Anti-inflammatory effects of dexamethasone in COVID-19 patients: Translational population PK/PD modeling and simulation.
Anti-inflammatory effects of dexamethasone in COVID-19 patients: Translational population PK/PD modeling and simulation.
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DOI：
10.1111/cts.13577
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发表时间：
2023-09
期刊：
影响因子：
--
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中科院分区：
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对于需要氧疗的2019冠状病毒病（COVID-19）患者，推荐使用地塞米松（DEX），剂量为6 mg，每日一次，持续10天。我们开发了COVID-19中DEX抗炎作用的群体药代动力学和药效学（PopPK/PD）模型，并提供了比较DEX四种给药方案预期疗效的模拟。使用Monolix Suite版本2021 R1（Lixoft，France）进行非线性混合效应建模和模拟。已发表的COVID-19患者的DEX PK数据显示出中度变异性，清除率约为健康成人的一半。即使每日口服剂量为12 mg，预期也不会发生药物蓄积。建立了DEX抑制TNFα、IL-6和CRP血浆浓度的间接效应模型，并对每日给予1.5、3、6和12 mg DEX持续10天进行了模拟。在治疗组之间比较了炎症生物标志物达到特定降低的个体数量。模拟结果表明，需要每日6或12 mg剂量的DEX，持续10天，以同时降低TNFα、IL-6和CRP。与6 mg相比，12 mg剂量的DEX可能有益。PopPK/PD模型可用于评估其他抗炎化合物以及治疗细胞因子风暴的药物组合。
Dexamethasone (DEX) given at a dose of 6 mg once‐daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID‐19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti‐inflammatory effects in COVID‐19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed‐effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID‐19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL‐6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL‐6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti‐inflammatory compounds as well as drug combinations in the treatment of cytokine storms.
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DOI：
10.1002/psp4.12574
发表时间：
2021-01
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Dai W;Rao R;Sher A;Tania N;Musante CJ;Allen R
通讯作者：
Allen R
影响因子：
2.9
作者：
Liu QQ;Cheng A;Wang Y;Li H;Hu L;Zhao X;Wang T;He F
通讯作者：
He F
DOI：
10.1186/s13054-021-03717-z
发表时间：
2021-08-05
期刊：
Critical care (London, England)
影响因子：
--
作者：
Kooistra EJ;van Berkel M;van Kempen NF;van Latum CRM;Bruse N;Frenzel T;van den Berg MJW;Schouten JA;Kox M;Pickkers P
通讯作者：
Pickkers P
影响因子：
3.5
作者：
Goncalves, Antonio;Bertrand, Julie;Guedj, Jeremie
通讯作者：
Guedj, Jeremie
影响因子：
82.9
作者：
Del Valle DM;Kim-Schulze S;Huang HH;Beckmann ND;Nirenberg S;Wang B;Lavin Y;Swartz TH;Madduri D;Stock A;Marron TU;Xie H;Patel M;Tuballes K;Van Oekelen O;Rahman A;Kovatch P;Aberg JA;Schadt E;Jagannath S;Mazumdar M;Charney AW;Firpo-Betancourt A;Mendu DR;Jhang J;Reich D;Sigel K;Cordon-Cardo C;Feldmann M;Parekh S;Merad M;Gnjatic S
通讯作者：
Gnjatic S