Jones Gregory, Zeng Lingxue, Kim Jonghan
Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, Massachusetts 01854, United States.
ACS Omega. 2023 Jul 18;8(30):27256-27263. doi: 10.1021/acsomega.3c02570. eCollection 2023 Aug 1.
Deferoxamine (DFO) is an effective FDA-approved iron chelator; however, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen involving daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating iron overload and associated physiological complications in rodent models with a substantially improved safety profile. While the dose- and administration route-dependent pharmacokinetics (PK) of DFO-NPs have been recently characterized, the optimized PK model was not validated, and the prior studies did not directly address the clinical translatability of DFO-NPs into humans. In the present work, these gaps were addressed by applying allometric scaling of DFO-NP PK in rats to predict those in mice and humans. First, this approach predicted serum concentration-time profiles of DFO-NPs, which were similar to those experimentally measured in mice, validating the nonlinear disposition and absorption models for DFO-NPs across the species. Subsequently, we explored the utility of allometric scaling by predicting the PK profile of DFO-NPs in humans under clinically relevant dosing schemes. These in silico efforts demonstrated that the novel nanochelator is expected to improve the PK of DFO when compared to standard infusion regimens of native DFO. Moreover, reasonable formulation strategies were identified and discussed for both early clinical development and more sophisticated formulation development.
去铁胺（DFO）是一种经美国食品药品监督管理局（FDA）批准的有效铁螯合剂；然而，其使用受到非靶向毒性以及极为繁琐的每日输注给药方案的极大限制。最近开发的一种具有选择性肾脏排泄功能的基于去铁胺的纳米螯合剂（DFO-NP），在改善啮齿动物模型中的铁过载及相关生理并发症方面显示出前景，且安全性显著提高。虽然最近已经对DFO-NP的剂量和给药途径依赖性药代动力学（PK）进行了表征，但优化的PK模型尚未得到验证，并且先前的研究并未直接探讨DFO-NP在人体中的临床可转化性。在本研究中，通过对大鼠中DFO-NP的PK进行异速生长标度来预测小鼠和人类中的PK，从而填补了这些空白。首先，这种方法预测了DFO-NP的血清浓度-时间曲线，该曲线与在小鼠中实验测量的曲线相似，验证了DFO-NP在不同物种间的非线性处置和吸收模型。随后，我们通过预测临床相关给药方案下DFO-NP在人体中的PK曲线，探索了异速生长标度的实用性。这些计算机模拟研究表明，与天然DFO的标准输注方案相比，这种新型纳米螯合剂有望改善DFO的PK。此外，还确定并讨论了适用于早期临床开发和更复杂制剂开发的合理制剂策略。
