Drug Interaction Study Between Inhaled Beclomethasone and Protease Inhibitors

吸入倍氯米松与蛋白酶抑制剂的药物相互作用研究

• 批准号: 8565307
• 负责人: Scott Penzak
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565307
• 关键词: Adrenal Cortex Hormones; Adrenal Glands; Adrenal gland hypofunction; Adverse effects; Area; Area Under Curve; Beclomethasone; Beclomethasone Dipropionate; Biological Availability; Breathing; Corticotropin; Cosyntropin; Cytochrome P450 3A4; Data; Dose; Drug Interactions; Drug Kinetics; Enzymes; HIV; Half-Life; Hydrocortisone; In Vitro; Investigation; Lung diseases; Metabolism; Methods; Outpatients; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Property; Protease Inhibitor; Randomized; Regimen; Risk; Ritonavir; Safety; Sampling; Secondary to; Serum; Testing; Time; base; clinically significant; design; esterase; fluticasone; healthy volunteer; in vivo; inclusion criteria; indexing; inhibitor/antagonist; meetings; open label; prospective; response

Objective: To assess the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, 17-monopropionate (17-BMP), in combination with the HIV protease inhibitors ritonavir (RTV), and darunavir/ritonavir (DRV/r). Design: Open label, prospective, randomized pharmacokinetic study in healthy volunteers. Methods: Thirty subjects received inhaled BDP 160 g twice daily (BID) from study days 1-14. On day 14, pharmacokinetic sampling for 17-BMP occurred. On day 15, subjects were randomized (1:1:1) into three groups: Group 1 (control) remained on BDP alone for 28 days; Group 2 received BDP + RTV 100 mg BID for 28 days, and Group 3 received BDP + DRV/r 600/100 mg BID for 28 days. On day 28, 17-BMP sampling was repeated and pharmacokinetic parameter values compared to those from day 14 using paired t-tests. Cortisol stimulation testing was also performed on days 14, 28, and 42 and compared within and between groups using paired t-tests and ANOVA, respectively. Results: Geometric mean ratios (day 28:day 14) (90% CI) for 17-BMP area under the concentration-time curve in Groups 1, 2, and 3, respectively, were 0.93 (0.81-1.06, p=0.27), 2.08 (1.52-2.65; p=0.006), and 0.89 (0.68-1.09; p=0.61). There were no significant reductions in serum cortisol levels within or between groups (p>0.05). Conclusions: DRV/r did not increase 17-BMP exposure while RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure; Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitor regimens.

目的：评估二丙酸倍氯米松（BDP）及其活性代谢产物17-单丙酸酯（17-BMP）与HIV蛋白酶抑制剂利托那韦（RTV）和地瑞那韦/利托那韦（DRV/r）联合给药的安全性和药代动力学。 设计：在健康志愿者中进行的开放标签、前瞻性、随机药代动力学研究。 方法：30例受试者从研究第1-14天接受吸入BDP 160 g每日两次（BID）。在第14天，进行17-BMP的药代动力学采样。第15天，受试者被随机（1：1：1）分为3组：第1组（对照）继续接受BDP单药治疗28天;第2组接受BDP + RTV 100 mg BID治疗28天，第3组接受BDP + DRV/r 600/100 mg BID治疗28天。在第28天，重复17-BMP取样，并使用配对t检验将药代动力学参数值与第14天的药代动力学参数值进行比较。还在第14、28和42天进行皮质醇刺激测试，并分别使用配对t检验和ANOVA在组内和组间进行比较。 结果如下：第1、2和3组中17-BMP浓度-时间曲线下面积的几何平均比（第28天：第14天）（90% CI）分别为0.93（0.81-1.06，p=0.27）、2.08（1.52-2.65; p=0.006）和0.89（0.68-1.09; p=0.61）。 组内或组间血清皮质醇水平无显著降低（p>0.05）。 结论：DRV/r未增加17-BMP暴露，而RTV单独给药使17-BMP暴露增加2倍，具有统计学显著性，但无临床意义;在任何研究组中均未观察到肾上腺抑制。这些数据表明，BDP可以安全地与DRV/r和其他可能的RTV增强蛋白酶抑制剂方案联合给药。