Department of Pharmaceutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA.
Pediatr Res. 2012 Apr;71(4 Pt 1):332-7. doi: 10.1038/pr.2011.75. Epub 2012 Feb 15.
Preterm infants commonly develop anemia requiring red blood cell transfusions (RBCTx). Although an alternative therapy is recombinant human erythropoietin (Epo), it is not widely employed. To provide a rigorous scientific basis supporting the latter approach, a model-based simulation analysis of endogenous erythropoiesis was developed.
The pharmacodynamic/pharmacokinetic (PK/PD) model identified an optimal Epo dosing algorithm in preterm infants that demonstrated maximal efficacy when Epo was dosed frequently during the early weeks of life (when phlebotomy loss is greatest). Model-based simulations employing optimized Epo dosing predicted that 13 of the 27 (46%) infants would avoid RBCTx ("good responders"). Importantly, simulation results identified five subject-specific covariate factors predictive of good Epo response.
This simulation study provides a basis for possibly eliminating RBCTx in infants who can be selected for optimized Epo therapy.
Epo PD hemoglobin production parameters were determined in 27 preterm infants studied intensively during the first 28 d of life. Model-derived Epo PD parameters were combined with PK parameters derived from the literature to simulate an optimized intravenous Epo bolus dosing schedule. The goal of this simulated optimized schedule was to eliminate RBCTx, as prescribed per current guidelines, in as many preterm infants as possible.
早产儿常发生贫血，需要输血治疗。虽然重组人促红细胞生成素（Epo）是一种替代疗法，但并未广泛应用。为了为这种治疗方法提供严格的科学依据，我们建立了基于模型的内源性红细胞生成动力学模拟分析。
该药代动力学/药效动力学（PK/PD）模型确定了早产儿中最佳的 Epo 给药方案，该方案在生命早期（当采血量最大时）频繁给予 Epo 时显示出最大疗效。采用优化 Epo 给药方案的基于模型的模拟预测，27 名婴儿中有 13 名（46%）可以避免输血（“良好反应者”）。重要的是，模拟结果确定了 5 个可预测良好 Epo 反应的个体特有的协变量因素。
这项模拟研究为可能在可选择的接受优化 Epo 治疗的婴儿中消除输血治疗提供了依据。
在 27 名早产儿出生后的前 28 天内进行了强化研究，以确定 Epo 的 PD 血红蛋白生成参数。从文献中推导的 PK 参数与模型衍生的 Epo PD 参数相结合，以模拟优化的静脉内 Epo 推注给药方案。该模拟优化方案的目的是尽可能多地消除按照当前指南规定需要输血的早产儿输血治疗。
