Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing.
Determination of Etelcalcetide Biotransformation and Hemodialysis Kinetics to Guide the Timing of Its Dosing.
复制标题
DOI：
10.1016/j.ekir.2016.04.002
复制
发表时间：
2016-05
影响因子：
6
通讯作者：
Subramanian R
中科院分区：
文献类型：
--
作者：
Edson KZ;Wu BM;Iyer A;Goodman W;Skiles GL;Subramanian R
Etelcalcetide是一种新型钙敏感受体的拟钙化激动剂，用于治疗血液透析慢性肾病患者的继发性甲状旁腺功能亢进，是一种d-氨基酸线性七肽，具有d-半胱氨酸，通过二硫键与l-半胱氨酸相连。除了与钙敏感受体结合外，乙替钙肽在全血中通过二硫交换进行生物转化，主要形成共价血清白蛋白肽偶联物（SAPC）。影响依替卡尔肽在血液透析的慢性肾病患者中的药代动力学和处置的关键因素是药物固有的透析特性和生物转化动力学。采用体外方法对这些因素进行了研究，并对研究结果进行了建模，得出了相应的动力学速率常数。头孢肽或SAPC在人全血中孵育后，生物转化是可逆的。乙硫代肽生成SAPC的速度比相反的过程快18倍。在血液中加入依替钙肽后立即开始血液透析时，血液透析清除依替钙肽的速度很快。血液透析前将依替卡尔肽在血液中预孵育3小时，可导致SAPC的形成，并由于SAPC形成依替卡尔肽的速度缓慢而降低其清除率。依替卡肽血液透析清除率比其生物转化快16倍。这些结果表明，依替卡尔肽应在血液透析后给予，以避免消除剂量的显著部分。
Etelcalcetide, a novel calcimimetic agonist of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in chronic kidney disease patients on hemodialysis, is a d-amino acid linear heptapeptide with a d-cysteine that is linked to an l-cysteine by a disulfide bond. In addition to binding to the calcium-sensing receptor, etelcalcetide is biotransformed by disulfide exchange in whole blood to predominantly form a covalent serum albumin peptide conjugate (SAPC). Key factors anticipated to affect the pharmacokinetics and disposition of etelcalcetide in chronic kidney disease patients on hemodialysis are the drug’s intrinsic dialytic properties and biotransformation kinetics. These factors were investigated using in vitro methods, and the findings were modeled to derive corresponding kinetic rate constants. Biotransformation was reversible after incubation of etelcalcetide or SAPC in human whole blood. The rate of SAPC formation from etelcalcetide was 18-fold faster than the reverse process. Clearance of etelcalcetide by hemodialysis was rapid in the absence of blood and when hemodialysis was initiated immediately after addition of etelcalcetide to blood. Preincubation of etelcalcetide in blood for 3 hours before hemodialysis resulted in formation of SAPC and decreased its clearance due to the slow rate of etelcalcetide formation from SAPC. Etelcalcetide hemodialysis clearance was >16-fold faster than its biotransformation. These results indicate that etelcalcetide should be administered after hemodialysis to avoid elimination of a significant fraction of the dose.