Pharmacokinetics of idarucizumab and its target dabigatran in patients requiring urgent reversal of the anticoagulant effect of dabigatran

Glund, Stephan; Coble, Kelly; Ganßer, Dietmar; Stangier, Joachim; Hoermann, Karin; Pollack, Charles V.; Reilly, Paul

doi:10.1111/jth.14476

Cited by 5 publications

(3 citation statements)

References 12 publications

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“…A signi cant increase in the risk of life-threatening bleedings during simultaneous use of NOACs and uconazole has been reported [25]. Moreover, during therapy with dabigatran, the use of itraconazole, a potent inhibitor of CYP3A4 and P-gp, is contraindicated [26,27]. Other anticoagulants include vitamin K antagonists (VKA) -warfarin and acenocoumarol.…”

Section: Discussionmentioning

confidence: 99%

Assessment of potential drug-to-drug interaction with antifungal agents in men with cardiovascular disease – a cross-sectional study of Polish population

Ryś-Czaporowska

Szykut-Badaczewska

Ulc

et al. 2023

Preprint

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Background Treatment of dermatological diseases in patients with concomitant cardiovascular is difficult due to reported interactions between antimycotic and cardiac drugs. The aim of the study was to assess the prescription frequency of drugs, causing potential interaction with antifungal drugs of superficial mycoses in patients with cardiovascular disease. Methods The study consisted of 166 consecutive men discharged from a tertiary cardiac department who were screened for topical fungal infections and were analyzed for drugs prescribed at discharge, with possible interference with typically used antimycotic treatment. Results The mean age of the study population was 62.8 ± 12.1 years. 57 (49.1%) of patients had a clinical suspicion of superficial mycosis and were referred for further dermatological investigation. The use of cardiovascular drugs was frequent, with 24.5% taking NOACs, 54.8% receiving diuretics and 76.5% receiving statins. No difference in the use of any drug was noted according to the mycosis status. Conclusions Polypharmacy with drugs exhibiting a potential for drug-to-drug interaction with antifungal agents is common in patients with cardiovascular disease. When choosing the appropriate option for superficial mycoses treatment, the knowledge of potential interaction is crucial in dermatologists and cardiologists to avoid their harmful consequences including serious bleeding or live threatening arrhythmias.

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Section: Discussionmentioning

confidence: 99%

Assessment of potential drug-to-drug interaction with antifungal agents in men with cardiovascular disease – a cross-sectional study of Polish population

Ryś-Czaporowska

Szykut-Badaczewska

Ulc

et al. 2023

Preprint

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“…Details on all utilized clinical studies and on their assignment to a test or training dataset are provided in Table 1 and Table S1 of the Electronic Supplementary Material (ESM). For the presented PBPK analysis, experimental data of five published clinical trials were available [14,[17][18][19][20][21][22][23], including healthy, elderly, and renally impaired Caucasian individuals, healthy Japanese individuals, and a diverse group of patients requiring dabigatran reversal. Idarucizumab was applied intravenously in doses between 20 mg and 8000 mg, either alone or in combination with orally applied, steady-state dabigatran (150 mg or 220 mg of dabigatran etexilate).…”

Section: Idarucizumab Physiologically Based Pharmacokinetic Modelmentioning

confidence: 99%

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

2020

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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.

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“…A phase III study that investigated idarucizumab in dabigatran etexilate-treated patients with uncontrollable or life-threatening bleeding or in need of an emergency surgery or procedure showed that 5 g of idarucizumab can reverse the anticoagulant effect of dabigatran [17,27]. On the basis of the results of these studies, idarucizumab has a low immunogenic potential [28,29]. However, to date, the clinical pharmacology data of idarucizumab in Chinese population has been limited.…”

Section: Introductionmentioning

confidence: 99%

Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study

Wang

Zhao

et al. 2020

Adv Ther

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Introduction: Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with high affinity and reverses its anticoagulant effect. This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab in healthy Chinese subjects at steady state of dabigatran and explored the effect of idarucizumab on PK and PD of dabigatran. Methods: Twelve subjects received dabigatran etexilate treatment alone (220 mg twice daily, b.i.d., oral). After a washout period, the 12 subjects again received dabigatran etexilate (220 mg b.i.d., oral) and idarucizumab (2.5 ? 2.5 g, intravenous) 2 h after the last administration of dabigatran etexilate. Results: The geometric mean (gMean) values of area under the plasma concentration-time curve (AUC 0-? ) and maximum concentration (C max ) were 44,200 nmol h/L and 30,900 nmol/ L, respectively. An amount of 35.3 lmol of idarucizumab, corresponding to 33.8% of the total dose, was excreted by urine over 72 h. The area under the effect (AUEC above,2-12 ) in the presence and absence of idarucizumab was close to zero for all coagulation parameters, diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT), which indicated the reversal of dabigatran anticoagulation by idarucizumab. There were no serious adverse events reported in this study. No subject tested positive for anti-idarucizumab antibodies. Conclusion: Idarucizumab was well tolerated and no subject tested positive for anti-idarucizumab antibodies in this study. PK and PD of idarucizumab in healthy Chinese subjects at a steady state of dabigatran were comparable with those in Japanese and Caucasian subjects. Clinical registration: ClinicalTrials.gov Identifier No. NCT03086356.Zining Wang and Xia Zhao contributed equally to this work.

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Pharmacokinetics of idarucizumab and its target dabigatran in patients requiring urgent reversal of the anticoagulant effect of dabigatran

Cited by 5 publications

References 12 publications

Assessment of potential drug-to-drug interaction with antifungal agents in men with cardiovascular disease – a cross-sectional study of Polish population

Assessment of potential drug-to-drug interaction with antifungal agents in men with cardiovascular disease – a cross-sectional study of Polish population

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

Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study

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