Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence: Analyses from the EURIDIS and ADONIS studies

Munveer Thind; David S. McKindley; James A. Reiffel; Gerald V. Naccarelli; John Stewart; Peter R. Kowey

doi:10.1002/clc.23768

Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence: Analyses from the EURIDIS and ADONIS studies

Munveer Thind, David S. McKindley, James A. Reiffel, Gerald V. Naccarelli, John Stewart, Peter R. Kowey

Research output: Contribution to journal › Article › peer-review

Abstract

Background: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. Hypothesis: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above- and below-median trough concentrations, does not impact the efficacy outcomes. Methods: Average trough concentrations (C_{trough_avg}) across multiple timepoints were calculated for each patient, and patient C_{trough_avg} values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone C_{trough_avg} was assessed in the below-median versus above-median groups. The effect of dronedarone in each C_{trough_avg} group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. Results: Overall, 1795 plasma samples were available from 507 dronedarone-treated patients. An above-median C_{trough_avg} was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below-median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56–0.91; p =.0054) and above-median groups (HR: 0.63; 95% CI: 0.50–0.81; p =.0002). No difference in risk of AF/AFL recurrence was observed between the above- and below-median groups. Safety and tolerability of dronedarone were similar between groups. Conclusion: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value.

Original language	English (US)
Pages (from-to)	119-128
Number of pages	10
Journal	Clinical Cardiology
Volume	45
Issue number	1
DOIs	https://doi.org/10.1002/clc.23768
State	Published - Jan 2022

All Science Journal Classification (ASJC) codes

Cardiology and Cardiovascular Medicine

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10.1002/clc.23768

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@article{232c81b2e6084f48b10bd49dcdbb09be,

title = "Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence: Analyses from the EURIDIS and ADONIS studies",

abstract = "Background: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. Hypothesis: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above- and below-median trough concentrations, does not impact the efficacy outcomes. Methods: Average trough concentrations (Ctrough_avg) across multiple timepoints were calculated for each patient, and patient Ctrough_avg values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone Ctrough_avg was assessed in the below-median versus above-median groups. The effect of dronedarone in each Ctrough_avg group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. Results: Overall, 1795 plasma samples were available from 507 dronedarone-treated patients. An above-median Ctrough_avg was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below-median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56–0.91; p =.0054) and above-median groups (HR: 0.63; 95% CI: 0.50–0.81; p =.0002). No difference in risk of AF/AFL recurrence was observed between the above- and below-median groups. Safety and tolerability of dronedarone were similar between groups. Conclusion: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value.",

author = "Munveer Thind and McKindley, {David S.} and Reiffel, {James A.} and Naccarelli, {Gerald V.} and John Stewart and Kowey, {Peter R.}",

note = "Funding Information: David S. McKindley and John Stewart are employees of Sanofi US Inc. James A. Reiffel has received personal fees (during the study) from Sanofi and personal fees (outside of the submitted work) from Acesion Pharma, Medtronic, Janssen Pharmaceuticals, and Roivant Sciences. Gerald V. Naccarelli has received the following (outside of the submitted work): personal fees from Acesion Pharma, GlaxoSmithKline, Janssen Pharmaceuticals, Milestone Pharmaceuticals, Omeicos Therapeutics, and Sanofi and grants from Janssen Pharmaceuticals. Peter R. Kowey is an ad hoc consultant for Sanofi. Munveer Thind has no conflict of interests. Funding Information: This study was supported by Sanofi US Inc., and was also responsible for generating the data for this analysis. The authors would like to thank all the patients and their caregivers who took part in the EURIDIS and ADONIS studies. Under the direction of the authors and in accordance with GPP3 guidelines, medical writing and editorial support was provided by Meenakshi Subramanian, PhD, CMPP, and Barrie Anthony, PhD, CMPP, Evidence Medical Affairs (Philadelphia, PA, USA). Funding Information: This study was supported by Sanofi US Inc., and was also responsible for generating the data for this analysis. The authors would like to thank all the patients and their caregivers who took part in the EURIDIS and ADONIS studies. Under the direction of the authors and in accordance with GPP3 guidelines, medical writing and editorial support was provided by Meenakshi Subramanian, PhD, CMPP, and Barrie Anthony, PhD, CMPP, Evidence Medical Affairs (Philadelphia, PA, USA). Publisher Copyright: {\textcopyright} 2022 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.",

year = "2022",

month = jan,

doi = "10.1002/clc.23768",

language = "English (US)",

volume = "45",

pages = "119--128",

journal = "Clinical Cardiology",

issn = "0160-9289",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

TY - JOUR

T1 - Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence

T2 - Analyses from the EURIDIS and ADONIS studies

AU - Thind, Munveer

AU - McKindley, David S.

