Mercier Cédric, Ciccolini Joseph, Pourroy Bertrand, Fanciullino Raphaelle, Duffaud Florence, Digue Laurence, Tranchand Brigitte, Monjanel-Mouterde Suzanne, Guillet Pierre, Nicoara Adriana, Baciuchka Marjorie, Bagarry-Liegey Danielle, Lacarelle Bruno, Noble Alex, Durand Alain, Favre Roger
Service d'oncologie médicale, C.H.U. Timone adultes, Marseille, France.
Ther Drug Monit. 2006 Apr;28(2):212-8. doi: 10.1097/01.ftd.0000198646.32128.ef.
Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60% higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.
卡铂（CBDCA）是一种广泛使用的抗癌药物，其剂量效应和剂量毒性关系已得到证实，因此强调了对该药物进行可控暴露的必要性。到目前为止，卡铂给药只能通过两种经典方法进行先验个体化，这两种方法基于肾清除率的评估：卡尔弗特公式和沙泰吕公式。本研究旨在开发和评估一种替代的卡铂120小时给药方案，并结合贝叶斯自适应给药和反馈策略。通过比较输注结束时观察到的卡铂血浆浓度与初始目标值，评估了84例患者（在10年期间进行了256个疗程）给药方法的准确性。还对治疗相关毒性进行了全面监测。最后，作者将剂量调整方法实际给予的剂量与使用卡尔弗特公式和沙泰吕公式回顾性计算的理论标准剂量进行了比较。实验浓度与理论浓度之间未发现显著差异。根据所选的目标暴露水平（3个水平），给予我们患者的平均卡铂剂量分别为517、719和902毫克，而按照卡尔弗特公式或沙泰吕公式分别给予的剂量为550、509和538毫克或657、604和644毫克。这些结果表明，与仅基于肾清除率评估的方法相比，我们的贝叶斯方法导致给予的卡铂剂量高出多达60%。尽管给予的剂量明显更高，但按照这个新方案治疗的患者中未报告严重毒性。值得注意的是，本研究中未使用通常与高剂量方案相关的血液学生长因子或干细胞作为支持。这些数据强烈表明，即使在未选择的老年患者中，也有可能在不增加毒性且无需生长因子支持的情况下给予更高剂量强度的卡铂，前提是实施实时定制给药的治疗药物监测策略。
