PHASE-I CLINICAL-TRIAL AND PHARMACOKINETIC EVALUATION OF DOXORUBICIN CARRIED BY POLYISOHEXYLCYANOACRYLATE NANOPARTICLES
PHASE-I CLINICAL-TRIAL AND PHARMACOKINETIC EVALUATION OF DOXORUBICIN CARRIED BY POLYISOHEXYLCYANOACRYLATE NANOPARTICLES
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DOI：
10.1007/bf00877245
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发表时间：
1992-08-01
影响因子：
3.4
通讯作者：
SANCHOGARNIER, H
中科院分区：
文献类型：
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作者：
KATTAN, J;DROZ, JP;SANCHOGARNIER, H
临床前研究表明，将多柔比星（DXR）掺入可生物降解的丙烯酸酯纳米颗粒（如聚异己基氰基丙烯酸酯（PIHCA））中可以通过改变组织分布来增加DXR的细胞毒性并降低心脏毒性。我们对21例难治性实体瘤患者进行了DXR-PIHCA的I期临床试验（男性10例，女性11例，中位年龄：53岁，中位PS: 1，既往无dxr治疗：7例）。共32个疗程，间隔28天，以6个剂量水平（15、30、45、60、75和90mg /m2）给药。首批5名患者于第1天静脉输注该药10分钟：其中2名患者在输注期间出现2级过敏反应（世卫组织标准），一旦停止给药，这种反应可迅速逆转。随后，在其他16例患者中，将给药改为静脉灌注250毫升葡萄糖5%稀释60分钟，只有1例患者出现相同的过敏反应。治疗后24 h， 9例患者出现2级发热和呕吐，7例患者出现2级发热和呕吐。18例可评估患者无心脏毒性。3级或4级血液毒性发生在75和90mg /M2剂量水平。剂量限制性毒性为中性粒细胞减少。最大耐受剂量为90mg /M2，推荐的II期剂量为75mg /M2。对3例不同剂量（60mg /M2、60mg /M2、75mg /M2）患者进行DXR- pihca的药代动力学评价，并与相同条件下给予相同患者的自由DXR进行比较。
Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 Mg/M2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/M2 and the recommended phase II dose was 75 mg/M2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60,60 and 75 Mg/M2) and was compared with free DXR given to the same patients in the same conditions.