A Randomized Four-Period Cross-Over Phase I Study to Assess Bioavailability, Bioequivalence, and Tolerability of...

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.

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 (C_max), area under curve from zero to last measurable concentration (AUC_0-last), and AUC from zero extrapolated to infinity (AUC_0-inf). All adverse events (AE) terms were coded using MedDRA^® Version 26.0.

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 AUC_0-inf (0.910 [90% CI 0.865, 0.958]) and AUC_0-last (0.882 [90% CI 0.838, 0.929]) but not for the C_max (0.597 [90% CI 0.550, 0.647]). For THC, BE was concluded for AUC_0-inf (0.948 [90% CI 0.822, 1.093]) but not for C_max (0.829 [90% CI 0.705, 0.975]) or AUC_0-last (0.877 [90% CI 0.762, 1.010]).

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.

NCT05857384 (Posted 12/05/2023).