Port R E, Ding R W, Fies T, Schärer K
German Cancer Research Center, Heidelberg.
Br J Clin Pharmacol. 1998 Nov;46(5):461-6. doi: 10.1046/j.1365-2125.1998.00797.x.
To establish a pharmacodynamic model that allows one to predict the haemoglobin (Hb) response to EPO in children as a function of dose and time, and to derive recommendations for initial dosing and subsequent dose adjustment.
Haemoglobin was monitored in eight children aged 8-15 years with anaemia due to renal failure during treatment with EPO. All patients were free of conditions known to impair the response to EPO. Pretreatment Hb was 4.9-9.0 g dl(-1). The drug was administered once weekly by subcutaneous injection; doses ranged from 1700 to 6800 U week (-1). Hb was monitored for 4-38 months. The Hb-time data were analysed by applying a population pharmacodynamic model proposed for EPO in adult haemodialysis patients. Internal model validation was carried out by using a bootstrap procedure.
The increase of Hb during treatment with EPO was linear until steady state was reached after 103+/-33 days (mean +/- interindividual s.d.). The weekly gain in Hb from the onset of therapy to steady state was 0.0805+/-0.026 g dl(-1) (mean +/- interindividual s.d.) for every 1000 U EPO week (-1); it did not exhibit a dependence on body weight. Estimated mean prediction errors are +/-1.53 g dl(-1) for predictions that are based on the mean population parameters and +/-0.83 g dl(-1) for predictions that take into account the complete individual Hb-time data up to and including steady state.
The model describes the time course of the Hb response to EPO in children with renal anaemia. The required weekly EPO dose should initially be calculated from the individual pretreatment Hb and the desired Hb at steady state by using the mean population estimates of the weekly gain in Hb per dose unit before steady state (beta) and the time needed to reach steady state (tau). A reduction of the initial dose according to body weight is not justified by the available evidence. beta should be re-estimated individually after 6 weeks of treatment and dose should be adjusted accordingly. A final dose adjustment should be made when steady state has been reached based on individual estimates of beta and tau.
建立一个药效学模型，用于预测儿童对促红细胞生成素（EPO）的血红蛋白（Hb）反应随剂量和时间的变化，并得出初始给药及后续剂量调整的建议。
对8名8至15岁因肾衰竭贫血的儿童在接受EPO治疗期间监测其血红蛋白。所有患者均无已知会损害对EPO反应的疾病。治疗前血红蛋白水平为4.9 - 9.0 g·dl⁻¹。药物通过皮下注射每周给药一次；剂量范围为1700至6800 U·周⁻¹。对血红蛋白进行了4至38个月的监测。通过应用针对成年血液透析患者的EPO提出的群体药效学模型对血红蛋白 - 时间数据进行分析。使用自举程序进行内部模型验证。
在EPO治疗期间，血红蛋白的增加呈线性，直至103±33天（平均值±个体间标准差）后达到稳态。从治疗开始到稳态，每1000 U EPO·周⁻¹的血红蛋白每周增加量为0.0805±0.026 g·dl⁻¹（平均值±个体间标准差）；其不表现出对体重的依赖性。基于群体平均参数的预测估计平均预测误差为±1.53 g·dl⁻¹，考虑直至并包括稳态的完整个体血红蛋白 - 时间数据的预测估计平均预测误差为±0.83 g·dl⁻¹。
该模型描述了肾性贫血儿童对EPO的血红蛋白反应的时间进程。初始每周所需的EPO剂量应首先根据个体治疗前血红蛋白和稳态时所需的血红蛋白，使用稳态前每剂量单位血红蛋白每周增加量（β）和达到稳态所需时间（τ）的群体平均估计值来计算。现有证据表明根据体重减少初始剂量是不合理的。治疗6周后应单独重新估计β，并相应调整剂量。当达到稳态时，应根据β和τ的个体估计值进行最终剂量调整。
