Ma Peiming, Wang Yanfeng, van der Hoek Joost, Nedelman Jerry, Schran Horst, Tran Ly-Le, Lamberts Steven W J
Novartis Pharma KK, Tokyo 106-8618, Japan.
Clin Pharmacol Ther. 2005 Jul;78(1):69-80. doi: 10.1016/j.clpt.2005.04.003.
Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients.
In a double-blind, 3-period, crossover, proof-of-concept study, 12 patients with active acromegaly were randomized to single subcutaneous doses of SOM230 (100 and 250 microg) and octreotide (100 microg). Concentrations of SOM230, octreotide, and GH were determined at designated times after dosing and at baseline. The PK properties of SOM230 and octreotide and the relationship of PK with GH were investigated by a nonlinear mixed-effects modeling analysis.
The apparent clearance for SOM230 is approximately half of that for octreotide (8.0 L/h versus 15.8 L/h). The elimination half-life for SOM230 is about 5 times longer than that for octreotide (11.8 hours versus 2.3 hours). The relationship between GH levels and plasma concentrations of SOM230 and octreotide is well described by a direct inhibitory model. The test drug concentration level at which half of the maximum drug effect is observed (EC50) is 46 and 553 pg/mL for octreotide and SOM230, respectively, with large interpatient variability (coefficients of variation, 164% and 65%, respectively), mainly attributable to the heterogeneous responses among patients.
SOM230 demonstrates a lower clearance and longer half-life than octreotide, which compensates for the lower potency in GH inhibition. As a result of the lower interpatient variability for EC50 , SOM230 is expected to have a more uniform clinical GH inhibition than octreotide for acromegalic patients at a clinically effective dosing regimen.
肢端肥大症是一种由垂体腺瘤导致生长激素（GH）分泌过多引起的严重激素紊乱疾病。生长抑素类似物如奥曲肽一直是首选的药物治疗方法。将新型生长抑素类似物SOM230与奥曲肽在肢端肥大症患者中的药代动力学（PK）特征及对GH分泌的抑制作用方面进行了比较。
在一项双盲、3期、交叉、概念验证研究中，12例活动性肢端肥大症患者被随机分配接受单次皮下注射剂量的SOM230（100和250微克）和奥曲肽（100微克）。给药后指定时间及基线时测定SOM230、奥曲肽和GH的浓度。通过非线性混合效应建模分析研究SOM230和奥曲肽的PK特性以及PK与GH的关系。
SOM230的表观清除率约为奥曲肽的一半（8.0升/小时对15.8升/小时）。SOM230的消除半衰期比奥曲肽长约5倍（11.8小时对2.3小时）。直接抑制模型很好地描述了GH水平与SOM230和奥曲肽血浆浓度之间的关系。奥曲肽和SOM230观察到最大药物效应一半时的测试药物浓度水平（EC50）分别为46和553皮克/毫升，患者间变异性较大（变异系数分别为164%和65%），主要归因于患者间的异质性反应。
SOM230的清除率低于奥曲肽，半衰期更长，这弥补了其在抑制GH方面较低的效力。由于EC50的患者间变异性较低，预计在临床有效给药方案下，SOM230对肢端肥大症患者的临床GH抑制作用比奥曲肽更均匀。
