Department of Pharmacy and Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiang Su, China.
Cancer Chemother Pharmacol. 2013 Nov;72(5):1111-23. doi: 10.1007/s00280-013-2288-5. Epub 2013 Sep 24.
The aim of this study was to describe the nonlinear pharmacokinetics of total and unbound plasma cisplatin under different administered time in patients with non-small-cell lung carcinoma.
Patients receiving chemotherapy with cisplatin were included in this analysis. Patients were divided into two groups depending on the administrated time of cisplatin: 6:00 (Group A) and 18:00 (Group B). The population pharmacokinetics of cisplatin was calculated using nonlinear mixed-effects modeling (NONMEM) method, and the possible influence of covariates on the population pharmacokinetics of cisplatin was also explored.
The pharmacokinetics of total and unbound cisplatin could be described well by a linear two-compartment model. The mean population estimates for total and unbound drug were, respectively, 0.463 (17.0 %) and 25.4 (14.0 %) l h⁻¹ for clearance (CL), 24.2 (19.9 %) and 20.5 (27.1 %) l for central distribution volume (V₁), 10.2 (18.2 %) and 9.82 (28.1) l h⁻¹ for intercompartmental clearance (Q) and 32.0 (24.1 %) and 6.77 (25.4 %) l for peripheral compartment volume (V₂). The CL for total and unbound cisplatin was dependent on body surface area (BSA). When cisplatin was administered at 18:00, the CL was 1.38- and 1.22-fold higher than those administered at 6:00 for total and unbound cisplatin, respectively (P < 0.05). The mean parameter estimates from a nonparametric bootstrap procedure were comparable and within 5 % of the estimates from NONMEM.
The results showed that circadian could influence the metabolism of cisplatin and suggested the conventional dose adjustment of cisplatin based on BSA.
本研究旨在描述非小细胞肺癌患者在不同给药时间下总血浆和游离血浆顺铂的非线性药代动力学。
本分析纳入接受顺铂化疗的患者。患者根据顺铂给药时间分为两组：6:00（A 组）和 18:00（B 组）。采用非线性混合效应模型（NONMEM）法计算顺铂的群体药代动力学，并探讨了协变量对顺铂群体药代动力学的可能影响。
总血浆和游离顺铂的药代动力学可以用线性二室模型很好地描述。总药物和游离药物的群体平均估计值分别为：清除率（CL）0.463（17.0%）和 25.4（14.0%）l h⁻¹，中央分布容积（V₁）24.2（19.9%）和 20.5（27.1%）l，隔室间清除率（Q）10.2（18.2%）和 9.82（28.1）l h⁻¹，外周室容积（V₂）32.0（24.1%）和 6.77（25.4%）l。总血浆和游离顺铂的 CL 与体表面积（BSA）有关。当顺铂在 18:00 给药时，CL 分别比在 6:00 给药时总血浆和游离顺铂高 1.38 倍和 1.22 倍（P<0.05）。非参数自举程序的平均参数估计值与 NONMEM 的估计值相当，且在 5%以内。
结果表明，昼夜节律会影响顺铂的代谢，并提示基于 BSA 调整顺铂的常规剂量。
