Miller A A, Schmidt C G
Cancer Res. 1987 Mar 1;47(5):1461-5.
The clinical pharmacology and toxicity of a novel anthracycline derivative, 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), was investigated in patients with advanced malignant diseases. The starting dose was 30 mg/m2 which was escalated by increments of 10 mg/m2. Twelve patients with a median age of 42 (range, 19-69) years and a median Eastern Cooperative Oncology Group performance score of 2 (range, 1-2) were entered into the study. The diagnoses included four testicular cancers, two breast cancers, two small cell lung cancers, two acute myeloid leukemias, one colon cancer, and one hemangiosarcoma. THP-adriamycin was given as an i.v. bolus injection every 3 weeks. Evaluable were 18 courses for general toxicity, 16 courses for hematological toxicity, and 16 courses for pharmacokinetics. THP-adriamycin had a short initial half-life of 1.4 +/- 0.3 min (mean +/- SD) due to rapid cellular uptake. Peak concentrations in unseparated blood cells were reached 5 min after drug injection and remained higher than in plasma throughout the observation period of 72 h. The half-lives of THP-adriamycin in plasma were 19 +/- 2.8 min in an intermediate and 13 +/- 1.6 h in the terminal phase. A linear correlation was observed between the dose and the areas under the concentration curves for THP-adriamycin in plasma (r2 = 0.97) and blood cells (r2 = 0.99). The volume of distribution was 2124 +/- 221 liters/m2 and the total clearance rate 115 +/- 11 liters/m2h. THP-adriamycin was metabolized to Adriamycin, THP-adriamycinol, and adriamycinol. The major metabolite was Adriamycin with a terminal half-life in plasma of 33 +/- 10 h. The area under the curve of Adriamycin was also correlated to the administered dose (r2 = 0.96). Since excessive peak concentrations of Adriamycin were avoided, the treatment with THP-adriamycin might be an alternative to continuous infusions or weekly administrations. The maximum tolerated dose was 70 mg/m2, and the dose-limiting toxicities were leukopenia and thrombocytopenia. Anemia, nausea, and vomiting were mild to moderate, and no other toxicity was observed. All side effects were dose dependent and reversible. In a patient with breast cancer, a disease stabilization was achieved lasting for 9 weeks. No objective remission was observed. We suggest 60 mg/m2 in pretreated or poor risk and 70 mg/m2 in untreated or good risk patients every 3 weeks for further clinical trials.
对新型蒽环类衍生物4'-O-四氢吡喃基阿霉素（THP-阿霉素）的临床药理学及毒性在晚期恶性疾病患者中进行了研究。起始剂量为30mg/m²，以每次增加10mg/m²的幅度递增。12名患者进入研究，中位年龄为42岁（范围19 - 69岁），东部肿瘤协作组体能状态评分中位数为2（范围1 - 2）。诊断包括4例睾丸癌、2例乳腺癌、2例小细胞肺癌、2例急性髓细胞白血病、1例结肠癌和1例血管肉瘤。THP-阿霉素每3周静脉推注给药。可评估一般毒性18个疗程、血液学毒性16个疗程及药代动力学16个疗程。由于细胞快速摄取，THP-阿霉素初始半衰期较短，为1.4±0.3分钟（均值±标准差）。药物注射后5分钟在未分离血细胞中达到峰值浓度，在整个72小时观察期内均高于血浆中的浓度。THP-阿霉素在血浆中的半衰期，中间相为19±2.8分钟，终末相为13±1.6小时。血浆中THP-阿霉素的剂量与浓度曲线下面积之间呈线性相关（r² = 0.97），血细胞中也是如此（r² = 0.99）。分布容积为2124±221升/m²，总清除率为115±11升/m²·小时。THP-阿霉素代谢为阿霉素、THP-阿霉素醇和阿霉素醇。主要代谢产物为阿霉素，其在血浆中的终末半衰期为33±10小时。阿霉素的曲线下面积也与给药剂量相关（r² = 0.96）。由于避免了阿霉素过高的峰值浓度，THP-阿霉素治疗可能是持续输注或每周给药的一种替代方法。最大耐受剂量为70mg/m²，剂量限制性毒性为白细胞减少和血小板减少。贫血、恶心和呕吐为轻至中度，未观察到其他毒性。所有副作用均呈剂量依赖性且可逆。1例乳腺癌患者病情稳定持续9周。未观察到客观缓解。我们建议预处理或预后差的患者每3周给予60mg/m²，未治疗或预后好的患者给予70mg/m²用于进一步的临床试验。
