Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, Utah, USA.
Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
Clin Transl Sci. 2021 Mar;14(2):683-691. doi: 10.1111/cts.12930. Epub 2020 Nov 30.
Sjögren's syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid-based specialized pro-resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically-based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS-like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01-10 mg/kg). The first-in-human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.
干燥综合征（SS）是一种自身免疫性疾病，目前尚无有效的治疗方法。解析素 D1（RvD1）属于一类基于脂质的专门的促解决介质，在 SS 的临床前模型中显示出疗效。我们在小鼠中开发了 RvD1 的基于生理的药代动力学（PBPK）模型，并使用在具有 SS 样特征的 NOD/ShiLtJ 小鼠中进行的血浆和唾液腺药代动力学（PK）研究对模型进行了优化。还使用来自文献的两个外部数据集评估了 PBPK 模型的预测性能，这些数据集报告了 RvD1 的 PK 数据。使用经过验证的 PBPK 模型在不同剂量下（0.01-10mg/kg）预测了虚拟人类中 RvD1 的 PK 数据。RvD1 的首次人体预测将有助于临床试验设计，并将 RvD1 转化为 SS 的有效治疗策略。
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