Pharmacodynamic modeling of antiarrhythmic drug effects--application to 3-methoxy-O-demethyl encainide.

The pharmacodynamic characteristics of 3-methoxy-O-demethyl encainide (MODE) were studied in instrumented, chloralose-anesthetized dogs. The HIS Purkinje conduction times (HV) were utilized to assess drug effect. Two protocols were conducted; the first protocol involved multiple pairs of loading and maintenance infusions to achieve several steady-state plasma drug concentrations. The second protocol involved a single short infusion. The data from both protocols supported a linear concentration-effect relationship for the concentration range studied. The slopes and intercepts were similar for both data sets. The data from the second protocol were also analyzed to assess the temporal aspects of the pharmacodynamics of MODE. Data analysis indicated that there is significant hysteresis in the plasma concentration-effect relationship that is characterized by a first-order rate constant corresponding to a half-life (t1/2) of approximately 10 min. These study results also demonstrated the advantages of single-infusion protocols over multiple-infusion studies for evaluating the concentration-effect relationship of antiarrhythmic drugs.