Phase I study finds mixed bioequivalence for a THC-OSA formulation
A Randomized Four-Period Cross-Over Phase I Study to Assess Bioavailability, Bioequivalence, and Tolerability of IHL-42X Compared with the Reference Drugs in Healthy Volunteers.
Clinical drug investigation•• Highly Relevant
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AI Summary
This randomized, four-period crossover phase I study asked whether IHL-42X—a capsule combining 5 mg dronabinol (a THC-related cannabinoid drug) with 250 mg acetazolamide—delivered these medicines into the bloodstream similarly to their separate reference products. The study included 125 healthy volunteers in Australia, who received the treatments while fasting and, for IHL-42X, after eating. Researchers measured blood concentrations of acetazolamide, THC, and major THC metabolites, along with safety outcomes.
IHL-42X was generally well tolerated, with no serious adverse events; nearly all reported adverse events were mild or moderate. The formulation met the study’s predefined bioequivalence criteria for acetazolamide exposure over time, but not for its peak concentration. For THC, bioequivalence was met for total exposure extrapolated over time, but not for peak concentration or exposure through the last measurable sample. Food increased overall THC exposure. Because this was a pharmacokinetic and tolerability study in healthy volunteers—not a treatment trial in people with obstructive sleep apnea—it cannot establish whether IHL-42X improves sleep apnea or is effective compared with positive airway pressure; this is an abstract-based summary, not a full-text review.
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Key Findings
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In 125 healthy volunteers, IHL-42X delivered both dronabinol and acetazolamide orally, with pharmacokinetic profiles broadly similar to the separate reference drugs.
High
95%
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IHL-42X met predefined bioequivalence criteria for acetazolamide exposure over time, but not for peak blood concentration.
High
95%
3
For THC, bioequivalence was met for total exposure extrapolated to infinity, but not for peak concentration or exposure through the last measurable sample.
High
95%
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IHL-42X was well tolerated, with no serious adverse events reported; food increased overall THC exposure.
High
90%
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Original Abstract
BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is a poorly diagnosed, serious, and potentially life-threatening condition that is estimated to impact the lives of up to a billion patients globally. Untreated OSA poses multiple, varied, and serious health risks involving cardiovascular, hepatic, metabolic, endocrine, neurological, and mental health indications. Effective management of OSA currently relies on device-based positive airway pressure (PAP), but poor adherence significantly affects clinical management and long-term use. The preliminary proof-of-concept study demonstrated the combination of dronabinol (DRN) and acetazolamide (ACZ) for treatment of OSA. IHL-42X is a proprietary formulation comprised of a solid, film coated ACZ tablet contained within a DRN-sesame oil solution gel cap. Each IHL-42X gel cap contained 5 mg of DRN and 250 mg of ACZ. This study assessed the bioavailability, food effect, and bioequivalence of IHL-42X compared with the reference listed drugs for DRN and ACZ.
METHODS: The study was a four-period crossover study in healthy volunteers (HVs) at two sites in Australia. A total of 125 participants were recruited and assigned to one of four treatment sequences (A-B-C-D, B-D-C-A, C-A-D-B, and D-C-B-A: A = DRN 5 mg, fasted; B = ACZ 250 mg, fasted; C = IHL-42X (5 mg DRN + 250 mg ACZ), fasted; and D = IHL-42X (5 mg DRN + 250 mg ACZ), fed), with a minimum 7-day washout period between doses. Safety assessments included vital signs, electrocardiogram (ECG) parameters, and clinical laboratory parameters. Plasma concentrations of ACZ and tetrahydrocannabinol (THC) plus major metabolites of THC, carboxy-THC (COOH-THC), and hydroxy-THC (OH-THC) were conducted on blood samples taken pre-dose and post-dose at 0.08, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 48 were determined using liquid chromatography-tandem mass spectrometry. Analysis of variance (ANOVA) with Dunnet's adjustment was used on log-transformed PK variables with sequence, treatment, period, and participants nested within a sequence as fixed effects to determine bioequivalence. Bioequivalence (BE) for ACZ, THC, OH-THC, and COOH-THC for IHL-42X relative to reference listed drugs (RLDs) was concluded if the 90% CI around the geometric least squares (LS) mean ratio fell within the predefined limits (0.80 and 1.25) for the maximum plasma concentration (Cmax), area under curve from zero to last measurable concentration (AUC0-last), and AUC from zero extrapolated to infinity (AUC0-inf). All adverse events (AE) terms were coded using MedDRA® Version 26.0.
RESULTS: Overall IHL-42X was well tolerated in both fasted and fed states with no serious adverse events (SAEs) reported during the study. At least one treatment-emergent adverse event (TEAE) was reported in 70 (57.4%), 63 (52.1%), and 45 (37.8%) subjects in the IHL-42X, DRN, and ACZ groups under fasted conditions, respectively, and in 70 (58.8%) subjects in the IHL-42X group under fed conditions. All but one of the TEAEs were mild or moderate in severity. The BE for ACZ was concluded for IHL-42X fasted versus ACZ based on AUC0-inf (0.910 [90% CI 0.865, 0.958]) and AUC0-last (0.882 [90% CI 0.838, 0.929]) but not for the Cmax (0.597 [90% CI 0.550, 0.647]). For THC, BE was concluded for AUC0-inf (0.948 [90% CI 0.822, 1.093]) but not for Cmax (0.829 [90% CI 0.705, 0.975]) or AUC0-last (0.877 [90% CI 0.762, 1.010]).
CONCLUSIONS: IHL-42X was well tolerated in both fasted and fed states with an increased overall exposure to THC when administered with food. No serious adverse events were reported during the study. The PK profiles IHL-42X were similar to the RLDs for DRN and ACZ, selected analytes, and PK parameters. The data support bioavailability of IHL-42X, confirming oral delivery of both DRN and ACZ from the formulations.
TRIAL REGISTRATION: NCT05857384 (Posted 12/05/2023).
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