Mick R, Gupta E, Vokes E E, Ratain M J
Department of Medicine, University of Chicago Pritzker School of Medicine, IL., USA.
J Clin Oncol. 1996 Jul;14(7):2012-9. doi: 10.1200/JCO.1996.14.7.2012.
To construct limited-sampling models (LSMs) for irinotecan (CPT-11) pharmacokinetic (PK) measures.
The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m2 with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. BI was the product of total CPT-11 area under the concentration-time curve (AUC) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m2, PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each time point, t, is denoted by CPT-11t. LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15).
LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R2 = .87, 0.75, and .98, respectively). AUCCPT-11 = 5.25 x CPT-11(3.0) + 20.60 x CPT-11(11.5) + 1,520.53; AUCSN-38 = 5.38 x SN-38(3.5) + 33.61 x SN-38(11.5) - 7.73; and AUCSN-38G = 10.73 x SN-38G9.5 + 20.66 x SN-38G11.5 + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11t x (SN-38t/SN-38Gt). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R2 = .63) or BI9.5 (R2 = .76), or BI5.5 paired with BI9.5 (R2 = .76). Predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P < or = .005).
These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback.
构建用于伊立替康（CPT-11）药代动力学（PK）测量的有限采样模型（LSM）。
推荐的每周一次CPT-11的II期剂量为145mg/m²，静脉输注90分钟，同时给予粒细胞集落刺激因子（G-CSF）并提供最大程度的止泻支持。腹泻是剂量限制性毒性反应。此前，我们已证明腹泻严重程度与胆汁指数（BI）（SN-38的估计胆汁暴露量）之间存在高度显著的相关性。BI是CPT-11浓度-时间曲线下总面积（AUC）与SN-38和SN-38葡萄糖醛酸苷（SN-38G）的相对面积比的乘积。在145mg/m²剂量下，有40例患者的PK数据可用；其中36例患者的肠道毒性也可进行评估。评估了输注开始后1.0至11.5小时内CPT-11、SN-38和SN-38G的总血浆浓度。每个时间点t的CPT-11浓度用CPT-11t表示。通过逐步线性回归在训练集（n = 25）上构建LSM，并在测试集（n = 15）上进行验证。
CPT-11、SN-38和SN-38G AUC的LSM对训练集显示出极佳的拟合度（R²分别为0.87、0.75和0.98）。AUCCPT-11 = 5.25×CPT-11(3.0) + 20.60×CPT-11(11.5) + 1520.53；AUCSN-38 = 5.38×SN-38(3.5) + 33.61×SN-38(11.5) - 7.73；AUCSN-38G = 10.73×SN-38G9.5 + 20.66×SN-38G11.5 + 142.69。每个时间点的BI（表示为BIt）计算为CPT-11t×(SN-38t/SN-38Gt)。由BI3.5与BI7.5（R² = 0.63）或BI9.5（R² = 0.76）配对，或BI5.5与BI9.5（R² = 0.76）配对定义了几个有前景的LSM。每个模型预测的BI（分为低、中或高）准确预测了观察到的肠道毒性等级（P≤0.005）。
这些LSM似乎能准确预测CPT-11的PK参数。值得注意的是，从几个LSM预测的BI能准确预测肠道毒性，因此可能对未来采用反馈式自适应控制的试验有用。
