大量危重病患者患有脓毒症诱导的免疫抑制。通过PD-1检查点抑制来逆转免疫抑制已被提出作为治疗这些患者免疫抑制的策略。PD-1抑制剂尼伏单抗，目前用于癌症治疗，已在脓毒症患者中进行了I/II期研究，显示出耐受性和临床疗效的迹象。这些研究中没有进行适当的剂量测定，在单次高剂量480毫克或960毫克尼伏单抗后，PD-1抑制持续时间在大多数情况下超过90天。由于脓毒症持续时间约为7-10天，长时间的PD-1抑制可能会不必要地引起长期的免疫相关副作用。基于先前发表的尼伏单抗药代动力学和药效学数据，我们对危重病患者进行了全面的旁注剂量寻找研究。我们发现，在脓毒症患者中，尼伏单抗的分布容积和清除率与目前批准使用尼伏单抗的癌症人群相比没有更高，且呈现显著的变异性。我们发现，使用单次20毫克的尼伏单抗，PD-1受体占据率预计会在中位数23天以上保持在90%的阈值以上（7-78天的90%预测区间）。我们建议在危重病患者中对这种剂量进行研究，作为治疗脓毒症诱导的免疫抑制的潜在安全和经济有效的药物治疗干预措施。©2023 The Authors. Clinical and Translational Science 由Wiley Periodicals LLC代表美国临床药理学和治疗学会出版。

A substantial part of critically ill patients suffer from sepsis-induced immunosuppression. Reversal of immunosuppression through PD-1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD-1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD-1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7-10 days, prolonged PD-1 inhibition may unnecessarily induce longer-term immune-related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD-1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7-78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost-effective pharmacotherapeutic intervention to treat sepsis-induced immunosuppression.© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.