Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran with very high affinity, approximately 300-fold more potent than the binding affinity of dabigatran for thrombin. The idarucizumab-dabigatran complex is characterised by a rapid on-rate and extremely slow off-rate resulting in a very stable complex. Idarucizumab potently and specifically binds to dabigatran and its metabolites and neutralises their anticoagulant effect.
The pharmacokinetics of idarucizumab were investigated in 224 subjects in Phase I studies, of which data for a representative subgroup of 6 healthy subjects aged 45 to 64 years receiving a dose of 5 g as intravenous infusion are presented.
Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV) 24.8%).
Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e. small peptides or amino acids, which are then reabsorbed and incorporated in the general protein synthesis.
Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%) and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.
After treatment with idarucizumab proteinuria has been observed. The transient proteinuria is a physiologic reaction to renal protein overflow after bolus/short term application of 5g idarucizumab intravenously. The transient proteinuria usually peaked about 4 h after idarucizumab administration and normalised within 12-24 hours. In single cases the transient proteinuria persisted for more than 24 hours.
In Phase I studies idarucizumab has been investigated in subjects with a creatinine clearance ranging from 44 to 213 mL/min. Subjects with a creatinine clearance below 44 mL/min have not been studied in Phase I. Depending on the degree of renal impairment the total clearance was reduced compared to healthy subjects, leading to an increased exposure of idarucizumab.
Based on pharmacokinetic data from 347 patients with different degrees of renal function (median creatinine clearance 21-99 mL/min) it is estimated that mean idarucizumab exposure (AUC0–24h) increases by 38% in patients with mild (CrCl 50-<80 mL/min), by 90% in moderate (30-<50 mL/min) and by 146% in severe (0-<30 mL/min) renal impairment. Since dabigatran is also excreted primarily via the kidneys, increases in the exposure to dabigatran are also seen with worsening renal function.
Based on these data and the extent of reversal of the anticoagulant effect of dabigatran in patients, renal impairment does not impact the reversal effect of idarucizumab.
An impact of hepatic impairment, assessed by hepatic injury as determined by elevated liver function tests, on the pharmacokinetics of idarucizumab has not been observed.
Idarucizumab has been studied in 58 patients with varying degrees of hepatic impairment. Compared to 272 patients without hepatic impairment, the median AUC of idarucizumab was changed by -6%, 37% and 10% in patients with AST/ALT elevations of 1 to <2x ULN (N=34), 2 to <3x ULN (N=3) and >3x ULN (N=21), respectively. Based on pharmacokinetic data from 12 patients with liver disease, the AUC of idarucizumab was increased by 10% as compared to patients without liver disease.
Based on population pharmacokinetic analyses, sex, age, and race do not have a clinically meaningful effect on the pharmacokinetics of idarucizumab.
Preclinical data reveal no special hazard for humans based on repeated dose toxicity studies of up to four weeks in rats and two weeks in monkeys. Safety pharmacology studies have demonstrated no effects on the respiratory, central nervous or cardiovascular system.
Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed. Based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects are anticipated.
Studies to assess the potential reproductive effects of idarucizumab have not been performed. No treatment-related effects have been identified in reproductive tissues of either sex during repeat dose intravenous toxicity studies of up to four weeks in the rat and two weeks in monkeys. Additionally, no idarucizumab binding to human reproductive tissues was observed in a tissue cross-reactivity study. Therefore, preclinical results do not suggest a risk to fertility or embryo-fetal development.
No local irritation of the blood vessel was observed after i.v. or paravenous administration of idarucizumab. The idarucizumab formulation did not produce haemolysis of human whole blood in vitro.
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