Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations
Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations
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DOI：
10.1023/a:1006204901140
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发表时间：
1999-01-01
影响因子：
3.4
通讯作者：
Appelt, K
中科院分区：
文献类型：
--
作者：
Shalinsky, DR;Brekken, J;Appelt, K
口服AG 3340（一种新的金属蛋白酶（MMP）抑制剂）在体内抑制人结肠腺癌（科洛-320 DM）肿瘤的生长（Proc Am Asphalt Cancer Res 39：2059，1998）。在本报告中，我们检验了以下假设：这些肿瘤的生长抑制与维持AG 3340的最低有效血浆浓度相关。裸小鼠每日总经口给药剂量为25或200 mg/kg; 6.25 mg/kg每日给药4次（QID）（25 mg/kg/天），100 mg/kg每日给药2次（BID）（200 mg/kg/天）。单次给药6.25 mg/kg和100 mg/kg AG 3340后30分钟，检测到血浆峰浓度（C（max））分别为83 +/- 43（平均值+/- SD）和1998 +/- 642 ng/ml。以25和200 mg/kg/天AG 3340给药估计的AUC（（0-24 h））值分别为672和10882 ng*h/ml。重要的是，两种方案对肿瘤生长的抑制作用相当（74 - 82%）。还通过给予AG 3340（QID（每剂6.25 mg/kg）、BID（每剂12.5 mg/kg）和每日一次（每剂25 mg/kg）），在25 mg/kg的总日剂量下比较功效。这些方案的C（max）分别为83 +/- 43、287 +/- 175和462 +/- 495 ng/ml。AG 3340在后两种方案下不抑制肿瘤生长。6.25 mg/kg QID（25 mg/kg/天）的疗效上级优于25 mg/kg BID（50 mg/kg/天）的疗效，证实了疗效与每日总剂量和C（max）的独立性。预期QID方案的峰谷波动显著小于BID和QD给药。24小时后，QID给药的谷值大于1 ng/ml，但QD和BID给药后小于1 ng/ml。这些结果表明，AG 3340的抗肿瘤疗效与维持AG 3340的最低有效血浆浓度相关，并证明在该肿瘤模型中，AG 3340的抗肿瘤疗效与每日总剂量、血浆峰浓度和药物暴露量无关。
Oral administration of AG3340, a novel metalloprotease (MMP) inhibitor, suppresses the growth of human colon adenocarcinoma (COLO-320DM) tumors in vivo (Proc Am Assoc Cancer Res 39: 2059, 1998). In this report, we tested the hypothesis that the growth inhibition of these tumors is associated with maintaining minimum effective plasma concentrations of AG3340. Nude mice were given a total oral daily dose of 25 or 200 mg/kg; 6.25 mg/kg was given four times per day (QID) (25 mg/kg/day), and 100 mg/kg was given in two daily doses (BID) (200 mg/kg/day). Peak plasma concentrations (C(max)) of 83 +/- 43 (mean +/- SD) and 1998 +/- 642 ng/ml were detected 30 min after a single dose with 6.25 mg/kg and 100 mg/kg AG3340, respectively. AUC((0-24 h)) values estimated from dosing with 25 and 200 mg/kg/day AG3340 were 672 and 10882 ng*h/ml, respectively. Importantly, both regimen inhibited tumor growth equivalently (74 to 82%). Efficacy was also compared at a total daily dose of 25 mg/kg by giving AG3340: QID (6.25 mg/kg per dose), BID (12.5 mg/kg per dose), and once daily (25 mg/kg per dose). The C(max) of these regimens was 83 +/- 43, 287 +/- 175 and 462 +/- 495 ng/ml, respectively. AG3340 did not inhibit tumor growth with the latter two regimens. The efficacy of 6.25 mg/kg QID (25 mg/kg/day) was superior to the efficacy of 25 mg/kg BID (50 mg/kg/day), substantiating the independence of efficacy from the total daily dose and C(max). Expectedly, peak to trough fluctuations were significantly smaller with the QID regimen than with BID and QD dosing. After 24 h, the trough was greater than 1 ng/ml with QID dosing but was less than 1 ng/ml after QD and BID dosing. These results suggest that the antitumor efficacy of AG3340 was associated with maintaining minimum effective plasma concentrations of AG3340 and demonstrate that the antitumor efficacy of AG3340 was independent of the total daily dose, peak plasma concentration, and drug exposure in this tumor model.