Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients
Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients
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DOI：
10.1002/cpt.936
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发表时间：
2018-08-01
影响因子：
6.7
通讯作者：
Goldbach-Mansky, Raphaela
中科院分区：
文献类型：
--
作者：
Kim, Hanna;Brooks, Kristina M.;Goldbach-Mansky, Raphaela
使用群体药代动力学（popPK）建模来表征口服Janus激酶（JAK）1/JAK 2抑制剂baricitinib在18例参与体恤使用计划的孟德尔干扰素病患者中的PK特征。患者每天接受0.1至17 mg的剂量。体重和肾功能的协变量分别显著影响分布容积和清除率。Baricitinib在体重小于40 kg的患者中的半衰期明显短于成人人群，需要每天给药4次。在治疗剂量下，平均浓度下面积与时间曲线为2，388 nM *hr，比接受4 mg每日一次剂量的类风湿性关节炎成年患者的平均巴瑞替尼暴露量高1.83倍。干扰素（IFN）生物标志物的剂量依赖性降低证实了baricitinib对1型IFN信号传导的体内作用。PopPK和药效学数据支持基于体重和估计肾小球滤过率的给药方案，以指导罕见干扰素病患者的baricitinib给药。
Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.