Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study.

ABSTRACT: BACKGROUND:Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. METHODS:In this multicenter, open-label phase 1/2 study, a single 480 or 960?mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3?mg/kg every 2 weeks [Q2W]). RESULTS:Single 480 and 960?mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480?mg (132??g/mL) was similar to the predicted concentration at the end of infusion with 3?mg/kg Q2W (117??g/mL). The concentration on Day 28 after 960?mg (33.1??g/mL) was within the predicted trough concentration range for 3?mg/kg Q2W (90% prediction interval 19.0-163??g/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480?mg and 960?mg groups, respectively. Drug-related AEs were observed in only one patient in the 480?mg group. No deaths related to nivolumab occurred. CONCLUSIONS:A single dose of 960?mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480?mg and 960?mg nivolumab seemed to improve immune system indices over time. TRIAL REGISTRATION:JAPIC, JapicCTI-173600.

SUBMITTER: Watanabe E 

PROVIDER: S-EPMC7448837 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature