IMMEDIATE-RELEASE VERSUS CONTROLLED-RELEASE DISOPYRAMIDE - IMPORTANCEOF SATURABLE BINDING

Objective: To examine the effects of saturable plasma binding on the p harmacokinetics of immediate-release (IR) and controlled-release (CR) disopyramide. Background: Saturable binding causes a lack of correspon dence between the pharmacokinetics of total and unbound plasma disopyr amide. Levels of total drug may therefore be insensitive to important differences between formulations. Methods: Patients receiving long-ter m disopyramide underwent serial blood sampling during withdrawal of eq uivalent doses of IR and CR disopyramide, and during accumulation of I R disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and alpha1- acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the c oncentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation w as determined by nonlinear modeling. Results: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug show ed that peak-to-trough ratios during steady state were smaller (1.45 v ersus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady-state lev els during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0. 05). Comparison of IR and CR disopyramide showed that unbound drug lev els for CR disopyramide revealed lower peak plasma concentrations (0.7 5 versus 0.96 mug/ml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in EC G intervals during usual dosing were observed only with IR disopyramid e. Conclusions: Because of saturable plasma binding, total plasma conc entrations underestimate fluctuations in unbound disopyramide during u sual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects.