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Elsevier
Veterinary Immunology and Immunopathology
Volume 203, September 2018, Pages 66-72
Veterinary Immunology and Immunopathology
Research paper
Pharmacokinetics of human recombinant C1-esterase inhibitor and development of anti-drug antibodies in healthy dogs
Author links open overlay panelCherylWongaDaniela HernandezMuguiroaSidonieLavergnecEricaBehling-Kellya1RobertGoggsb1
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doi.org/10.1016/j.vetimm.2018.08.006Get rights and content
Highlights
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IV administration of recombinant C1 esterase inhibitor (rC1-INH) to dogs is safe.
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Peak plasma rC1-INH concentration is 0.21?IU/mL after 500?IU (~50?IU/kg) IV dose.
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rC1-INH concentrations are significantly increased for 100?min post-injection.
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rC1-INH administration incites a robust antibody response in dog.
Abstract
Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors such as recombinant C1 esterase inhibitor (rC1-INH) might prevent this process and alter the disease course. This study aimed to characterize the pharmacokinetics of a single 500?IU IV dose of rC1-INH in 8 healthy beagle dogs, evaluate the dogs for any adverse effects of drug administration, and determine whether rC1-INH administration induces anti-drug antibody formation. Serum rC1-INH concentrations were measured using a commercial functional ELISA at baseline and at 10, 20, 40, 60, 80, 100, 120, 240, 360, 480, 600, 720, 960, and 1440?min post drug administration. Complete blood counts were conducted at baseline, 720 and 1440?min. Western blot analysis, using rC1-INH as the target antigen was used to detect anti-drug antibodies in 14-day serum samples. No adverse clinical reactions were noted following rC1-INH administration. Pharmacokinetic modelling suggested that the peak C1-INH concentration achieved is 0.21?IU/mL and that C1-INH concentration is significantly greater than baseline for 100?min following injection. A robust antibody response was detected which suggests that rC1-INH should not be re-administered after an initial course. Clinical trials of rC1-INH in dogs with intravascular IMHA are now warranted.
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Abbreviations
AUCarea under the curveAUClastarea under the plasma concentration-time curve from the time of dosing to the last measurable (positive) concentrationAUC-INFobsarea under the plasma concentration-time curve from the time of dosing extrapolated to infinityC1-INHcomplement C1-esterase inhibitorCmaxmaximum observed plasma concentrationCLobstotal body clearanceIMHAimmune-mediated hemolytic anemiaMACmembrane attack complexNOAELno adverse effect levelPKpharmacokineticPNHparoxysmal nocturnal hemoglobinuriarC1-INHrecombinant C1-esterase inhibitorTlasttime of last measurable (positive) concentrationTmaxtime of maximum observed concentrationT½terminal half-lifeVDobsvolume of distribution based on the terminal phase
Keywords
C1-INHComplementC3IMHARuconestAnti-drug antibodies
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