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。
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.