一项随机四周期交叉I期研究，评估IHL-42X与参比药物在健康志愿者中的生物利用度、生物等效性和耐受性。

文献信息

中文摘要

背景与目的： 阻塞性睡眠呼吸暂停（OSA）是一种诊断不足、严重且可能危及生命的疾病，估计影响全球多达十亿患者的生活。未经治疗的OSA会带来多种、多样且严重的健康风险，涉及心血管、肝脏、代谢、内分泌、神经和精神健康适应症。目前OSA的有效管理依赖于基于设备的持续气道正压（PAP），但依从性差显著影响临床管理和长期使用。初步的概念验证研究表明，屈大麻酚（DRN）与乙酰唑胺（ACZ）联合用于治疗OSA。IHL-42X是一种专有制剂，由固体薄膜包衣的ACZ片剂置于DRN-芝麻油溶液凝胶胶囊内组成。每粒IHL-42X凝胶胶囊含5 mg DRN和250 mg ACZ。本研究评估了IHL-42X与DRN和ACZ的参比上市药物相比的生物利用度、食物效应和生物等效性。
方法： 该研究是在澳大利亚两个中心进行的健康志愿者（HVs）四周期交叉研究。共招募125名参与者，并分配到四个治疗序列之一（A-B-C-D、B-D-C-A、C-A-D-B和D-C-B-A：A = DRN 5 mg，空腹；B = ACZ 250 mg，空腹；C = IHL-42X（5 mg DRN + 250 mg ACZ），空腹；D = IHL-42X（5 mg DRN + 250 mg ACZ），进食），给药间至少有7天洗脱期。安全性评估包括生命体征、心电图（ECG）参数和临床实验室参数。在给药前和给药后0.08、0.25、0.5、1、1.5、2、2.5、3、3.5、4、6、8、12、16、24、36和48小时采集血样，使用液相色谱-串联质谱法测定ACZ和四氢大麻酚（THC）及THC主要代谢物羧基-THC（COOH-THC）和羟基-THC（OH-THC）的血浆浓度。对对数转换后的药代动力学变量采用方差分析（ANOVA）并进行Dunnet校正，以序列、治疗、周期和嵌套于序列内的参与者作为固定效应，以确定生物等效性。如果IHL-42X相对于参比上市药物（RLDs）的ACZ、THC、OH-THC和COOH-THC的几何最小二乘（LS）均值比值的90%置信区间落在最大血浆浓度（Cmax）、从零到最后可测浓度的曲线下面积（AUC0-last）和从零外推至无穷大的AUC（AUC0-inf）的预定义限值（0.80和1.25）内，则判定生物等效性（BE）。所有不良事件（AE）术语均使用MedDRA® 26.0版编码。
结果： 总体而言，IHL-42X在空腹和进食状态下均耐受良好，研究期间未报告严重不良事件（SAEs）。在空腹条件下，IHL-42X、DRN和ACZ组分别有70名（57.4%）、63名（52.1%）和45名（37.8%）受试者报告至少一次治疗中出现的不良事件（TEAE），在进食条件下IHL-42X组有70名（58.8%）受试者报告。除一例外，所有TEAE的严重程度均为轻度或中度。基于AUC0-inf（0.910 [90% CI 0.865, 0.958]）和AUC0-last（0.882 [90% CI 0.838, 0.929]），IHL-42X空腹与ACZ相比的ACZ生物等效性成立，但Cmax（0.597 [90% CI 0.550, 0.647]）不成立。对于THC，基于AUC0-inf（0.948 [90% CI 0.822, 1.093]）生物等效性成立，但Cmax（0.829 [90% CI 0.705, 0.975]）或AUC0-last（0.877 [90% CI 0.762, 1.010]）不成立。
结论： IHL-42X在空腹和进食状态下均耐受良好，与食物同服时THC总体暴露量增加。研究期间未报告严重不良事件。IHL-42X的药代动力学特征与DRN和ACZ的RLDs、所选分析物和PK参数相似。数据支持IHL-42X的生物利用度，证实了制剂中DRN和ACZ的口服递送。
试验注册： NCT05857384（发布于2023年5月12日）。

英文摘要

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).