Immediate- versus controlled-release disopyramide: importance of saturable binding

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Clinical Pharmacy

Background:

• Saturable plasma protein binding can create a disconnect between total and unbound drug concentrations.
• This phenomenon may obscure pharmacokinetic differences between immediate-release (IR) and controlled-release (CR) formulations.
• Disopyramide exhibits saturable binding, necessitating careful pharmacokinetic evaluation.

Purpose of the Study:

• To investigate the impact of saturable plasma binding on disopyramide pharmacokinetics.
• To compare the pharmacokinetic profiles of IR and CR disopyramide formulations.
• To assess the relationship between drug formulation, binding characteristics, and pharmacologic effect.

Main Methods:

• Serial blood sampling during drug withdrawal and accumulation in patients on long-term disopyramide.
• Measurement of plasma disopyramide, protein binding, and alpha 1-acid glycoprotein levels.
• Assessment of pharmacologic effect using high-speed electrocardiograms (ECGs) and determination of pharmacokinetic parameters via nonlinear modeling.

Main Results:

• Saturable plasma binding was observed in all participants.
• Compared to total drug, unbound disopyramide exhibited longer elimination half-life and altered accumulation rates.
• CR disopyramide demonstrated lower peak unbound concentrations and reduced peak-to-trough ratios versus IR disopyramide, with less ECG variability.

Conclusions:

• Total plasma disopyramide concentrations do not accurately reflect unbound drug fluctuations or formulation-specific differences due to saturable binding.
• CR disopyramide formulation leads to diminished interdose variability in free drug levels.
• Controlled-release disopyramide provides more consistent pharmacologic effects, enhancing therapeutic management.