Foster B J, Newell D R, Graham M A, Gumbrell L A, Jenns K E, Kaye S B, Calvert A H
Wayne State University School of Medicine, Division of Hematology and Oncology, Detroit, Michigan 48202-0188.
Eur J Cancer. 1992;28(2-3):463-9. doi: 10.1016/s0959-8049(05)80077-2.
The development of new drugs in early clinical trials is currently based upon the results of preclinical antitumour and toxicity studies in animals. More recently, the use of preclinical pharmacokinetic information in mice has been proposed to also provide information that might expedite early clinical trials and more specifically phase I studies. The anthrapyrazole CI-941 was one of three chosen for phase I anticancer drug development. In addition, because of the predictability of the preclinical dose limiting toxicity and linear CI-941 pharmacokinetics in mice; a pharmacokinetically guided dose escalation scheme was attempted during the phase I trial, but had to be abandoned. 44 patients were entered who received 95 courses of treatment using a bolus injection every 21 days. The dose range was 5-55 mg/m2. The dose limiting toxicity was leucopenia and other toxicities, which included nausea and vomiting, mucositis, diarrhoea, alopecia and skin discolouration were either mild or manageable. Pharmacokinetic studies were performed with 27 courses. There were wide interpatient variations in the dose-AUC relationship (r = 0.7496) that hampered application of the proposed pharmacokinetically guided dose escalation scheme as planned. No complete or partial responses were observed. The recommended phase II dose using this schedule is 50 mg/m2.
早期临床试验中新型药物的研发目前基于动物临床前抗肿瘤和毒性研究的结果。最近，有人提议利用小鼠临床前药代动力学信息来提供可能加快早期临床试验，尤其是I期研究的信息。蒽吡唑CI-941是被选用于I期抗癌药物研发的三种药物之一。此外，由于小鼠临床前剂量限制毒性和CI-941药代动力学的可预测性，在I期试验中尝试了药代动力学指导的剂量递增方案，但不得不放弃。44名患者入组，每21天接受一次大剂量注射，共接受95个疗程的治疗。剂量范围为5-55mg/m²。剂量限制毒性为白细胞减少，其他毒性包括恶心、呕吐、粘膜炎、腹泻、脱发和皮肤变色，均为轻度或可控制。对27个疗程进行了药代动力学研究。患者之间的剂量-AUC关系存在很大差异（r = 0.7496），这妨碍了按计划应用提议的药代动力学指导的剂量递增方案。未观察到完全或部分缓解。使用该方案推荐的II期剂量为50mg/m²。
