Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Clin Ther. 2009 Dec;31(12):3009-20. doi: 10.1016/j.clinthera.2009.12.012.
Mirodenafil, a phosphodiesterase 5 inhibitor reported to be effective in the treatment of erectile dysfunction, is metabolized by cytochrome P450 (CYP) 3A4 to the active metabolite N-dehydroxyethyl mirodenafil. Mirodenafil may have drug-drug interactions with ketoconazole and/or rifampicin.
The aim of this study was to investigate the effects of a potent inhibitor (ketoconazole) and inducer (rifampicin) of the CYP3A4 isozyme on the pharmacokinetics of mirodenafil to meet the regulatory requirements for the marketing of mirodenafil in Korea.
An open-label, 1-sequence, 3-period, 3-treatment crossover study was conducted over 22 days in healthy Korean male volunteers. Each subject received 100 mg of mirodenafil in each of 3 study periods: mirodenafil alone (period 1); mirodenafil after pretreatment with ketoconazole 400 mg once daily for 3 days (period 2); and mirodenafil after pretreatment with rifampicin 600 mg once daily for 10 days (period 3). Serial blood samples were collected for pharmacokinetic analysis after the administration of mirodenafil in each study period. Plasma concentration-time data for mirodenafil and its major metabolite, N-dehydroxyethyl mirodenafil, were determined using LC-MS/MS and analyzed by a noncompartmental method. The results for mirodenafil coadministration with either ketoconazole or rifampicin were compared with those for mirodenafil alone. Adverse events (AEs) were identified by asking general health-related questions of the subjects, by physical examination, and by subject self-report throughout the study period.
Nineteen subjects were enrolled (mean [SD] age, 23.2 [2.76] years [range, 19-29 years]; weight, 69.3 [6.50] kg [range, 61.0-84.0 kg]; body mass index, 22.4 [1.77] kg/m(2) [range, 20.0-26.0 kg/m(2)]) and 18 subjects completed the study. One subject discontinued the study due to protocol violation and was replaced. The AUC(0-infinity) of mirodenafil increased 5.04-fold (90% CI, 3.78-6.72) and the metabolic ratio decreased 0.21-fold after pretreatment with ketoconazole compared with mirodenafil alone. After pretreatment with rifampicin, the AUC(0-infinity) of mirodenafil decreased 0.03-fold (90% CI, 0.02-0.05) and the metabolic ratio increased 2.9-fold. Twelve cases of headache, 6 of nasal congestion, 2 of feeling hot, 2 of epistaxis, and 1 each of dizziness, nausea, and somnolence were considered to be related to administration of mirodenafil. Twenty-eight AEs were reported in period 2 (in 68.4% of subjects), during which systemic exposure to mirodenafil was highest, whereas 7 AEs were reported in period 1 (in 31.6% of subjects) and 5 AEs in period 3 (in 16.7% of subjects).
In these healthy Korean male volunteers, the coadministration of ketoconazole and rifampicin resulted in significant changes in systemic exposure to mirodenafil.
米罗地尔是一种磷酸二酯酶 5 抑制剂，据报道可有效治疗勃起功能障碍，其通过细胞色素 P450（CYP）3A4 代谢为活性代谢物 N-去羟乙基米罗地尔。米罗地尔可能与酮康唑和/或利福平发生药物相互作用。
本研究旨在调查一种强效抑制剂（酮康唑）和诱导剂（利福平）对 CYP3A4 同工酶的米罗地尔药代动力学的影响，以满足米罗地尔在韩国上市的监管要求。
在 22 天内，19 名健康的韩国男性志愿者参与了一项开放标签、1 序列、3 期、3 处理交叉研究。每位受试者在 3 个研究期间分别接受 100mg 米罗地尔：米罗地尔单药治疗（第 1 期）；酮康唑 400mg 每日 1 次预处理 3 天后给予米罗地尔（第 2 期）；利福平 600mg 每日 1 次预处理 10 天后给予米罗地尔（第 3 期）。在每个研究期间给予米罗地尔后，采集血样进行药代动力学分析。采用 LC-MS/MS 法测定米罗地尔及其主要代谢物 N-去羟乙基米罗地尔的血浆浓度-时间数据，并采用非房室法进行分析。比较酮康唑或利福平与米罗地尔合用的结果。通过询问受试者的一般健康相关问题、体格检查和受试者自我报告，在整个研究期间确定不良事件（AE）。
19 名受试者入选（平均[标准差]年龄为 23.2[2.76]岁[范围为 19-29 岁]；体重为 69.3[6.50]kg[范围为 61.0-84.0kg]；体重指数为 22.4[1.77]kg/m2[范围为 20.0-26.0kg/m2]），18 名受试者完成了研究。1 名受试者因违反方案而退出研究，并被替换。与米罗地尔单药治疗相比，酮康唑预处理后米罗地尔的 AUC（0-无穷大）增加了 5.04 倍（90%置信区间，3.78-6.72），代谢比降低了 0.21 倍。利福平预处理后，米罗地尔的 AUC（0-无穷大）降低了 0.03 倍（90%置信区间，0.02-0.05），代谢比增加了 2.9 倍。12 例头痛、6 例鼻塞、2 例发热、2 例鼻出血、1 例头晕、1 例恶心和 1 例嗜睡被认为与米罗地尔给药有关。第 2 期（68.4%的受试者）报告了 28 例不良事件，在此期间米罗地尔的全身暴露量最高，而第 1 期（31.6%的受试者）报告了 7 例不良事件，第 3 期（16.7%的受试者）报告了 5 例不良事件。
在这些健康的韩国男性志愿者中，酮康唑和利福平的联合用药导致米罗地尔的全身暴露量发生显著变化。
