将静脉注射达雷妥尤单抗的首剂量拆分用于多发性骨髓瘤（MM）的治疗：临床和群体药代动力学分析。
Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses.
机构信息
Janssen Research & Development, LLC, Raritan, NJ, USA.
University Hospital of Nantes, Nantes, France.
出版信息
Adv Ther. 2020 Apr;37(4):1464-1478. doi: 10.1007/s12325-020-01247-8. Epub 2020 Feb 20.
INTRODUCTION
Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers.
METHODS
The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications.
RESULTS
In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab.
CONCLUSION
These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM.
TRIAL REGISTRATION
ClinicalTrials.gov number, NCT01998971.
简介
达雷妥尤单抗是一种靶向 CD38 的人源化 IgGκ 单克隆抗体，已被批准用于多发性骨髓瘤的单药治疗和联合标准治疗方案。在临床研究中，达雷妥尤单抗的首次、第二次和后续静脉输注的中位持续时间分别为 7.0、4.3 和 3.4 小时。将达雷妥尤单抗的首次静脉输注分为 2 天输注是一种已批准的替代剂量方案，可缩短首次输注的持续时间，并为患者和医疗保健提供者提供灵活性。
方法
在 MMY1001 研究的两个队列（达雷妥尤单抗、卡非佐米和地塞米松[D-Kd]和达雷妥尤单抗、卡非佐米、来那度胺和地塞米松[D-KRd]）中，研究了将首次 16mg/kg 输注分为两个 8mg/kg 单独输注的可行性。此外，还进行了群体药代动力学（PK）分析和模拟，以比较在先前批准的适应症中，首次剂量分割方案与达雷妥尤单抗推荐的单次首次剂量方案的 PK 特征。
结果
在 MMY1001 中，在第一个周期的第 2 天接受了第一次剂量的第二次半量输注后，第二次剂量后中位数（范围）达雷妥尤单抗浓度在首次剂量分割组[D-Kd，254.9（125.8-435.5）μg/ml；D-KRd，277.2（164.0-341.8）μg/ml；合并，256.8（125.8-435.5）μg/ml]和单次首次剂量[D-Kd，319.2（237.5-394.7）μg/ml]之间相似。在每周给药结束时，第三个周期的第 1 天的中位（范围）周期 3 天前输注达雷妥尤单抗浓度在首次剂量分割组[D-Kd，663.9（57.7-1110.7）μg/ml；D-KRd，575.1（237.9-825.5）μg/ml；合并，639.2（57.7-1110.7）μg/ml]和单次首次剂量[D-Kd，463.2（355.9-792.9）μg/ml]之间相似。群体 PK 模拟显示，在所有批准的适应症和达雷妥尤单抗推荐的剂量方案中，在治疗的第一天后，PK 特征几乎相同。
结论
这些数据支持将静脉注射达雷妥尤单抗的替代首次剂量方案用于治疗多发性骨髓瘤。
试验注册
临床试验.gov 编号，NCT01998971。
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