Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.

译文

吡咯酮(PRX,NSC 349174)是新型插层剂中的第一类,蒽吡唑类经过临床评估。此外,这是第一个前瞻性测试针对抗癌化合物的I期临床试验提出的基于新药理学的剂量递增方案的药物试验。在该I期试验中,PRX每3周输注1小时给晚期癌症患者。四十四名可评估的患者接受了116个疗程,剂量范围为7.5至190 mg / m2。剂量限制性毒性为以白细胞减少为主的骨髓抑制。非血液学毒性最小,包括恶心和呕吐,脱发,粘膜炎和静脉炎。根据该试验,按此时间表施用的PRX的最大II期耐受剂量和推荐剂量分别为190 mg / m2和150 mg / m2。通过两室模型,对于接受大于或等于90 mg / m2的患者中的17名,PRX血浆清除速度很快且最合适。血浆清除率是1290 /-484 ml / min(720 /-210 ml / min / m2),并且不随剂量而变化。 t1 / 2 alpha为2.9 /-5.3(SD)分钟,t1 / 2 beta为18.7 /-36.5分钟。在最大耐受剂量(MTD)下,浓度-时间曲线下的面积(AUC)为435摩尔/分钟/升,比临床前测试中预测的AUC高40%。 WBC和中性粒细胞计数的百分比降低与AUC相关。在这项研究中,基于药理学的剂量递增的潜在优势受到测定法的不敏感性,极快的血浆消除以及起始剂量与达到目标AUC并开始标准剂量递增的剂量的接近程度的限制。因此,定义最大耐受剂量所需的剂量递增次数没有减少。但是,已经建立了该方法的实践方面,建议将其用于可进行详细临床前药理学研究的进一步试验。

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