A population pharmacokinetic-pharmacodynamic analysis and model validationof azimilide

Background. Pharmacokinetic (PK) and pharmacodynamic (PD) models for azimil ide were developed and validated with sparse blood sampling and QTc interva l data obtained during three clinical trials of azimilide for prevention of supraventricular arrhythmia recurrence. Methods: Patients were orally administered placebo or azimilide dihydrochlo ride, 35, 50, 75, 100, or 125 mg/d, for 6 to 9 months. NONMEM was used for data fitting and assessment of selected patient covariates and concomitant medication classes for PK/PD relationships. Results. Results indicate that azimilide clearance (CL) was dependent on bo dy weight (WTKG), gender, and current tobacco use, where CL (L/h) = 3.92 x (WTKG - 43)(0.208), with a 17% increase for male subjects and a 15.5% incre ase for current tobacco use. Volume of distribution (V) was also dependent on WTKG and total bilirubin (BIL), where V (L) = 9.88 x (WTKG - 43) + 717 x (BIL)(0.348). The PK/PD analysis indicated that the baseline QTc interval was dependent on gender, New York Heart Association Class, digoxin, and pac ed artificial pacemaker spike, whereas the 50% effective concentration (EC5 0) was dependent on the serum potassium (K) level, where EC50 = 107 x K. Th e change in EC50 was not clinically significant within the normal range for potassium. The mean E-max (maximum increase in the QTc interval for the E- max models) was a 61.7 ms increase from baseline. At 125 mg/d the predicted percent increase in the QTc interval at the maximum plasma drug concentrat ion at steady state was 9% and 10% for male and female patients, respective ly. The values of the median prediction error were -3% and -0.4% for the PK and PK/PD models, respectively, and the values of the absolute prediction error were 21% and 4% for the PK and PK/PD models, respectively, indicating that both models are essentially unbiased and acceptably accurate. Conclusions: Azimilide PK parameters are dependent on body weight, gender, smoking status, and bilirubin and are independent of the coadministration o f digoxin, warfarin, and cytochrome P4503A4 inhibitors and inducers. The re lationship between azimilide concentration and change in QTc is primarily d ependent on serum potassium.