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) 及其活性代谢物 17-单丙酸 (17-BMP) 与 HIV 蛋白酶抑制剂利托那韦 (RTV) 和达芦那韦/利托那韦 (DRV/r) 联合使用的安全性和药代动力学。 设计：在健康志愿者中进行开​​放标签、前瞻性、随机药代动力学研究。 方法：30 名受试者从研究第 1-14 天每天两次 (BID) 吸入 BDP 160 g。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) 分为三组：第 1 组（对照组）仅服用 BDP 28 天；第 1 组（对照组）仅服用 BDP 28 天；第 2 组接受 BDP + RTV 100 mg BID，持续 28 天，第 3 组接受 BDP + DRV/r 600/100 mg BID，持续 28 天。第 28 天，重复进行 17-BMP 采样，并使用配对 t 检验将药代动力学参数值与第 14 天的参数值进行比较。还在第 14、28 和 42 天进行了皮质醇刺激测试，并分别使用配对 t 检验和方差分析在组内和组间进行比较。 结果：第 1、2 和 3 组浓度-时间曲线下 17-BMP 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没有显着降低（p>0.05）。 结论：DRV/r 不会增加 17-BMP 暴露量，而单独使用 RTV 会使 17-BMP 暴露量增加 2 倍，具有统计学意义，但临床上无关紧要；在任何研究组中均未观察到肾上腺抑制。这些数据表明，BDP 可以与 DRV/r 以及可能的其他 RTV 增强的蛋白酶抑制剂方案安全地共同给药。