BACKGROUND

Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol.

METHODS

Eighty-eight patients received 400 mg/m²/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.

RESULTS

The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.

CONCLUSIONS

The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.

中文翻译：

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依托泊苷在高剂量方案（TI-CE）中用于晚期生殖细胞肿瘤的药代动力学和药代动力学研究。

背景

依托泊苷的剂量基于身体表面积。我们评估了TI-CE（紫杉醇，异环磷酰胺，卡铂和依托泊苷）方案中的高剂量（HD）依托泊苷是否需要进一步的剂量个体化。

方法

II期临床试验评估了卡铂治疗性药物监测（TDM）的II期试验，其中88名患者在3个周期内连续3天连续3天接受了1个小时的静脉输注依托泊苷400 mg / m ² /天。 CE HD协议。在NONMEM上使用群体PK模型分析了药代动力学（PK）数据，以量化个体间和个体内的变异性。评估了依托泊苷暴露与药效学（PD）终点之间，选定的遗传多态性与肿瘤反应或毒性之间的关系。

结果

患者间，周期间和周期内清除率的差异分别为16％，9％和0.1％。尽管对治疗有反应的患者依托泊苷的暴露量有增加的趋势，但PK-PD关系并不显着。发现在第3周期暴露与中性粒细胞减少与延长之间存在显着相关性。UGT1A1* 28多态性与晚期中性粒细胞减少之间存在显着相关性，但需要进一步评估。

结论

本研究表明，无需先验剂量个体化或使用TDM进行剂量适应，即可在TI-CE方案中验证依托泊苷的体表面积剂量。