Amantea M A, Forrest A, Northfelt D W, Mamelok R
SEQUUS Pharmaceuticals, Inc., Menlo Park, CA 94025, USA.
Clin Pharmacol Ther. 1997 Mar;61(3):301-11. doi: 10.1016/S0009-9236(97)90162-4.
To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency disease (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure.
Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proven cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first two doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response.
The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (Cmax,avg) and dose intensity.
The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both Cmax,avg and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.
描述聚乙二醇化脂质体阿霉素在获得性免疫缺陷病（AIDS）相关卡波西肉瘤患者中的群体药代动力学特征，并探讨皮肤卡波西肉瘤病变对治疗的反应与药物暴露量度之间的关系。
43例男性患者（中位年龄40岁；年龄范围28至50岁，体表面积1.89 m²；范围1.5至2.3 m²）患有艾滋病且至少有5个经活检证实的皮肤卡波西肉瘤病变，随机分为在第一个周期接受10或20 mg/m²剂量的研究药物，3周后接受交替剂量。患者继续每3周接受20 mg/m²剂量的研究药物。在前两剂后采集系列血样，通过高效液相色谱法分析以测定血浆阿霉素总浓度。卡波西肉瘤病变反应分为疾病进展、疾病稳定、部分缓解或完全缓解。使用分类与回归树（CART）分析来确定药物暴露与分类病变反应之间的关系。采用迭代两阶段分析来描述聚乙二醇化脂质体阿霉素的药代动力学特征，并对实现特定病变反应的概率进行建模。
聚乙二醇化脂质体阿霉素的药代动力学最好用二室线性结构模型来描述。病变反应与平均每日最大阿霉素浓度（Cmax,avg）和剂量强度均显著相关。
聚乙二醇化脂质体阿霉素的药代动力学与传统阿霉素显著不同。将Cmax,avg和剂量强度均确定为病变反应的预测指标将为未来给药方案设计提供指导。
