The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination

Q: What is the clinical evidence from this study?

Population: Dabigatran anticoagulation reversal and renal impairment (n=90). Intervention: Idarucizumab with or without dabigatran etexilate vs. Matching placebo or sham-operated controls, with or without background dabigatran administration. Primary outcome: Pharmacokinetics (AUC, clearance, half-life) and cumulative urinary excretion (fe) of idarucizumab and dabigatran.

Stephan Glund; Guanfa Gan; Viktoria Moschetti; Paul Reilly; Markus Honickel; Oliver Grottke; Joanne van Ryn

doi:10.1177/1076029618755947

March 13, 2018Clinical and Applied Thrombosis/HemostasisOpen Access

The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination

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Key result

Idarucizumab clears renally alongside dabigatran, with dose-dependent urinary excretion reaching ~39%.

n=90

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Why the study?

How does renal impairment affect the elimination of idarucizumab, and how do idarucizumab and dabigatran influence each other's pharmacokinetics and renal elimination?

Key Points

To characterize the renal elimination pathways of the reversal agent idarucizumab and examine how idarucizumab and dabigatran mutually influence their pharmacokinetics.
Pharmacokinetic and excretion evaluations conducted in 5/6 nephrectomized and sham-operated rats, healthy human volunteers, and human participants with mild-to-moderate renal impairment.
Measurement of plasma exposure (AUC 0–∞), clearance, initial and terminal half-lives, and cumulative urinary excretion of dabigatran and idarucizumab administered alone or in combination.
In 5/6 nephrectomized rats, dabigatran plasma exposure increased by 1.89-fold and idarucizumab exposure increased by 2.32-fold, accompanied by a 48% decrease in dabigatran clearance and a 56% decrease in idarucizumab clearance.
In healthy humans, urinary excretion of unchanged idarucizumab increased from 10.7% with a 1-g dose to 38.9% with a 4-g dose, while dabigatran had no effect on idarucizumab pharmacokinetics.
Idarucizumab administration caused dabigatran redistribution to plasma and delayed dabigatran urinary excretion (producing two excretion peaks), but did not alter the total fraction of dabigatran excreted across 72 hours.

Structured PICO

How does renal impairment affect the elimination of idarucizumab, and how do idarucizumab and dabigatran influence each other's pharmacokinetics and renal elimination?

P

Population

90 human volunteers (healthy males, middle-aged 45-64 years, elderly 65-80 years, and individuals with mild-to-moderate renal impairment), alongside rat (n=61) and porcine (n=30) models, evaluated for up to 122 hours after dosing.

I

Intervention

Idarucizumab intravenous infusion (1 g, 2 g, 2.5 g, 4 g, 5 g, or 2 x 2.5 g over 5 minutes in humans; 20 mg/kg IV bolus in rats; 30, 60, or 120 mg/kg IV in pigs) administered alone or after oral dabigatran etexilate (220 mg or 150 mg twice daily in humans; 30 mg/kg twice daily plus IV dabigatran in pigs; 0.2 mg/kg IV bolus in rats).

C

Comparator

Matching placebo (or saline in pigs), idarucizumab alone without dabigatran, dabigatran alone without idarucizumab, and sham-operated control rats with normal renal function.

O

Outcome

Pharmacokinetic parameters (plasma AUC0-∞, clearance, initial and terminal half-life) and cumulative fraction of unchanged idarucizumab and dabigatran dose recovered in urine (fe) over 48 hours (rats), 4 hours (pigs), and up to 122 hours (humans).surrogate

Main Result

Absolute Event Rate: 38.9% vs 10.7%

Idarucizumab and dabigatran are eliminated together as a stable complex via renal catabolism and urinary excretion, with renal impairment increasing exposure to both agents without causing re-release of active dabigatran into plasma.

Limitations

Only subjects with mild and moderate renal impairment were included, so effects in severe renal impairment are unknown.
Animal models may not accurately reflect human pharmacokinetics of dabigatran or idarucizumab (e.g., larger biliary excretion of dabigatran in rats than humans).
Only subjects with mild and moderate renal impairment were included, and the effects in patients with severe renal impairment are not known.
Animal models may not accurately reflect the human pharmacokinetics of dabigatran or idarucizumab (e.g., the proportion of dabigatran cleared via biliary excretion is larger in rats than in humans).

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Implication

Renal impairment may increase exposure without active dabigatran re-release; leaves open human translation.

Abstract

Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of idarucizumab and investigate the influence of idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged idarucizumab increased with increasing idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of idarucizumab was unaffected by dabigatran. In contrast, idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by idarucizumab. Urinary excretion of dabigatran after administration of idarucizumab was delayed, but total dabigatran excreted in urine was unaffected. Idarucizumab and dabigatran were eliminated together via renal pathways.

Discussion

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Cite This Study

Glund et al. (2018) studied Dabigatran anticoagulation reversal and renal impairment (n=90). Idarucizumab with or without dabigatran etexilate vs. Matching placebo or sham-operated controls, with or without background dabigatran administration was evaluated on Pharmacokinetics (AUC, clearance, half-life) and cumulative urinary excretion (fe) of idarucizumab and dabigatran. Idarucizumab and dabigatran are eliminated together via renal pathways with dose-dependent idarucizumab urinary excretion and unchanged total dabigatran excretion.

synapsesocial.com/papers/6a848f712327ba91ab8d98d8 https://doi.org/10.1177/1076029618755947

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The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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