Wu Liviawati, Melhem Murad, Subramanian Raju, Wu Benjamin
Clinical Pharmacology Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, USA.
Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA.
J Pharmacokinet Pharmacodyn. 2017 Feb;44(1):43-53. doi: 10.1007/s10928-016-9503-z. Epub 2017 Jan 6.
Etelcalcetide (AMG 416) is an allosteric activator of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of [C]etelcalcetide (10 mg; 710 nCi) after hemodialysis (study NCT02054572). A three-compartment model with the following attributes adequately described the observed concentration-time profiles of etelcalcetide in the different matrices: biotransformation in the central compartment; elimination in dialysate, urine, and feces; and a nonspecific elimination process. The terminal half-life of total C-14 in plasma was approximately 56 days. The ratio of conjugation-deconjugation rate constants between etelcalcetide and biotransformed products was 11.3. Simulations showed that three hemodialysis sessions per week for 52 weeks would contribute to 60.1% of the total clearance of etelcalcetide following single-dose intravenous etelcalcetide administration. Minimal amounts were eliminated in urine (2.5%) and feces (5.7%), whereas nonspecific elimination accounted for 31.2% of total elimination. In addition to removal of etelcalcetide, ~10% of small-molecular weight biotransformed products was estimated to have been removed through hemodialysis and in urine. This model provided a quantitative approach to describe biotransformation, distribution, and elimination of etelcalcetide, a unique synthetic D-amino acid peptide, in the relevant patient population.
依特卡肽（AMG 416）是一种钙敏感受体变构激活剂，用于治疗接受血液透析的慢性肾脏病（CKD）患者的继发性甲状旁腺功能亢进。为了描述依特卡肽在不同基质（血浆、透析液、尿液和粪便）中的时间过程，建立了一个药物处置模型。使用非线性混合效应模型来描述6名接受血液透析的CKD成年患者的数据，这些患者在血液透析后接受了单次静脉注射[C]依特卡肽（10 mg；710 nCi）（研究NCT02054572）。一个具有以下特征的三室模型充分描述了依特卡肽在不同基质中观察到的浓度-时间曲线：中央室的生物转化；透析液、尿液和粪便中的消除；以及一个非特异性消除过程。血浆中总C-14的终末半衰期约为56天。依特卡肽与生物转化产物之间的结合-去结合速率常数之比为11.3。模拟显示，每周进行3次血液透析，共52周，将占单次静脉注射依特卡肽后依特卡肽总清除率的60.1%。尿液（2.5%）和粪便（5.7%）中的消除量极少，而非特异性消除占总消除量的31.2%。除了清除依特卡肽外，估计约10%的小分子生物转化产物已通过血液透析和尿液清除。该模型提供了一种定量方法，用于描述依特卡肽（一种独特的合成D-氨基酸肽）在相关患者群体中的生物转化、分布和消除。
