AUTHOR=Admiraal M. M. , Velseboer D. C. , Tjabbes H. , Vis P. , Peeters-Scholte C. , Horn J. 

TITLE=Neuroprotection after cardiac arrest with 2-iminobiotin: a single center phase IIa study on safety, tolerability, and pharmacokinetics

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1136046

DOI=10.3389/fneur.2023.1136046

ISSN=1664-2295

ABSTRACT=BACKGROUND: Cerebral ischemia with subsequent reperfusion injury is a serious problem in patients surviving out-of-hospital cardiac arrest (OHCA). The aim of this study was to investigate safety, tolerability and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal and inducible nitric oxide synthase. 
METHODS: Single center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC0-24h of 600-1200 ng*h/m in cohort A, of 2100-3300 ng*h/mL in cohort B, and 7200-8400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 minutes after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed.  Brain biomarkers and patient outcomes were collected at 30 days after OHCA. 
RESULTS: A total of 21 patients was included, 8 in cohort A and B, and 5 in cohort C. No changes in vital signs were observed and no adverse events related to 2-IB were reported. A two-compartment PK model described data best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC0-24h 2398 ng*h/mL). Renal function was an important covariate, therefore in cohort B dosing was performed on eGFR on admission. In cohort B and C the targeted exposure was met (median AUC0-24h 2917 and 7323 ng*h/mL, respectively).
CONCLUSION: Administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed.