Fan Xiaoqing, Krzyzanski Wojciech, Liu Dongyang, Wong Raymond S M, Yan Xiaoyu
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14260, USA.
Pharmaceutics. 2023 Jan 19;15(2):344. doi: 10.3390/pharmaceutics15020344.
Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce precursor cell depletion, resulting in EPO-resistance. We further found that the combination of EPO with romiplostim, a thrombopoietin receptor agonist that can stimulate the expansion of hematopoietic stem cells, can treat EPO-resistance. In this study, we performed interspecies pharmacodynamic (PD) scaling of this combination therapy for human dose prediction. The pharmacokinetic parameters of both rHuEPO and romiplostim in humans were obtained from previous studies. The PD parameters obtained in rats were scaled to humans using allometric equations. The relationship between PD parameters of the megakaryocyte lineage from rats, monkeys, and humans was in agreement with those from the literature on allometric scaling. The PD response was translated to humans based on allometric scaling and agreed with the observed data. These parameters were used to simulate hemoglobin and platelet response in humans. RHuEPO 50 IU/kg thrice weekly and romiplostim 1 μg/kg once every 4 weeks from the second week is the recommended combination dosing regimen according to the model prediction. Our work successfully scaled the PD of rHuEPO and romiplostim monotherapy from rats to humans. The predicted dosing regimen of each drug in the combination therapy is less intensive than the approved starting dose of each drug, which supports additional evaluations of the combination therapy in humans.
重组人促红细胞生成素（rHuEPO）是治疗慢性肾脏病患者贫血最有效的药物之一。然而，促红细胞生成素抵抗是不良反应风险增加的一个重要因素。我们之前表明，促红细胞生成素治疗可诱导前体细胞耗竭，从而导致促红细胞生成素抵抗。我们进一步发现，促红细胞生成素与罗米司亭（一种可刺激造血干细胞扩增的血小板生成素受体激动剂）联合使用可治疗促红细胞生成素抵抗。在本研究中，我们对这种联合疗法进行了种间药效学（PD）标度，以预测人体剂量。rHuEPO和罗米司亭在人体中的药代动力学参数来自先前的研究。大鼠中获得的PD参数使用异速生长方程标度至人体。大鼠、猴子和人类巨核细胞系的PD参数之间的关系与异速生长标度文献中的一致。基于异速生长标度将PD反应转化至人体，并与观察数据相符。这些参数用于模拟人体中的血红蛋白和血小板反应。根据模型预测，推荐的联合给药方案为：从第二周起，每周三次给予rHuEPO 50 IU/kg，每4周一次给予罗米司亭1 μg/kg。我们的工作成功地将rHuEPO和罗米司亭单药治疗的PD从大鼠标度至人体。联合疗法中每种药物的预测给药方案比每种药物的批准起始剂量强度更低，这支持在人体中对联合疗法进行进一步评估。
