Dashboards for Therapeutic Monoclonal Antibodies: Learning and Confirming
Dashboards for Therapeutic Monoclonal Antibodies: Learning and Confirming
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DOI：
10.1208/s12248-018-0237-2
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发表时间：
2018-07-01
期刊：
影响因子：
4.5
通讯作者：
Dubinsky, Marla C.
中科院分区：
文献类型：
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作者：
Mould, Diane R.;Upton, Richard N.;Dubinsky, Marla C.
炎症性疾病（ID）是无法治愈的进行性疾病。文献证据表明，这些疾病的发病率在全球范围内不断增加。当用化学免疫抑制剂治疗失败时，患者通常用单克隆抗体（MAb）治疗。然而，单克隆抗体的失败率通常很高，大约一半的患者在4年内停药，需要改用另一种单克隆抗体。治疗失败的一个潜在原因是亚治疗暴露。几项研究证明了谷MAb浓度与临床应答之间的相关性，支持了改善药物暴露可能导致结局改善的观点。单克隆抗体在ID患者中表现出复杂且高度可变的药代动力学，影响清除率的因素众多。仪表板系统的贝叶斯指导给药是一种正在研究的治疗ID以减少暴露变异性的新工具。模拟表明，仪表板将有效地将患者维持在目标低谷。然而，当患者使用处方信息中列出的剂量或间隔以外的剂量或间隔给药时，人们担心患者的药物暴露可能超出或低于安全有效的范围。本手稿回顾了仪表板开发的基本原理、预期性能评价以及基于仪表板给药与基于处方信息给药的MAb暴露模拟评估。我们引入了药理学等效性的概念-如果患者根据个体药代动力学给药，则所得暴露量与使用标示剂量获得的暴露量一致。我们进一步表明，基于仪表板的给药导致观察到的暴露量通常包含在标记给药所达到的暴露量范围内。
Inflammatory diseases (ID) are incurable, progressive diseases. Literature evidence cites increasing incidence of these diseases worldwide. When treatments with chemical immunosuppressive agents fail, patients are often treated with monoclonal antibodies (MAbs). However, MAb failure rates are generally high, with approximately half the patients being discontinued within 4 years, necessitating switching to another MAb. One potential cause of treatment failure is subtherapeutic exposure. Several studies demonstrated associations between trough MAb concentrations and clinical response, supporting the notion that improving drug exposure may result in improved outcomes. MAbs exhibit complex and highly variable pharmacokinetics in ID patients with numerous factors affecting clearance. Bayesian-guided dosing with dashboard systems is a new tool being investigated in the treatment of ID to reduce variability in exposure. Simulations suggest dashboards will be effective at maintaining patients at target troughs. However, when patients are dosed using doses or intervals outside those listed in prescribing information, there is concern that patients may have drug exposures beyond or below the ranges found to be safe and efficacious. This manuscript reviews the rationale behind dashboard development, evaluations of expected performance, and a simulated assessment of MAb exposure with dashboard-based dosing versus dosing based on the prescribing information. We introduce the concept of pharmacologic equivalence-if patients are dosed based on individual pharmacokinetics, the resulting exposure is consistent with exposures achieved using labeled dosing. We further show that dashboard-based dosing results in observed exposures that are generally contained within the range of exposures achieved with labeled dosing.