Garadacimab is a fully human IgG4/lambda recombinant monoclonal antibody which binds to the catalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. The inhibition of FXIIa, the first factor activated in the contact system, prevents HAE attacks by blocking the activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in HAE attacks.
Concentration-dependent inhibition of FXIIa-mediated kallikrein activity was demonstrated after subcutaneous administration of garadacimab once monthly in patients with HAE.
In the VANGUARD pivotal trial, patients treated with 200 mg garadacimab subcutaneous once monthly presented mean (SD) area under the curve over the dosing interval at steady-state (AUCtau,ss), maximum concentration at steady-state (Cmax,ss), and minimum concentration at steady-state (Cmin,ss) of 10300 (3380) mcg∙h/mL, 21.2 (6.58) mcg/mL, and 9.30 (3.73) mcg/mL, respectively. Steady-state exposure of garadacimab was achieved after the initial subcutaneous administration of loading dose of 400 mg (2 doses of 200 mg).
Following subcutaneous administration, the time to maximum concentration is approximately 6 days. The site of subcutaneous injection (thigh, arm, or abdomen) did not affect the absorption of garadacimab. The absorption rate of garadacimab was 0.00824/h. The mean absolute bioavailability of garadacimab in HAE patients was 39.5% on the basis of the population pharmacokinetic analysis.
The mean (SD) apparent volume of distribution of garadacimab in patients with HAE was 7.42 litres (4.20). Garadacimab is a monoclonal antibody and is not expected to bind to plasma proteins.
Similar to other monoclonal antibodies, garadacimab is expected to be degraded by enzymatic proteolysis into small peptides and amino acids. Therefore, specific metabolism studies were not conducted with garadacimab.
Garadacimab had a mean (SD) apparent clearance of 0.0217 L/h (0.00793) and a terminal elimination half-life of approximately 19 days.
No dedicated studies have been conducted to evaluate the pharmacokinetics of garadacimab in special patient populations including gender, age, pregnant women.
In a population pharmacokinetic analysis, after correcting for body weight (43.3 to 153 kg), no influence of gender, age (12 to 73 years), race, or ethnicity was apparent on clearance or volume of distribution of garadacimab.
Although body weight was identified as an important covariate describing the variability of clearance and volume of distribution, the difference was not clinically relevant and no dose adjustments are recommended.
Dedicated studies on subjects with renal or hepatic impairment were not conducted.
As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment or hepatic impairment is not expected to influence clearance of garadacimab.
Based on population pharmacokinetic analysis, hepatic impairment had no effect on the pharmacokinetics of garadacimab.
In a population pharmacokinetic analysis, renal impairment (estimated glomerular filtration rate: ≥90 mL/min [normal, N=149], 60 to <90 mL/min [mild, N=22], and 30 to <60 mL/min [moderate, N=1]) had no effect on the pharmacokinetics of garadacimab.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.
Male and female fertility were unaffected based upon no observed adverse findings on mating, fecundity, fertility indices, on maternal reproductive parameters, embryo survival or sperm assessment in sexually mature rabbits that received garadacimab intravenously once every three days resulting in approximately 83- and 103-fold the exposure (based on AUC) in females and males, respectively, at the recommended human dose of 200 mg subcutaneously once monthly.
In a pre- and post-natal development study, pregnant rabbits were administered garadacimab subcutaneously once every five days from implantation through weaning. There was no maternal and off-spring, through six months of age, garadacimab-related toxicity in rabbits receiving subcutaneous garadacimab resulting in approximately 53-fold the clinical exposure (based on AUC) at the recommended human dose of 200 mg subcutaneously once monthly.
Garadacimab crossed the placenta in rabbits. With subcutaneous administration of garadacimab corresponding to approximately 53-fold the clinical exposure (based on AUC) at the recommended human dose of 200 mg subcutaneously once monthly, at gestation day 29, fetal plasma concentrations were 40.8% of maternal concentrations.
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