Application of Allometric Scaling to Nanochelator Pharmacokinetics.
Application of Allometric Scaling to Nanochelator Pharmacokinetics.
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DOI：
10.1021/acsomega.3c02570
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发表时间：
2023-08-01
期刊：
影响因子：
4.1
通讯作者：
Kim, Jonghan
中科院分区：
文献类型：
--
作者：
Jones, Gregory;Zeng, Lingxue;Kim, Jonghan
去铁胺（DFO）是一种有效的fda批准的铁螯合剂；然而，由于脱靶毒性和每日输注的极其繁琐的剂量方案，其使用受到很大限制。最近开发的一种选择性肾排泄的去铁胺纳米螯合剂（DFO-NP）在啮齿类动物模型中显示出改善铁超载和相关生理并发症的希望，并大大提高了安全性。虽然DFO-NPs的剂量和给药途径依赖的药代动力学（PK）最近已经被表征，但优化的PK模型尚未得到验证，并且先前的研究没有直接解决DFO-NPs在人体中的临床可翻译性。在目前的工作中，通过应用大鼠DFO-NP PK的异速缩放来预测小鼠和人类的差异，解决了这些差距。首先，该方法预测了DFO-NPs的血清浓度-时间谱，这与在小鼠中实验测量的结果相似，验证了DFO-NPs在物种中的非线性配置和吸收模型。随后，我们通过预测临床相关给药方案下人类DFO-NPs的PK谱，探讨了异速缩放的效用。这些在计算机上的努力表明，与天然DFO的标准输注方案相比，新型纳米螯合剂有望改善DFO的PK。此外，确定并讨论了合理的配方策略，用于早期临床开发和更复杂的配方开发。
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.
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影响因子：
6
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影响因子：
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通讯作者：
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