Thygesen Peter, Andersen Henrik Sune, Behrens Carsten, Fels Johannes Josef, Nørskov-Lauritsen Leif, Rischel Christian, Johansen Nils Langeland
Novo Nordisk A/S, Haemophilia Pharmacology, DK-2760, Maaloev, Denmark.
Novo Nordisk A/S, Protein & Peptide Chemistry, DK-2760, Maaloev, Denmark.
Growth Horm IGF Res. 2017 Aug;35:8-16. doi: 10.1016/j.ghir.2017.05.006. Epub 2017 May 24.
Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys.
Pharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production.
Pharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5-6h in rats, 10-12h in minipigs, and 17-20h in monkeys. Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3-4days in each dosing interval (p<0.001).
The nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species. Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3-4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level.
索马帕西坦是一种白蛋白结合生长激素衍生物，拟每周给药一次，目前正处于治疗成人及青少年生长激素缺乏症的临床开发阶段。对索马帕西坦进行非临床体内药理学特性研究以支持临床试验。在此，我们展示索马帕西坦在大鼠、小型猪和食蟹猴体内的药代动力学和药效学效应。
在所有物种中进行了药代动力学研究，调查单次静脉注射（i.v.）和皮下注射（s.c.）后的暴露量、吸收、清除率和生物利用度。对垂体切除的大鼠进行了五个剂量水平的剂量反应研究和每周一次、共四个剂量的多次剂量药效学研究，以评估索马帕西坦对生长和IGF-I产生的影响。
药代动力学曲线表明，在所有三个物种中，索马帕西坦皮下注射后从皮下组织呈一级吸收。大鼠的表观终末半衰期为5 - 6小时，小型猪为10 - 12小时，猴子为17 - ２０小时。单次给药后，索马帕西坦在垂体切除的大鼠中诱导剂量依赖性生长（p<0.001），并使大鼠（p<0.01）、小型猪（p<0.01）和食蟹猴（p<0.05）的血浆IGF-I水平升高。在垂体切除的大鼠中每周一次多次给药索马帕西坦会导致体重逐步增加，在每个给药间隔的前3 - 4天有一个初始线性阶段（p<0.001）。
索马帕西坦的非临床药代动力学和药效学研究显示出相似的药代动力学特性，无吸收限制消除，清除率增加，单次给药后在所有三个物种中血浆IGF-I水平升高并持续长达10天。索马帕西坦在垂体切除的大鼠中诱导体重和IGF-I水平呈剂量依赖性增加。在垂体切除的大鼠中多次给药索马帕西坦表明，在每个每周给药间隔的前3 - 4天呈线性生长，而每日注射人生长激素在达到平台期水平前约两周呈线性生长。
