Edson Katheryne Z, Wu Benjamin M, Iyer Abhinaya, Goodman William, Skiles Gary L, Subramanian Raju
Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA.
Clinical Pharmacology Modeling and Simulations, Amgen Inc., Thousand Oaks, California, USA.
Kidney Int Rep. 2016 Apr 21;1(1):24-33. doi: 10.1016/j.ekir.2016.04.002. eCollection 2016 May.
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 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.
依特卡肽是一种新型的钙敏感受体激动剂，用于治疗接受血液透析的慢性肾病患者的继发性甲状旁腺功能亢进，它是一种d -氨基酸线性七肽，含有一个通过二硫键与l -半胱氨酸相连的d -半胱氨酸。除了与钙敏感受体结合外，依特卡肽在全血中通过二硫键交换进行生物转化，主要形成一种共价血清白蛋白肽缀合物（SAPC）。预计会影响依特卡肽在接受血液透析的慢性肾病患者体内药代动力学和处置的关键因素是药物的固有透析特性和生物转化动力学。
使用相关方法对这些因素进行了研究，并对研究结果进行建模以得出相应的动力学速率常数。
将依特卡肽或SAPC在人全血中孵育后，生物转化是可逆的。依特卡肽形成SAPC的速率比逆向过程快18倍。在无血液的情况下以及将依特卡肽加入血液后立即开始血液透析时，依特卡肽通过血液透析的清除速度很快。在血液透析前将依特卡肽在血液中预孵育3小时会导致SAPC的形成，并由于从SAPC形成依特卡肽的速率较慢而降低其清除率。依特卡肽的血液透析清除率比其生物转化快16倍以上。
这些结果表明，依特卡肽应在血液透析后给药，以避免消除相当一部分剂量。