AU - Reiffel, James A.

AU - Naccarelli, Gerald V.

AU - Stewart, John

AU - Kowey, Peter R.

N1 - Funding Information: David S. McKindley and John Stewart are employees of Sanofi US Inc. James A. Reiffel has received personal fees (during the study) from Sanofi and personal fees (outside of the submitted work) from Acesion Pharma, Medtronic, Janssen Pharmaceuticals, and Roivant Sciences. Gerald V. Naccarelli has received the following (outside of the submitted work): personal fees from Acesion Pharma, GlaxoSmithKline, Janssen Pharmaceuticals, Milestone Pharmaceuticals, Omeicos Therapeutics, and Sanofi and grants from Janssen Pharmaceuticals. Peter R. Kowey is an ad hoc consultant for Sanofi. Munveer Thind has no conflict of interests. Funding Information: This study was supported by Sanofi US Inc., and was also responsible for generating the data for this analysis. The authors would like to thank all the patients and their caregivers who took part in the EURIDIS and ADONIS studies. Under the direction of the authors and in accordance with GPP3 guidelines, medical writing and editorial support was provided by Meenakshi Subramanian, PhD, CMPP, and Barrie Anthony, PhD, CMPP, Evidence Medical Affairs (Philadelphia, PA, USA). Funding Information: This study was supported by Sanofi US Inc., and was also responsible for generating the data for this analysis. The authors would like to thank all the patients and their caregivers who took part in the EURIDIS and ADONIS studies. Under the direction of the authors and in accordance with GPP3 guidelines, medical writing and editorial support was provided by Meenakshi Subramanian, PhD, CMPP, and Barrie Anthony, PhD, CMPP, Evidence Medical Affairs (Philadelphia, PA, USA). Publisher Copyright: © 2022 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.

PY - 2022/1

Y1 - 2022/1

N2 - Background: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. Hypothesis: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above- and below-median trough concentrations, does not impact the efficacy outcomes. Methods: Average trough concentrations (Ctrough_avg) across multiple timepoints were calculated for each patient, and patient Ctrough_avg values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone Ctrough_avg was assessed in the below-median versus above-median groups. The effect of dronedarone in each Ctrough_avg group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. Results: Overall, 1795 plasma samples were available from 507 dronedarone-treated patients. An above-median Ctrough_avg was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below-median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56–0.91; p =.0054) and above-median groups (HR: 0.63; 95% CI: 0.50–0.81; p =.0002). No difference in risk of AF/AFL recurrence was observed between the above- and below-median groups. Safety and tolerability of dronedarone were similar between groups. Conclusion: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value.

AB - Background: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. Hypothesis: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above- and below-median trough concentrations, does not impact the efficacy outcomes. Methods: Average trough concentrations (Ctrough_avg) across multiple timepoints were calculated for each patient, and patient Ctrough_avg values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone Ctrough_avg was assessed in the below-median versus above-median groups. The effect of dronedarone in each Ctrough_avg group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. Results: Overall, 1795 plasma samples were available from 507 dronedarone-treated patients. An above-median Ctrough_avg was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below-median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56–0.91; p =.0054) and above-median groups (HR: 0.63; 95% CI: 0.50–0.81; p =.0002). No difference in risk of AF/AFL recurrence was observed between the above- and below-median groups. Safety and tolerability of dronedarone were similar between groups. Conclusion: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value.

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DO - 10.1002/clc.23768

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SN - 0160-9289

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JO - Clinical Cardiology

JF - Clinical Cardiology

IS - 1

ER -

Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence: Analyses from the EURIDIS and ADONIS studies

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