Global Discovery and Development Sciences, Novo Nordisk A/S, Måløv, Denmark.
Stem Cell Development, Novo Nordisk A/S, Måløv, Denmark.
Eur J Pharm Sci. 2021 Dec 1;167:106030. doi: 10.1016/j.ejps.2021.106030. Epub 2021 Oct 1.
Somapacitan is a reversible albumin-binding growth hormone (GH) derivative in clinical development for once-weekly administration in patients with adult GH deficiency (AGHD) and children with GH deficiency (GHD). To date, the use of somapacitan in AGHD or severe AGHD has been approved in the USA and Japan, respectively. This study (ClinicalTrials.gov, NCT02962440) investigated the absorption, metabolism and excretion, as well as the pharmacokinetics (PK), of tritium-labelled somapacitan ([H]-somapacitan). Seven healthy males received a single subcutaneous dose of 6 mg somapacitan containing [H]-somapacitan 20 MBq. Blood, serum, plasma, urine, faeces, and expired air were collected for radioactivity assessment. Metabolites were identified and quantified in plasma and urine collected. The PK of plasma components were determined, and the radioactive peaks of the most abundant plasma metabolites and urine metabolites were selected for analysis. Twenty-eight days after dosing, 94.0% of the administered dose was recovered as [H]-somapacitan-related material, most of which was excreted in urine (80.9%); 12.9% was excreted in faeces, and an insignificant amount (0.2%) was exhaled in expired air. PK properties of [H]-somapacitan-related material appeared to be consistent across plasma, serum and blood. Three abundant plasma metabolites (P1, M1 and M1B) and two abundant urine metabolites (M4 and M5) were identified. The total exposure of intact somapacitan accounted for 59% of the total exposure of all somapacitan-related material, P1 accounted for 21% and M1 plus M1B accounted for 12%. M4 and M5 were the most abundant urine metabolites and accounted for 37% and 8% of the dosed [H]-somapacitan radioactivity, respectively. No intact somapacitan was found in excreta. Two subjects had six adverse events (AEs); all were mild in severity and unlikely to be related to trial product. The majority of dosed [H]-somapacitan (94%) was recovered as excreted metabolites. Urine was the major route for excretion of somapacitan metabolites, followed by faeces, and exhalation in expired air was negligible. The low molecular weights of identified urine metabolites demonstrate that somapacitan was extensively degraded to small residual fragments that were excreted (fully biodegradable). The extensive metabolic degradation and full elimination of metabolites in excreta were the major clearance pathways of somapacitan and the key elements in its biological fate. A single dose of 6 mg somapacitan (containing [H]-somapacitan) in healthy male subjects was well tolerated with no unexpected safety issues identified.
索马帕坦是一种可逆转的白蛋白结合型生长激素（GH）衍生物，正在临床开发中，用于每周一次给药治疗成人生长激素缺乏症（AGHD）和儿童生长激素缺乏症（GHD）患者。迄今为止，索马帕坦在 AGHD 或严重 AGHD 中的应用已分别在美国和日本获得批准。这项研究（ClinicalTrials.gov，NCT02962440）调查了氚标记的索马帕坦（[H]-索马帕坦）的吸收、代谢和排泄以及药代动力学（PK）。7 名健康男性接受了单次皮下 6mg 索马帕坦剂量，其中包含[H]-索马帕坦 20MBq。采集血液、血清、血浆、尿液、粪便和呼出的空气以评估放射性。在收集的血浆和尿液中鉴定和定量了代谢物。确定了血浆成分的 PK，并选择了最丰富的血浆代谢物和尿液代谢物的放射性峰进行分析。给药后 28 天，94.0%的给药剂量以[H]-索马帕坦相关物质回收，其中大部分以尿液（80.9%）形式排泄；12.9%以粪便形式排泄，呼出的空气中排泄量微不足道（0.2%）。[H]-索马帕坦相关物质的 PK 特性似乎在血浆、血清和血液中一致。鉴定出三种丰富的血浆代谢物（P1、M1 和 M1B）和两种丰富的尿液代谢物（M4 和 M5）。完整索马帕坦的总暴露量占所有索马帕坦相关物质总暴露量的 59%，P1 占 21%，M1 和 M1B 占 12%。M4 和 M5 是最丰富的尿液代谢物，分别占给予的[H]-索马帕坦放射性的 37%和 8%。粪便中未发现完整的索马帕坦。两名受试者发生了 6 起不良事件（AE）；均为轻度，不太可能与试验产品有关。给予的[H]-索马帕坦（94%）大部分以排泄的代谢物回收。尿液是索马帕坦代谢物的主要排泄途径，其次是粪便，呼出的空气可以忽略不计。鉴定出的尿液代谢物的低分子量表明，索马帕坦被广泛降解为小的残留片段而被排泄（完全可生物降解）。代谢物在粪便中的广泛代谢降解和完全消除是索马帕坦的主要清除途径，也是其生物学命运的关键因素。健康男性单次给予 6mg 索马帕坦（包含[H]-索马帕坦），耐受性良好，未发现意外的安全性问题。
