Miller A A, Tolley E A, Niell H B
Department of Veteran Affairs Medical Center, University of Tennessee, Memphis 38163, USA.
Clin Cancer Res. 1998 Jul;4(7):1705-10.
The purpose of this study was to prospectively test a pharmacodynamic model for therapeutic drug monitoring of 21-day oral etoposide. In our previous studies, etoposide trough concentrations on this schedule were related to the hematological toxicity, expressed as WBC and neutrophil counts at the nadir. The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (ANCn) based on the etoposide concentration (Ec) and the pretreatment count (ANCp): ANCn=0.32(1 + ANCp x e(-2.47 x Ec)). Patients were treated with 40 mg/m2/day etoposide p.o. x 21 days and 100 mg/m2 cisplatin i.v. on day 1. All patients had non-small cell lung cancer stage IIIB or IV, had a performance status of 0-2, and had a median age of 66 (range, 42-80). Etoposide was measured in the plasma on day 8 by high-performance liquid chromatography, and dosage adjustments were made for the remainder of the course. We targeted for grade 3 neutropenia (ANCn, 500 to 999/microl) and attempted to avoid grade 4 neutropenia (ANCn, <500/microl). Of 25 patients entered, 22 were evaluable for therapeutic drug monitoring in the first course. Three patients developed grade 3 neutropenia, and seven patients developed grade 4 neutropenia. Etoposide concentrations were significantly correlated with ANCn in the first course (r=-0.50, P < 0.02). For those patients whose dosages were not changed, the estimated correlation between predicted and actual ANCn was 0.77 (P < 0.01). No evidence of significant bias of the pharmacodynamic model was detected. The etoposide dosages were increased in 12 patients and were not changed in the remaining patients. The precision of the model was good in patients whose dosages were not changed but poor in patients whose dosages were increased. The actual observed ANCn was compared with the predicted ANCn based on the pharmacodynamic model. The prediction was considered accurate if the predicted and actual ANCn values were within 500/microl of each other. Using this margin, the ANCn was accurately predicted in 10 of 22 patients. Etoposide concentrations >0.3 microg/ml on this schedule were significantly correlated with combined grades 3 and 4 neutropenia (P < 0.0001). In conclusion, the pharmacodynamic model is statistically sound when applied to a population of patients. However, when applied to individual patients for therapeutic drug monitoring, the model lacks precision and accuracy.
本研究的目的是前瞻性地验证一个用于21日口服依托泊苷治疗药物监测的药效学模型。在我们之前的研究中，按照此方案测得的依托泊苷谷浓度与血液学毒性相关，血液学毒性以最低点时的白细胞计数和中性粒细胞计数表示。以下药效学模型根据依托泊苷浓度（Ec）和预处理计数（ANCp）估算最低点时的绝对中性粒细胞计数（ANCn）：ANCn = 0.32(1 + ANCp × e(-2.47 × Ec))。患者接受40 mg/m²/天口服依托泊苷×21天治疗，并于第1天静脉注射100 mg/m²顺铂。所有患者均为ⅢB期或Ⅳ期非小细胞肺癌，体能状态为0 - 2，中位年龄为66岁（范围42 - 80岁）。在第8天通过高效液相色谱法测定血浆中的依托泊苷，并对疗程剩余时间进行剂量调整。我们将目标设定为3级中性粒细胞减少（ANCn，500至999/μl），并试图避免4级中性粒细胞减少（ANCn，<500/μl）。入组的25例患者中，22例可在第一个疗程进行治疗药物监测。3例患者发生3级中性粒细胞减少，7例患者发生4级中性粒细胞减少。在第一个疗程中，依托泊苷浓度与ANCn显著相关（r = -0.50，P < 0.02）。对于那些剂量未改变的患者，预测的ANCn与实际ANCn之间的估计相关性为0.77（P < 0.01）。未检测到药效学模型存在显著偏差的证据。12例患者的依托泊苷剂量增加，其余患者剂量未改变。该模型在剂量未改变的患者中精度良好，但在剂量增加的患者中精度较差。将实际观察到的ANCn与基于药效学模型预测的ANCn进行比较。如果预测的ANCn值与实际ANCn值相差在500/μl以内，则认为预测准确。按照这个界限，22例患者中有10例的ANCn得到了准确预测。在此方案下，依托泊苷浓度>0.3 μg/ml与3级和4级中性粒细胞减少合并症显著相关（P < 0.0001）。总之，该药效学模型应用于患者群体时在统计学上是合理的。然而，当应用于个体患者进行治疗药物监测时，该模型缺乏精度和准确性。
