Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer
Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer
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DOI：
10.1200/jco.1998.16.1.187
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发表时间：
1998-01-01
影响因子：
45.3
通讯作者：
Sheiner, LB
中科院分区：
文献类型：
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作者：
Bruno, R;Hille, D;Sheiner, LB
目的：将群体药代动力学/药效学 (PK/PD) 方法前瞻性地整合到多西他赛的临床开发中，以评估大量患者的 PK 概况，并调查全身暴露作为临床结果的预后因素。患者和方法：在 24 项多西他赛单药治疗 II 期研究中的第一个疗程中进行 PK 分析，使用四个随机有限抽样方案，贝叶斯估计 使用清除率（CL）、浓度-时间曲线下面积（AUC）以及血浆水平高于阈值水平的峰值和持续时间作为暴露量的测量。 PD数据包括乳腺癌和非小细胞肺癌(NSCLC)的疗效、缓解率、首次缓解时间和进展时间(TTP)，以及毒性、4级中性粒细胞减少症和第一个疗程的发热性中性粒细胞减少症和液体潴留发生时间，使用Logistic和Cox多元回归模型进行PK/PD分析。结果：PK方案实施成功。大多数注册患者（936 名患者中的 721 名，77%）均被抽样，其中 68% 可评估 PK（640 名患者），首疗程多西他赛 AUC 是 NSCLC (n = 151) 中 TTP 的显着预测因子 (P = .0232)，多西他赛 CL 是 4 级中性粒细胞减少症和发热的 ct 强独立预测因子 (P < .0001)中性粒细胞减少症（n = 582）。累积剂量是液体潴留发生时间的最强预测因子 (P < .0001) (n = 631)。然而，第一个疗程暴露时间超过 0.20 μmol/L (0.16 μg/mL) 是一个独立的预测因素 (P = .0029)。少数患者 (n = 25, 4%) 接受了推荐的地塞米松术前用药。结论：首疗程多西他赛 PK 是首疗程血液毒性的预测因子，也是液体潴留的预测因子，液体潴留本质上是累积性的。肝酶升高的患者多西紫杉醇 CL 降低 27%，并且毒性风险较高。目前正在该人群中评估 75 mg/m(2) 的起始剂量。大规模人群 PK/PD 评估的前瞻性实施在早期药物开发中是可行的，并且这种方法产生了临床相关的结果，(C) 1998 年，美国临床肿瘤学会。
Purpose: The population pkarmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome,Patients and Methods: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules, Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention, PK/PD analysis was conducted using logistic and Cox multivariate regression models,Results: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients), First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151), Docetaxel CL was ct strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However,the duration of exposure over 0.20 mu mol/L (0.16 mu g/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication.Conclusion: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity, A starting dose of 75 mg/m(2) is currently being evaluated in this population. prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings, (C) 1998 by American Society of Clinical Oncology.