Evaluation of dosing strategy for pembrolizumab for oncology indications
Evaluation of dosing strategy for pembrolizumab for oncology indications
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DOI：
10.1186/s40425-017-0242-5
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发表时间：
2017-05-16
影响因子：
10.9
通讯作者：
Stone, Julie A.
中科院分区：
文献类型：
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作者：
Freshwater, Tomoko;Kondic, Anna;Stone, Julie A.
背景资料：传统上，大多数单克隆抗体（mAb）的给药基于体重，因为身体大小在药代动力学变异性中的作用。在最初的帕博利珠单抗研究中使用了相同的方法;然而，在获得PK数据后，重新评估了帕博利珠单抗基于体重给药的必要性。既往建立的群体PK（popPK）模型以及晚期黑色素瘤或非小细胞肺癌（NSCLC）患者的疗效-缓解结果用于评价固定给药方案的潜在应用，目的是将帕博利珠单抗暴露量维持在证明可提供接近最大疗效和可接受安全性的范围内。使用最近完成的头颈癌、NSCLC、结直肠癌（CRC）和尿路上皮癌中微卫星不稳定性高（MSI-H）试验中选定的固定给药方案的个体PK暴露量来确认可接受性。为了确定固定剂量是否会将暴露量维持在临床经验范围内，将固定剂量的个体AUC分布与早期研究中评价的帕博利珠单抗剂量的暴露量范围进行比较（2 mg/kg Q3W，10 mg/kg Q3W/Q2W）。清除率的体重依赖性特征为幂关系，指数为0.578，该值与固定剂量和基于体重的剂量一致，可提供相似的PK变异性控制。在试验中，基于所有患者的预测暴露量维持在既定暴露量范围内，研究了200 mg Q3 W的固定剂量。在接受200 mg、2 mg/kg和10 mg/kg Q3 W派姆单抗治疗的患者中，平均（% CV，n）AUC（ss，）（6周）为1.87（37%，830）、1.38（38%，760）和7.63（35%，1405）mg* 天/mL。高体重患者有最低的暴露与200毫克Q3 W，然而，在这组（> 90公斤）的暴露范围内的先前临床经验在2毫克/公斤Q3 W与接近最大effictiveness.Conclusions：剂量200毫克和2毫克/公斤提供类似的暴露分布没有优势，任何剂量的方法控制PK变异性。这些结果表明，基于体重和固定剂量方案适用于帕博利珠单抗。
Background: Traditionally, most monoclonal antibodies (mAbs) have been dosed based on body weight because of perceived contribution of body size in pharmacokinetic variability. The same approach was used in the initial pembrolizumab studies; however, following availability of PK data, the need for weight-based dosing for pembrolizumab was reassessed.Methods: A previously established population PK (popPK) model as well as exposure-response results from patients with advanced melanoma or non-small cell lung cancer (NSCLC) were used to evaluate the potential application of a fixed dosing regimen with the aim of maintaining pembrolizumab exposures within the range demonstrated to provide near maximal efficacy and acceptable safety. Individual PK exposures for the selected fixed dosing regimen from recently completed trials with head and neck cancer, NSCLC, microsatellite instability high (MSI-H) in colorectal cancer (CRC) and urothelial cancer were used to confirm acceptability. To determine whether fixed dosing would maintain exposures within the range of clinical experience, the individual AUC distributions with fixed dosing were compared with the range of exposures from the pembrolizumab doses that were evaluated in early studies (2 mg/kg Q3W, 10 mg/kg Q3W/Q2W).Results: Body-weight dependence of clearance was characterized by a power relationship with an exponent of 0.578, a value consistent with fixed-and weight-based dosing providing similar control of PK variability. A fixed dose of 200 mg Q3W was investigated in trials based on predicted exposures maintained within the established exposure range in all patients. Mean (% CV, n) AUC(ss,) (6-weeks) was 1.87 (37%, 830), 1.38 (38%, 760) and 7.63 (35%, 1405) mg*day/mL in patients receiving 200 mg, 2 mg/kg and 10 mg/kg Q3W pembrolizumab. High-weight patients had the lowest exposures with 200 mg Q3W; however, exposures in this group (> 90 kg) were within the range of prior clinical experience at 2 mg/kg Q3W associated with near maximal efficacy.Conclusions: Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no advantage to either dosing approach with respect to controlling PK variability. These findings suggest that weight-based and fixed-dose regimens are appropriate for pembrolizumab.