Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea.
Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
BioDrugs. 2019 Feb;33(1):101-112. doi: 10.1007/s40259-018-0323-0.
This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and safety properties of the test (CJ-40001) and reference (NESP) versions of darbepoetin alfa following a single subcutaneous (SC) or intravenous (IV) administration in healthy male subjects.
A single-blind, randomized, single-dose, two-period, two-intervention crossover study was conducted, with two separate parts consisting of SC or IV administration. In each period, either a test or reference product was administered via the SC or IV route. Serial blood samples for PK analysis and the reticulocyte, hematocrit, hemoglobin, and red blood cell counts for PD analysis were collected for up to 360 or 264 h after SC or IV administration, respectively. The PK and PD parameters were calculated using non-compartmental methods. The 90% confidence intervals of the geometric mean ratios for the PK and PD parameters between the two interventions were estimated. Safety and anti-drug antibody profile assessments were performed.
The mean darbepoetin alfa concentration-time profiles were comparable between the two products for SC and IV administration. Additionally, the PD and safety profiles were similar between the two products. Anti-drug antibody reactivity was negative for all samples from both intervention groups for SC and IV administration. The time-matched serum darbepoetin alfa concentration and the PD markers presented a counter-clockwise hysteresis, which suggests a time delay between the exposure and response.
The test and reference darbepoetin alfa formulations had similar PK, PD, and safety profiles. Thus, it is expected that the two formulations are able to be used interchangeably in clinical settings. ClinicalTrials.gov Identifier: NCT03542916.
本研究比较了单次皮下（SC）或静脉（IV）给药后健康男性受试者中试验（CJ-40001）和参比（NESP）版本达贝泊汀α的药代动力学（PK）、药效动力学（PD）和安全性特征。
进行了一项单盲、随机、单剂量、两周期、两交叉研究，分为 SC 或 IV 给药两部分。在每个时期，通过 SC 或 IV 途径分别给予试验或参比产品。分别在 SC 或 IV 给药后长达 360 或 264 小时内采集用于 PK 分析的连续血样和用于 PD 分析的网织红细胞、血细胞比容、血红蛋白和红细胞计数。使用非房室方法计算 PK 和 PD 参数。估计两个干预措施之间 PK 和 PD 参数的几何均数比值的 90%置信区间。进行安全性和抗药物抗体分析。
SC 和 IV 给药时，两种产品的达贝泊汀α浓度-时间曲线相似。此外，两种产品的 PD 和安全性特征相似。SC 和 IV 给药时，两个干预组的所有样本均未出现抗药物抗体反应。时匹配的血清达贝泊汀α浓度和 PD 标志物呈逆时针滞后，表明暴露和反应之间存在时间延迟。
试验和参比达贝泊汀α制剂具有相似的 PK、PD 和安全性特征。因此，预计两种制剂可在临床环境中互换使用。临床试验标识符：NCT03542916。
