Tolerability and Dose Proportional Pharmacokinetics of Pasireotide Administered as a Single Dose or Two Divided Doses in Healthy Male Volunteers: A Single-Center, Open-Label, Ascending-Dose Study

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• 作者：Stephan Petersenn ; MD¹ ; ^{stephan.petersenn@endoc-med.de} ; Ke Hu ; PhD² ; Mario Maldonado ; MD³ ; Yilong Zhang ; PhD² ; Janet Lasher² ; Emmanuel Bouillaud ; PhD³ ; Yanfeng Wang ; PhD² ; Klaus Mann ; MD¹ ; Nicole Unger ; MD¹
• 关键词：pasireotide ; SOM230 ; tolerability ; pharmacokinetics ; healthy volunteer
• 刊名：Clinical Therapeutics
• 出版年：2012
• 期刊代码：65_01492918
• 类别：med
• 出版时间：March, 2012
• 卷：34
• 期：3
• 页码：677-688
• 文件大小：746 K

摘要

Background

Pasireotide is a multireceptor-targeted somatostatin analogue with high binding affinity for somatostatin receptor subtypes SST 1, 2, 3, and 5.

Objective

To evaluate the safety profile, tolerability, and pharmacokinetic profile of pasireotide in single- and divided-dose regimens in healthy volunteers.

Methods

A single-center, open-label, ascending-dose study was performed in healthy volunteers. Pasireotide, 900, 1200, and 1500 渭g SC, was administered as either a single dose or as two divided doses given 12 hours apart, with a 7-day washout period between treatments.

Results

Seventeen men (median age, 26 years) were enrolled. Their median weight was 81 kg, and 65%were white. One participant dropped out because of a grade 2 adverse event; most other adverse events were mild and affected the gastrointestinal tract. Blood glucose concentration increased after pasireotide administration, but returned to normal within 10 hours. After single-dose administration, pasireotide plasma concentration peaked rapidly at 15 minutes to 1 hour after dosing, followed by a tri-exponential (伪, 尾, and 纬 phases) decline over time. Mean t_陆 values during the 伪, 尾, and 纬 phases were approximately 2 to 3, 12 to 17, and 54 to 97 hours, respectively. In the single-dose cohort, the mean (SD) AUC_{鈭?/sub> was 110 (29), 149 (42), and 188 (52) h 路 ng/mL in the 900-, 1200-, and 1500-渭g groups, respectively. Time to reach Cmax was 0.69 (0.41), 0.59 (0.38), and 0.56 (0.18) hours in the 900-, 1200-, and 1500-渭g groups, respectively. AUC鈭?/sub> values were similar in the single-dose and divided-dose cohorts. Mean total body clearance was 8 to 9 L/h across the dosage groups and dosing regimens, indicating a linear pharmacokinetic profile between doses.}

Conclusions

When administered as a single- or divided-dose regimen, pasireotide had a favorable tolerability profile in this selected group of healthy male volunteers. Its pharmacokinetic profile indicated rapid absorption, low clearance, high volume of distribution, and a long terminal half-life.