Furman W L, Baker S D, Pratt C B, Rivera G K, Evans W E, Stewart C F
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
J Clin Oncol. 1996 May;14(5):1504-11. doi: 10.1200/JCO.1996.14.5.1504.
To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia.
Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course.
Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted.
The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.
确定连续输注拓扑替康在复发急性白血病儿童中的最大耐受全身暴露量（MTSE）和暴露限制毒性。
患者接受拓扑替康全身暴露量逐步递增，通过稳态拓扑替康内酯浓度（Css）进行测量。在最初24小时内采集的样本通过高压液相色谱法（HPLC）检测拓扑替康。使用贝叶斯算法将二室模型拟合到数据中。计算每位患者的Css；如果与目标值相差超过20%，则在6小时内开始新的剂量。获取后续浓度以及输注后的系列血浆样本。每个疗程后评估毒性和活性证据。
13名男孩和5名女孩接受了23个疗程的拓扑替康治疗。目标Css范围为1.0至5.3 ng/mL（拓扑替康剂量，0.5至3.3 mg/m²/天）。调整后，23个疗程中有19个在目标值的±20%范围内（范围为77%至139%）。MTSE为4.0 ng/mL，粘膜炎在5.3 ng/mL时为暴露限制毒性。观察到拓扑替康内酯Css与粘膜炎严重程度之间存在显著关系。出现了骨髓抑制，但不认为是暴露限制毒性。记录到1例完全缓解和1例部分缓解。
连续输注拓扑替康的MTSE为4.0 ng/mL。在Css水平观察到的反应与严重联合免疫缺陷（SCID）小鼠模型中产生反应的Css水平相当。有必要对拓扑替康进行进一步研究。
