Together, these findings support the continued clinical development of CBtru® as a potentially more consistent, predictable, and bioavailable oral CBD formulation.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to thank the volunteers who participated in the trial and the staff who provided dedicated support throughout its conduct. They would also like to gratefully acknowledge Dr. Anthony Bier, Principal Investigator, for expert guidance and leadership, as well as Lukas Ramasauskas, Lukas Meier, Richard Gössl, Benjamin Barth, Markus Nowotny, Maggie Georges, Ann Fowler, Thomas Zwick, and Thomas Lindemann for their valuable contributions, which were instrumental in the successful completion of this trial.
Funding
This trial was funded by DSM Nutritional Products AG. Open access funding was provided by dsm-firmenich Switzerland AG.
Declarations
Conflict of interest
This study was sponsored by DSM Nutritional Products AG (now dsm-firmenich Switzerland AG), who developed CBtru®. Igor Bendik, Mareike Beck, Franz Roos, Deanna McCarthy, Christiane Schweiggert, Ahmed Besheer, Zdravka Misic, Bernd Mussler and Szabolcs Peter are employees of dsm-firmenich Switzerland AG. Anu Manderna, Jun Wang, Josh Baisley, and Adam Kuttenkeuler are employed by Nutrasource Pharmaceutical and Nutraceutical Services, the company that dsm-firmenich Switzerland AG contracted to conduct the study.
Ethics approval
This trial was conducted in accordance with International Conference on Harmonisation Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki. Protocols were approved by the Advarra Institutional Review Board (6100 Merriweather Dr., Suite 600, Columbia, Maryland 21044) before eligibility screening.
Consent to participate
All participants signed an informed consent form as evidence of consent.
Consent for publication
Not applicable.
Data availability statement
The datasets generated and/or analyzed during the current trial are not yet publicly available.
Code availability statement
The code used for data analysis in this study is not yet publicly available.
Footnotes
Footnote Group
Contributor Information
Igor Bendik, Email: igor.bendik@dsm-firmenich.com.
Szabolcs Péter, Email: szabolcs.peter@dsm-firmenich.com.
References
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Associated Data
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current trial are not yet publicly available.