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  1. Advancing Regulatory Science

A Clinical Pharmacology Based Approach to Optimizing Digoxin Dosing in the Older Adult Population

CERSI Collaborators: Allison Dunn, PharmD, MS; Sandeep Devabhakthuni, PharmD, BCPS 
FDA Collaborators: Qi Liu, PhD; Shiew-Mei Huang, PhD; S. W. Johnny Lau, RPh, PhD; Doanh Tran, PhD; Lixia Zhang, PhD; Hao Zhu, PhD; Robert Temple, MD 
Project Start Date: May 24, 2023

Regulatory Science Challenge:

Cardiovascular disease is a substantial burden to the US healthcare system and is one of the leading causes of death. Under the umbrella of cardiovascular disease, millions of adults are diagnosed with heart failure each year. Digoxin is a highly effective treatment option for this disease; however, it poses a major challenge for clinicians due to its risk of severe toxicities, narrow therapeutic index, and extensive drug-drug interaction potential. Although the prevalence of heart failure only increases with age, digoxin has not been well characterized in older adults and uncertainty still exists around appropriateness of dose selection and accuracy of therapeutic targets. Therefore, a comprehensive assessment in older adults is necessary for clinicians to improve informed decisions on digoxin dosing and monitoring strategies.  

Project Description and Aims/Goals:

In this study, investigators will evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of digoxin to provide insight into optimal dosing and monitoring strategies for older adults. This will be accomplished through a three-step approach. First, investigators will assess the relationship between individual patient characteristics and digoxin exposure-response. These characteristics will include age, concomitant medications, comorbidities, and more. They will use this characterization to identify the need for adjustments in dosing and monitoring approaches among subpopulations. Second, they will assess the extent to which achieving current digoxin exposure targets results in the intended clinical outcome. Based on this culmination of information, investigators will explore alternative dosing and monitoring strategies that may inform therapy optimization.  

Anticipated Outcomes/Impact:

Investigators have collected and compiled the necessary data. They have also thoroughly summarized digoxin dosing and concentration measurements, identified key patient characteristics, and explored endpoints of interest. These endpoints include heart rate, time to restoration of normal sinus rhythm, echocardiographic parameters, cardiac performance biomarkers, such as brain natriuretic peptide (BNP) and N-terminal proBNP, number of hospitalizations, time to re-hospitalization, and mortality. Lastly, they have performed a preliminary analysis of the relationship between individual patient characteristics and these endpoints of interest.

By the end of this project, investigators will demonstrate a methodological framework to leverage real-world data to better inform clinical decision making in the under-studied older adult population. Investigators will provide insight into different patient- and treatment-related variables that explain the high variability of digoxin pharmacokinetics to increase understanding and safety of digoxin use in older adult populations.

 

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