Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Clin Pharmacokinet. 2023 Jun;62(6):789-806. doi: 10.1007/s40262-023-01240-8. Epub 2023 May 2.
Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6-9 weeks followed by a less frequent dosing regimen, once every 2-4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure-efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg of daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related reactions are frequently observed in patients given daratumumab, particularly with the first infusion, thus prompting long durations of infusion (~ 7 h) and splitting of the first dose across 2 days. This led to the development of a subcutaneous delivery formulation for daratumumab (Dara-SC). Dara-SC provides a similar efficacy and safety profile to intravenous daratumumab (Dara-IV) but has a much lower rate of infusion-related reactions and a shorter infusion time. Exposure-response relationships for efficacy and safety endpoints were similar between Dara-SC and Dara-IV, and co-administered drugs with either Dara-IV or Dara-SC do not significantly affect daratumumab PK. Except for baseline myeloma type and albumin level, none of the other investigated disease and patient characteristics (renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group performance status) was identified to have clinically relevant effects on exposure to daratumumab monotherapy or combination therapy regimens. Dara-IV exposure was significantly lower in patients with immunoglobulin G myeloma compared with patients with non-immunoglobulin G myeloma (p < 0.0001) and in patients with a lower albumin level, whereas the overall response rate was similar regardless of the myeloma type and albumin level. Daratumumab dose adjustment is not currently recommended based on disease and patient characteristics.
达雷妥尤单抗是一种完全人源化的单克隆 IgG1 抗体，也是首个获批的靶向 CD38 的药物，用于治疗复发/难治性多发性骨髓瘤或新诊断的轻链淀粉样变性患者。CD38 在恶性骨髓瘤细胞中高度表达，达雷妥尤单抗通过免疫介导机制、直接诱导凋亡和免疫调节发挥抗骨髓瘤作用。达雷妥尤单抗可作为单药或与骨髓瘤标准治疗联合使用，包括蛋白酶体抑制剂、免疫调节剂、DNA 烷化剂和皮质类固醇。静脉输注后，达雷妥尤单抗表现出非线性药代动力学（PK），因为随着剂量的增加和时间的推移，由于靶向介导的作用，清除率降低。剂量方案因适应证和联合用药而异，但一般情况下，达雷妥尤单抗每周给药 6-9 周，然后每 2-4 周进行一次频率较低的给药方案。达雷妥尤单抗的暴露量与疗效密切相关，暴露-疗效关系呈最大效应模型，而暴露量与安全性终点无关。在大多数患者中，每周剂量结束时，达雷妥尤单抗 16mg/kg 的批准剂量可使 99%的靶标饱和，并且在较频繁的剂量方案期间，靶标保持高饱和度。接受达雷妥尤单抗治疗的患者常出现输注相关反应，特别是首次输注时，因此需要延长输注时间（~7h）并将首剂量分为 2 天输注。这导致了达雷妥尤单抗的皮下给药制剂（Dara-SC）的开发。Dara-SC 与静脉注射达雷妥尤单抗（Dara-IV）具有相似的疗效和安全性，但输注相关反应发生率更低，输注时间更短。Dara-SC 和 Dara-IV 的疗效和安全性终点的暴露-反应关系相似，联合使用 Dara-IV 或 Dara-SC 的药物不会显著影响达雷妥尤单抗的 PK。除了基线骨髓瘤类型和白蛋白水平外，其他研究的疾病和患者特征（肾功能/肝功能、年龄、性别、种族、体重、东部肿瘤协作组体能状态）均未被确定对达雷妥尤单抗单药或联合治疗方案的暴露量有临床相关影响。与非免疫球蛋白 G 骨髓瘤患者相比，免疫球蛋白 G 骨髓瘤患者的达雷妥尤单抗暴露量显著降低（p<0.0001），且白蛋白水平较低的患者的达雷妥尤单抗暴露量也较低，而无论骨髓瘤类型和白蛋白水平如何，总体缓解率相似。目前不建议根据疾病和患者特征调整达雷妥尤单抗的剂量。
