Pharmacokinetic determinants for the right dose of antiarrhythmic drugs

ABSTRACT

Introduction

Antiarrhythmic drugs (AADs) show a narrow therapeutic range and marked intersubject variability in pharmacokinetics (PK), which may lead to inappropriate dosing and drug toxicity.

Areas covered

The aim of the present review is to describe PK properties of AADs, discussing the main changes in different clinical scenarios, such as the elderly and patients with obese, chronic kidney, liver, and cardiac disease, in order to guide their right prescription in clinical practice.

Expert opinion

There are few data about PK properties of AADs in a special population or challenging clinical setting. The use and dose of AADs is commonly based on physicians’ clinical experience observing the clinical effects rather than being personalized on the individual patients PK profiles. More and updated studies are needed to validate a patient centered approach in the pharmacological treatment of arrhythmias based on patients’ clinical features, including pharmacogenomics, and AAD pharmacokinetics.

KEYWORDS:

• Antiarrhythmic drug
• arrhythmia
• pharmacokinetics
• pharmacogenomics
• therapeutic drug monitoring

Article highlights

• A limited number of clinical trials are directly addressed to the pharmacokinetics (PK) of antiarrhythmic drugs (AADs) in elderly patients. Significant age-related increases in drug half-life have been reported for digoxin, disopyramide, lidocaine, and quinidine. By contrast, aging does not seem to affect mexiletine PK.

• A 50% reduction in the AADs starting dose should be administered in the elderly compared to young patients.

• Obesity may affect AADs PK, however no specific recommendations are yet available for AADs dose adjustment in overweight and obese patients.

• Polymorphisms and mutations in the genes encoding proteins involved in drug metabolism seem to be important contributors to interindividual pharmacokinetic variability. Available guidelines recommend dose adjustment and specific prescription according to genetic polymorphisms.

• Liver, kidney and cardiac diseases may be responsible for PK variations of AADs. In these clinical settings, it seems appropriate to start at a low dose and to titrate until therapeutic response or evidence of toxic effects.

• Further studies are needed to validate a patient centered approach in the pharmacological treatment of arrhythmias based on patients’ clinical features, including pharmacogenomics, and AADs pharmacokinetics.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.