Morgan D J, Hill J S, Clarke K, Stylli S S, Park S J, Cebon J, Basser R L, Kaye A H, Geldard H, Maher D W, Green M D
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Melbourne, Australia.
Cancer Chemother Pharmacol. 1998;41(5):423-6. doi: 10.1007/s002800050761.
To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2.
A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50-80 mg/m2 (74-152 mg) with concomitant filgrastim (G-CSF, 5 microg/kg) given daily beginning at 24 h after the dose of MX2.
The mean fast distribution half-life (1.5 +/- 1.0 min) and the mean plasma clearance (2.18 +/- 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8-107.5 mg) alone (3.3 +/- 2.2 min and 2.98 +/- 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 +/- 14.7 and 11.8 +/- 5.0 h for M1 and 14.8 +/- 4.1 and 12.3 +/- 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2-filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2.
This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.
研究粒细胞集落刺激因子（G-CSF）对新型吗啉代蒽环类药物MX2药代动力学和药效学的影响。
25例晚期恶性疾病患者参与了剂量递增研究，在治疗的第一个周期静脉注射，剂量为50-80mg/m²（74-152mg），同时从MX2给药后24小时开始每天给予非格司亭（G-CSF，5μg/kg）。
平均快速分布半衰期（1.5±1.0分钟）和平均血浆清除率（2.18±0.95升/分钟）显著低于先前一项研究中的相应平均值，在该研究中27例患者单独接受MX2（16.8-107.5mg）（分别为3.3±2.2分钟和2.98±1.68升/分钟；P<0.05）。单独使用MX2组和MX2-非格司亭联合组的血浆清除率与给药剂量之间均无相关性，这表明在G-CSF组中观察到的较低清除率可能不是由于较高剂量所致。非格司亭组中代谢物M1和M4的消除半衰期显著更长（M1分别为19.8±14.7和11.8±5.0小时，M2分别为14.8±4.1和12.3±6.3小时）。与单独使用MX2组不同，MX2-非格司亭组中相对最低点中性粒细胞计数与剂量之间或IV级中性粒细胞减少持续时间与MX2剂量之间均无关联。
本研究表明，非格司亭使MX2的血浆清除率降低了约25%，可能是通过抑制代谢实现的。
