分类： 医学、药学 >> 药学 提交时间： 2022-12-26
Chen-yu Wang
Di-hong Yang
Xiao-min Niu
Lu Han
Wen Wang
Roman Filimonov
Sajid Ali Shah
Xin-yang Weng
Zheng Jiao
摘要： 目的：在非小细胞肺癌患者中，免疫检查点抑制剂联合化疗方案比传统化疗方案为患者提供了更多获益。然而，依然有部分患者无法得到获益，存在着免疫耐受的现象。临床可测量的生物标志物是预测临床结果和优化剂量策略所必需的。本研究旨在通过定量系统药理学（QSP）研究可获得的生物标志物，这些生物标志物可以预测非小细胞肺癌患者的临床结果，并优化atezolizumab和nab紫杉醇联合治疗的给药策略。 方法：使用MATLAB中的SimBiology工具箱，基于已发表的三阴性乳腺癌QSP模型开发该模型。利用该模型，我们生成了一个虚拟患者队列以进行虚拟临床试验模拟，并使用来自真实临床试验（IMpower131）的数据进行模型校准和验证。 结果：最终QSP模型预测与临床报告的疗效终点一致。患者的肿瘤中基线CD8+和CD4+T细胞密度与临床获益显著相关。Roc分析进一步揭示了它们作为联合治疗方案的预测生物标志物的潜力。虚拟临床试验模拟显示，将nab紫杉醇剂量从100 mg/m2降至75 mg/m2将导致ORR降低，但依然高于atezolizumab单药治疗。三种atezolizumab给药策略联合nab紫杉醇显示出相似的疗效。 结论：本研究提供了一个QSP模型，可用于生成虚拟患者队列并进行虚拟临床试验。我们的研究结果证明了它在预测免疫疗法和化疗的疗效、识别预测性生物标志物以及指导未来临床试验设计方面的潜力。
分类： 医学、药学 >> 临床医学 提交时间： 2022-12-22
摘要： Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients. Methods: Monte Carlo simulations are based on all previous population pharmacokinetic models for pediatric, adult and elderly patients with epilepsy. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed. Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas Strategy C was recommended when the delayed dose was close to the next scheduled dose. Strategy D was only suggested for delayed two doses. Conclusion: Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen for each patient based on the individual's status.
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