Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker.
Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker.
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丙氯拉嗪 2-h i.v. 的 I 期和药代动力学研究
DOI：
10.1007/bf00685561
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发表时间：
1994
影响因子：
3
通讯作者：
Benedetto,PW
中科院分区：
文献类型：
--
作者：
Sridhar,KS;Krishan,A;Samy,TS;Duncan,RC;Sauerteig,A;McPhee,GV;Auguste,ME;Benedetto,PW
在早期的 I 期研究中，我们报道了丙氯拉嗪 (PCZ) 的最大耐受剂量 (MTD) 静脉注射 15 分钟。输注量为75 mg/m2。达到的最高峰值血浆 PCZ 浓度为 1100 ng/ml。本研究的目的是确定是否可以通过增加静脉注射持续时间在体外达到并维持体内足够高的 PCZ 水平以阻止阿霉素 (DOX) 外流。输注15分钟至2小时。治疗方案包括静脉注射。用至少 500 ml 生理盐水 (NS) 预水化，并静脉注射固定标准剂量 60 mg/m2DOX。 15 分钟内推注，然后静脉注射2 小时内在 250 ml NS 中剂量为 75、105、135 或 180 mg/m2PCZ。 DOX 引起的血液学毒性与预期一致，且与 PCZ 剂量无关。 PCZ 引起的毒性包括镇静、口干、焦虑、静坐不能、低血压、痉挛和精神错乱。 PCZ 的 MTD 为 180 mg/m2。 PCZ 血浆峰浓度 (91–3215 ng/ml) 存在较大的患者间差异，给予 135–180 mg/m2 PCZ 的患者血浆半衰期 (t1/2α) 约为 57 分钟。给予180 mg/m2PCZ的患者的分布容积(Vd)、总清除率(ClT)和曲线下面积(AUC)分别为350.1±183.8 l/m2、260.7±142.7 l m2h−1和1539±922 ng ml h−1，接受135 mg/m2的患者的相应值是48.9±23.76 l/m2、33.2±2.62 l m2h−1 和 4117±302 ng ml h−1。所有接受 135 mg/m2PCZ 治疗长达 24 小时的患者均维持高 PCZ 血浆水平（>600 ng/ml）。 DOX 血浆消除在 135 和 180 mg/m2PCZ 下呈双相，并且 >10 ng/ml DOX 血浆水平维持 24 小时。六名恶性间皮瘤患者中的三名、十名非小细胞肺癌患者中的两名以及一名肝癌患者中观察到部分缓解。我们的数据表明，PCZ 可以以 135 mg/m2 的剂量安全地进行 2 小时输注，且毒性在临床上是可控的。 DOX和PCZ组合的抗肿瘤活性需要在II期试验中得到证实。
In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m2. The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m2DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m2PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m2. Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2α) being approximately 57 min in patients given 135–180 mg/m2PCZ. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) were 350.1±183.8 l/m2, 260.7±142.7 l m2h−1and 1539±922 ng ml h−1, respectively, in patients given 180 mg/m2PCZ and the respective values for patients receiving 135 mg/m2were 48.9±23.76 l/m2, 33.2±2.62 l m2h−1, and 4117±302 ng ml h−1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m2PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m2PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m2with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.