St. John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
St. John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Clin Transl Sci. 2020 Mar;13(2):400-409. doi: 10.1111/cts.12725. Epub 2020 Jan 29.
Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (E ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes.
针对炎症性疾病（如银屑病）的生物治疗反应存在差异，这在一定程度上是由药物暴露的差异所驱动。本研究利用真实世界的银屑病数据，开发了一线治疗性抗体乌司奴单抗的药代动力学/药效学（PK/PD）模型，并探讨了不同给药策略对疗效的影响。该研究数据来自英国前瞻性多中心观察队列（491 例接受乌司奴单抗单药治疗的患者，共采集了 797 份血清样本的药物水平和抗药物抗体检测值，以及 1590 次银屑病面积和严重程度指数（PASI）测量值）。采用线性单室模型描述乌司奴单抗的 PK 特征。最大效应（E）模型抑制了治疗过程中银屑病皮损进展的 PD 机制，描述了 PASI 的演变。半数有效浓度的混合模型确定了一个潜在的无应答者群体，模拟结果表明，未来该模型可纳入贝叶斯治疗药物监测“仪表盘”，以实现个体化给药并改善治疗结局。
