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Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding.

ABSTRACT: Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown.In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 microg x kg-1 after transfusion of eight red blood cell units, followed by additional doses of 100 microg x kg-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)).Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml x kg-1 x h-1; central volume of distribution 89 (32% CV) ml x kg-1; inter-compartmental clearance 24 ml x kg-1 x h-1; and peripheral compartment volume 31 ml x kg-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U x ml-1, initial half-life was 0.6 (34% CV) hours, and terminal half-life 2.4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters.A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.

SUBMITTER: Klitgaard T

PROVIDER: S-EPMC1750999 | biostudies-other | 2006

REPOSITORIES: biostudies-other

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Project description:Objective: Annexin A5 is a phosphatidylserine binding protein with anti-inflammatory, anticoagulant and anti-apoptotic properties. Preclinical studies have shown that annexin A5 inhibits pro-inflammatory responses and improves organ function and survival in rodent models of sepsis. This clinical trial aimed to evaluate the pharmacokinetic (PK) properties of the recombinant human annexin A5 (SY-005) in severe COVID-19. Methods: This was a pilot randomized, double-blind, placebo-controlled trial. Severe COVID-19 patients were randomly assigned to receive intravenous 50 μg/kg (low dose, n = 3), 100 μg/kg (high dose, n = 5) of SY-005 or placebo (n = 5) every 12 h for 7 days. Plasma SY-005 levels were assessed using enzyme-linked immunosorbent assay (ELISA) and the PK parameters were determined using non-compartmental analysis. Results: All patients treated with SY-005 had a normal baseline estimated glomerular filtration rate (eGFR, 104-125 mL/min/1.73 m2). Both low and high doses of SY-005 were cleared within 6 h after intravenous administration. Plasma maximum concentrations (Cmax), half-life, clearance and volume distribution of low and high doses of SY-005 were 402.4 and 848.9 ng/mL, 0.92 and 0.96 h, 7.52 and 15.19 L/h, and 9.98 and 20.79 L, respectively. Daily pre-dose circulating annexin A5 levels were not significantly different when SY-005 was administered at the low or the high dose 12-h intervals. There was no significant effect on activated partial thromboplastin time (aPTT) or INR (international normalized ratio of prothrombin time) during 7 days of SY-005 treatment. Conclusion: SY-005 doses of 50 and 100 μg/kg were detectable and subsequently cleared from the plasma in severe COVID-19 patients with normal baseline renal function. There was no significant plasma SY-005 accumulation 6 h after drug administration and coagulation was not altered during 7 days of treatment. Clinical trials Registration: This study was registered with ClinicalTrials.gov (NCT04748757, first posted on 10 February 2021).

Project description:ImportanceIntracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy.ObjectiveTo investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH.Design, setting, and participantsIn parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017.InterventionsEligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset.Main outcomes and measuresHead CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial.ResultsOf the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60).Conclusions and relevanceAmong patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes.Trial registrationClinicalTrials.gov identifier: NCT01359202 and NCT00810888.

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Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding.

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