Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis

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Abstract

Background

Application of idarucizumab and hemodialysis are options to reverse the action of the oral anticoagulant dabigatran in emergency situations.

Objectives

The objectives of this study were to build and evaluate a mechanistic, whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of idarucizumab, including its effects on dabigatran plasma concentrations and blood coagulation, in healthy and renally impaired individuals, and to include the effect of hemodialysis on dabigatran exposure.

Methods

The idarucizumab model was built with the software packages PK-Sim® and MoBi® and evaluated using the full range of available clinical data. The default kidney structure in MoBi® was extended to mechanistically describe the renal reabsorption of idarucizumab and to correctly reproduce the reported fractions excreted into urine. To model the PD effects of idarucizumab on dabigatran plasma concentrations, and consequently also on blood coagulation, idarucizumab-dabigatran binding was implemented and a previously established PBPK model of dabigatran was expanded to a PBPK/PD model. The effect of hemodialysis on dabigatran was implemented by the addition of an extracorporeal dialyzer compartment with a clearance process governed by dialysate and blood flow rates.

Results

The established idarucizumab-dabigatran-hemodialysis PBPK/PD model shows a good descriptive and predictive performance. To capture the clinical data of patients with renal impairment, both glomerular filtration and tubular reabsorption were modeled as functions of the individual creatinine clearance.

Conclusions

A comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy.

Electronic supplementary material

The online version of this article (10.1007/s40262-019-00857-y) contains supplementary material, which is available to authorized users.

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Most cited references 25

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The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).

Paul Reilly, Thorsten Lehr, Sebastian Haertter … (2014)

The goal of this study was to analyze the impact of dabigatran plasma concentrations, patient demographics, and aspirin (ASA) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients. The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, but a therapeutic concentration range has not been defined. In a pre-specified analysis of RE-LY, plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily (bid) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models. Patient demographics and ASA use were assessed descriptively and as covariates. Plasma concentrations were obtained from 9,183 patients, with 112 ischemic strokes/systemic emboli (1.3%) and 323 major bleeds (3.8%) recorded. Dabigatran levels were dependent on renal function, age, weight, and female sex, but not ethnicity, geographic region, ASA use, or clopidogrel use. A multiple logistic regression model (c-statistic 0.657, 95% confidence interval [CI]: 0.61 to 0.71) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations (p = 0.045), with age and previous stroke (both p < 0.0001) as significant covariates. Multiple logistic regression (c-statistic 0.715, 95% CI: 0.69 to 0.74) showed major bleeding risk increased with dabigatran exposure (p < 0.0001), age (p < 0.0001), ASA use (p < 0.0003), and diabetes (p = 0.018) as significant covariates. Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.

Stephen S Connolly, S Haertter, Muredach Reilly … (2011)

Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment. © 2011 International Society on Thrombosis and Haemostasis.

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Proteinuria: detection and role in native renal disease progression.

José Górriz, Alberto Martínez-Castelao (2012)

The presence of albuminuria or proteinuria constitutes a sign of kidney damage and, together with the estimation of glomerular filtration rate, is based on the evaluation of chronic kidney disease. Proteinuria is a strong marker for progression of chronic kidney disease, and it is also a marker of increased cardiovascular morbimortality. Filtration of albumin by the glomerulus is followed by tubular reabsorption, and thus, the resulting albuminuria reflects the combined contribution of these 2 processes. Dysfunction of both processes may result in increased excretion of albumin, and both glomerular injury and tubular impairment have been involved in the initial events leading to proteinuria. Independently of the underlying causes, chronic proteinuric glomerulopathies have in common the sustained or permanent loss of selectivity of the glomerular barrier to protein filtration. The integrity of the glomerular filtration barrier depends on its 3-layer structure (the endothelium, the glomerular basement membrane, and the podocytes). Increased intraglomerular hydraulic pressure or damage to glomerular filtration barrier may elicit glomerular or overload proteinuria. The mechanisms underlying glomerular disease are very variable and include infiltration of inflammatory cells, proliferation of glomerular cells, and malfunction of podocyte-associated molecules such as nephrin or podocin. Albumin is filtered by the glomeruli and reabsorbed by the proximal tubular cells by receptor-mediated endocytosis. Internalization by endocytosis is followed by transport into lysosomes for degradation. The multiligand receptors megalin and cubilin are responsible for the constitutive uptake in this mechanism. Albumin and its ligands induce expression of inflammatory and fibrogenic mediators resulting in inflammation and fibrosis resulting in the loss of renal function as a result of tubular proteinuria. TGF-β, which may be induced by albumin exposure, may also act in a feedback mechanism increasing albumin filtration and at the same time inhibiting megalin- and cubilin-mediated albumin endocytosis, leading to increased albuminuria. Urinary proteins themselves may elicit proinflammatory and profibrotic effects that directly contribute to chronic tubulointerstitial damage. Multiple pathways are involved, including induction of tubular chemokine expression, cytokines, monocyte chemotactic proteins, different growth factors, and complement activation, which lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis. This tubulointerstitial injury is one of the key factors that induce the renal damage progression. Therefore, high-grade proteinuria is an independent mediator of progressive kidney damage. Glomerular lesions and their effects on the renal tubules appear to provide a critical link between proteinuria and tubulointerstitial injury, although several other mechanisms have also been involved. Injury is transmitted to the interstitium favoring the self-destruction of nephrons and finally of the kidney structure. Copyright © 2012. Published by Elsevier Inc.

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Author and article information

Contributors

Thorsten Lehr:

ORCID: http://orcid.org/0000-0002-8372-1465

thorsten.lehr@mx.uni-saarland.de

Journal

Journal ID (nlm-ta): Clin Pharmacokinet

Journal ID (iso-abbrev): Clin Pharmacokinet

Title: Clinical Pharmacokinetics

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0312-5963

ISSN (Electronic): 1179-1926

Publication date (Electronic): 4 February 2020

Publication date PMC-release: 4 February 2020

Publication date (Print): 2020

Volume: 59

Issue: 6

Pages: 809-825

Affiliations

[1 ]GRID grid.11749.3a, ISNI 0000 0001 2167 7588, Clinical Pharmacy, , Saarland University, ; Campus C2 2, Saarbruecken, 66123 Germany

[2 ]GRID grid.267301.1, ISNI 0000 0004 0386 9246, Department of Pharmaceutical Sciences, College of Pharmacy, , The University of Tennessee Health Science Center, ; Memphis, TN USA

Author information

Thorsten Lehr http://orcid.org/0000-0002-8372-1465

Article

Publisher ID: 857

DOI: 10.1007/s40262-019-00857-y

PMC ID: 7292816

PubMed ID: 32020532

SO-VID: 50119a21-b915-4167-8aa1-98e49d6f7aa7

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;

Award ID: 031L0161C

Award Recipient : Thorsten Lehr

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Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis

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Abstract

Background

Objectives

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Open source discrete and agent-based modeling frameworks for biology

Most cited references 25

The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.

Proteinuria: detection and role in native renal disease progression.

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Cited by 4

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