Phase I trial of chloroguinoxaline sulfonamide, with correlation of its pharmacokinetics and pharmacodynamics.
Phase I trial of chloroguinoxaline sulfonamide, with correlation of its pharmacokinetics and pharmacodynamics.
复制标题
氯喹喔啉磺酰胺的 I 期试验及其药代动力学和药效学的相关性。
DOI：
10.1007/bf00685641
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发表时间：
1995
影响因子：
3
通讯作者：
VanEcho,DA
中科院分区：
文献类型：
--
作者：
Conley,BA;O'Hara,S;Wu,S;Melink,TJ;Parnes,H;Pardoe,E;Egorin,MJ;VanEcho,DA
为了确定最大耐受量，对没有有效标准治疗的癌症患者，每28天给予氯喹恶啉磺胺(CQS)1小时输注。每个队列中至少有三名患者增加了剂量。在首次输注期间和之后，以及在可能的情况下，如果剂量减少，在随后输注CQS期间和之后，获得用于表征游离和总CQS药代动力学的血浆。共评估了55名患者的101个疗程的CQS。剂量水平从18到3,700毫克/平方米不等。剂量限制性毒性是低血糖，最先发现的剂量是3,700毫克/平方米。当剂量限制低血糖被识别时，患者以连续较低的剂量进入，并对26名患者进行血糖和胰岛素浓度的密切监测。CQS停药后4h内出现1~3级低血糖，24 h后消失，CQS剂量大于1000 mg/m2时，26例患者合并5%回旋时出现症状性低血糖。对26例患者进行1-3级低血糖密切监测血糖和胰岛素浓度。CQS停药后4h内出现1~3级低血糖，24 h后消失。CQS剂量>1000 mg/m2时，症状性低血糖发生率更高。同时服用5%葡萄糖并不能改善CQS剂量为1,000 mg/m2的低血糖。在获得这些数据的12名患者中，总卡路里摄入量、理想体重百分比或体重减轻百分比不能解释低血糖的发生率或严重程度。7例服用≥1000 mg/m2的患者出现快速性心律失常，3例合并低血糖。其他毒性是零星的，但CQS剂量为1,000 mg/m2的≥的毒性频率更高。这些毒性包括发热、皮疹、头晕、白细胞减少、血小板减少、脱发、腹泻、恶心和呕吐。所有毒性反应都是可逆的。平均峰值血浆[CQS]和AUC随着剂量的增加而增加，提示峰值血浆[CQS]在较高剂量时趋于平稳。血浆[CQS]的下降符合三室开放线性模型。终末半衰期为28~206h，总清除量为44~881ml/h，未见饱和现象。母体化合物在24小时内的尿排出量平均为5%。未与血浆蛋白结合的CQS(游离CQS)占血浆总CQS的1%~17%，与剂量无关。定义了低血糖程度和CQS药代动力学参数之间的关系。血浆[葡萄糖]下降的百分比，即(服药前[葡萄糖]-谷氨酸[葡萄糖]/服药前[葡萄糖])×100，与游离和总峰值血浆[CQS]相关。关系用Hill方程描述：效应=(Emax)(峰值)H/(Peak50)H+(峰值)H，其中最大效应(Emax)等于血浆[血糖]下降的最大可能百分比等于100%，峰值50是峰值总[CQS]，在峰值总[CQS]达到半峰值(326 mg/L)，希尔常数是关系的Sigmoidality的量度(1.06)。该关系精确地拟合了数据，平均绝对误差(MAE)为10.42，无偏倚，平均误差(ME)为−0.06。CQS第二阶段的推荐剂量为1,000 mg/m2。因为服用CQS后的低血糖程度与峰值血浆[CQS]有关，重复剂量的≤1,000 mg/m2在…中可能是可以耐受的
To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m2. The dose-limiting toxicity was hypoglycemia, first recognized at the 3,700-mg/m2dose. When dose-limiting hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma glucose and insulin concentrations being done in 26 patients. grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m2Concomitant administration of 5% gyciosion being done in 26 patients. Grade 1–3 hypoglycemia close monitoring of plasma glucose and insulin concentrations being done in 26 patients. Grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m2. Concomitant administration of 5% glucose did not ameliorate the hypoglycemia associated with CQS doses of >1,000 mg/m2. The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of hypoglycemia in 12 patients in whom these data were obtained. Cardiac tachyarrhythmias occured in 7 patients who received CQS at doses of ≥1,000 mg/m2, and tachyarrhythmia was associated with hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of ≥1,000 mg/m2. These toxicities included fever, rash, lightheadedness, leukopenia, thrombocytopenia, alopecia, diarrhea, nausea, and vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged <5%. CQS not bound to plasma protein (free CQS) comprised 1%–17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [glucose], i.e., (predose [glucose]-nadir [glucose]/predose [glucose])×100, correlated with both free and total peak plasma [CQS]. The relationship was described by the Hill equation:Effect=(Emax) (peak)H/(peak50)H+(peak)H, where the maximal effect (Emax) equals the maximal possible percentage of decrease in plasma [glucose] equals 100%,peak50is the peak total [CQS] at whichEis half-maximal (326 mg/l), andHis the Hill constant, a measure of the sigmoidicity of the relationship (1.06). The relationship fit the data precisely with a mean absolute error (MAE) of 10.42 and was unbiased with a mean error (ME) of −0.06. The recommended phase II dose of CQS is 1,000 mg/m2. Because the magnitude of hypoglycemia after CQS administration is related to peak plasma [CQS], repetitive CQS doses of ≤1,000 mg/m2would probably be tolerated …