Merkel Ute, Wedding Ulrich, Roskos Martin, Höffken Klaus, Hoffmann Annemarie
Department of Clinical Pharmacology, Friedrich Schiller University, Jena, Germany.
Exp Toxicol Pathol. 2003 Jun;54(5-6):475-9. doi: 10.1078/0940-2993-00283.
Several clinical trials have demonstrated that the three-drug combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) administered chronomodulated improved antitumour efficacy in the treatment of metastatic colorectal cancer and was better tolerated than constant-rate infusion. However, only a few pharmacokinetic data of 5-FU during chronomodulated infusion are available but up to now not for oxaliplatin. In this pilot study, the platinum levels of plasma ultrafiltrate (PUF) and total plasma were monitored during chronomodulated infusion of oxaliplatin, 5-FU and LV in 7 patients with metastatic gastrointestinal cancer. A cycle of the 4-day chemotherapeutic regimen consisted of 12-h infusions with sinusoidal drug delivery rate of: oxaliplatin (25 mg/m2/d, peak at 16:00 hours), 5-FU and LV (750 mg/m2/d and 150 mg/m2/d, respectively, peak at 4:00 hours), the same scheme was reinitiated on day 15. Blood samples were collected on day 1 and day 4 during different cycles. Concentration-time profiles of ultrafilterable and total platinum in plasma during chronomodulated infusion were characterised. As expected, we found residual platinum levels in total plasma but not in PUF prior next cycle. Comparing day 1 with day 4, Cmax of platinum in PUF was significantly increased (84 +/- 13 ng/ml vs. 131 +/- 22 ng/ml, P = 0.012) as well as AUC0-24h of platinum in PUF (0.97 +/- 0.29 microg x h/ml vs. 1.90 +/- 0.44 microg x h/ml, P = 0.018). The same effect was observed for total plasma platinum suggesting an accumulation within the cycle. The observed interindividual variability of Cmax, tmax, AUC0-24h, t1/2 was moderate. Because of the small sample size in this pilot investigation, the findings need to be confirmed in larger pharmacokinetic studies. In a next step individual pharmacokinetic parameters should be associated with patient specific parameters and treatment-induced toxicity.
多项临床试验表明，奥沙利铂、5-氟尿嘧啶（5-FU）和亚叶酸钙（LV）三药联合进行时辰调节给药，可提高转移性结直肠癌的抗肿瘤疗效，且耐受性优于恒速输注。然而，关于5-FU在时辰调节输注期间的药代动力学数据较少，而奥沙利铂的此类数据至今尚未见报道。在这项前瞻性研究中，对7例转移性胃肠道癌患者在奥沙利铂、5-FU和LV时辰调节输注期间的血浆超滤液（PUF）和总血浆中的铂水平进行了监测。为期4天的化疗方案的一个周期包括12小时输注，药物输送速率呈正弦曲线变化：奥沙利铂（25mg/m²/d，16:00达到峰值），5-FU和LV（分别为750mg/m²/d和150mg/m²/d，4:00达到峰值），在第15天重新开始相同方案。在不同周期的第1天和第4天采集血样。对时辰调节输注期间血浆中可超滤铂和总铂的浓度-时间曲线进行了表征。正如预期的那样，我们发现在下一个周期之前，总血浆中有残留铂水平，但PUF中没有。比较第1天和第4天，PUF中铂的Cmax显著增加（84±13ng/ml对131±22ng/ml，P = 0.012），PUF中铂的AUC0-24h也显著增加（0.97±0.29μg·h/ml对1.90±0.44μg·h/ml，P = 0.018）。总血浆铂也观察到相同的效应，表明在周期内有蓄积。观察到的Cmax、tmax、AUC0-24h、t1/2的个体间变异性为中等。由于这项前瞻性研究的样本量较小，这些发现需要在更大规模的药代动力学研究中得到证实。下一步，应将个体药代动力学参数与患者特定参数以及治疗引起的毒性联系起来。
