Merck & Co., Inc., Kenilworth, New Jersey, USA.
Cognigen, a Simulations Plus Company, Buffalo, New York, USA.
AAPS J. 2022 Apr 6;24(3):53. doi: 10.1208/s12248-022-00682-5.
In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.
在两项评估 verubecestat 用于阿尔茨海默病的 3 期临床试验（EPOCH [NCT01739348]和 APECS [NCT01953601]）中，纳入了门诊静脉血干血斑（DBS）药代动力学（PK）采样，作为替代血浆 PK 采样的潜在方法。最初，同时采集血浆和 DBS PK 样本，以更好地了解 DBS-血浆 verubecestat 浓度关系，计划在中期分析后停止 DBS 或血浆采样。初步分析并根据预设选择标准比较结果后，停止了血浆 PK 采样；但是，随后发现（与 DBS 样本处理不遵守相关）存在导致 DBS 中 verubecestat 浓度普遍较低且采集到检测时间较长的稳定性问题，随后重新引入了血浆采样。为了能够将 DBS 数据纳入群体 PK 分析中，使用 EPOCH 研究中配对（时间匹配）的血浆和 DBS 数据开发了一种计算血浆等效浓度（考虑到 DBS 样本不稳定性）的转换算法。使用来自 1 期/1b 期和 EPOCH 数据的汇总数据，通过（1）仅血浆数据或（2）血浆和血浆等效浓度（根据非配对 DBS 样本计算）开发的 verubecestat 群体 PK 模型产生了相似的结果。使用 APECS 研究中的配对样本的 DBS 数据和血浆与血浆等效浓度之间的比较，验证了算法的稳健性。使用 APECS 数据（如果没有血浆样本，则为血浆等效物）更新了群体 PK 模型。结果表明，两个 3 期人群的 PK 相似，暴露量与 1 期数据的预期一致。本案例研究说明了在大型全球试验中采用新采样技术所面临的挑战，并描述了所获得的经验教训。
