Graf N, Winkler K, Betlemovic M, Fuchs N, Bode U
Universitätsklinik für Kinder- und Jugendmedizin, Homburg/Saar, Germany.
J Clin Oncol. 1994 Jul;12(7):1443-51. doi: 10.1200/JCO.1994.12.7.1443.
The influence of methotrexate (MTX) pharmacokinetic parameters on the efficacy of high-dose MTX (HDMTX) in osteosarcoma was analyzed.
MTX serum peak values from 198 patients in 1,703 treatment courses and more detailed pharmacokinetic data from 185 patients in 1,045 treatment courses from the Cooperative Osteosarcoma Study Group (COSS) studies COSS-80, COSS-82, and COSS-86 were investigated.
A mean threshold peak level of > or = 1,000 mumol/L for the repeated MTX courses of individual patients was found to correlate significantly to prognosis in study COSS-80 (18% v 64% actuarial 10-year disease-free survival [DFS], P = .0001). Six courses of HDMTX per patient who achieved peak values > or = 1,000 mumol/L were found to be sufficient for a full effect to be seen in DFS in COSS-80. The MTX peak level was found to correlate closely to the area under the curve (AUC). However, AUC was a less powerful determinator of prognosis than the mean threshold MTX peak value. In patients who received cisplatin (DDP) as one of the additional drugs to MTX, the peak values and AUC were significantly increased (1,396 v 1,276 mumol/L, P = .011; 6,684 v 5,820 h.mumol/L, P < or = .002) and only a few patients (6%) did not achieve mean threshold MTX peak values. In addition, following restriction of hydration fluid after the MTX infusion from 4.5 to 3.0 L/m2 per 24 hours, the early MTX half-life (t1/2) and the AUC, but not the MTX peak value, were significantly increased (3.4 v 3.05 hours, and 6,760 v 5,998 h.mumol/L, respectively, P < or = .002).
MTX pharmacokinetics significantly influence the efficacy of MTX in osteosarcoma. Individual adaptation of the MTX dose to ensure a threshold peak serum level > or = 1,000 mumol/L does not seem necessary at a fixed dose of 12 g MTX/m2, restriction of hydration fluid to 3 L/m2 per 24 hours, and concomitant use of DDP within the drug regimen.
分析甲氨蝶呤（MTX）药代动力学参数对骨肉瘤大剂量MTX（HDMTX）疗效的影响。
对骨肉瘤协作研究组（COSS）的COSS - 80、COSS - 82和COSS - 86研究中198例患者1703个疗程的MTX血清峰值以及185例患者1045个疗程更详细的药代动力学数据进行了研究。
在COSS - 80研究中发现，个体患者重复MTX疗程的平均阈值峰值水平≥1000μmol/L与预后显著相关（10年无病生存率[DFS]精算值分别为18%和64%，P = 0.0001）。在COSS - 80研究中，每位达到峰值水平≥1000μmol/L的患者接受六个疗程的HDMTX足以在DFS中看到充分疗效。发现MTX峰值水平与曲线下面积（AUC）密切相关。然而，AUC对预后的决定作用不如平均阈值MTX峰值强大。在接受顺铂（DDP）作为MTX附加药物之一的患者中，峰值和AUC显著升高（分别为1396 vs 1276μmol/L，P = 0.011；6684 vs 5820 h·μmol/L，P≤0.002），只有少数患者（6%）未达到平均阈值MTX峰值。此外，在MTX输注后将水化液量从每24小时4.5 L/m²限制为3.0 L/m²后，早期MTX半衰期（t1/2）和AUC显著增加，但MTX峰值未增加（分别为3.4 vs 3.05小时，以及6760 vs 5998 h·μmol/L，P≤0.002）。
MTX药代动力学显著影响MTX在骨肉瘤中的疗效。在MTX剂量固定为12 g/m²、将水化液量限制为每24小时3 L/m²并在药物方案中同时使用DDP的情况下，似乎无需根据个体情况调整MTX剂量以确保血清峰值水平≥1000μmol/L。
