Rational quinidine dosage regimen for atrial fibrillation in Thoroughbred racehorses based on population pharmacokinetics

Figures

• 

  Figure 1. Semilogarithmic spaghetti plots of the disposition curves of quinidine after administration of QND sulfate dihydrate at 20 mg/kg BW (16.58 mg/kg as QND base) in 6 healthy horses (black circle) at a single PO dose and in 4 healthy horses (open circle) administered twice at 6 h intervals.

• 

  Figure 2. Semilogarithmic spaghetti plots of the disposition curves of quinidine after a single IV dose administration of 5 mg/kg BW of QND sulfate (4.28 mg/kg as QND base) in 6 healthy horses.

• 

  Figure 3. Semilogarithmic spaghetti plots of the disposition curves of quinidine after multiple PO dose administrations between 9.3–30.6 mg/kg of QND sulfate dihydrate (7.7–25.4 mg/kg as QND base) in 19 horses that developed atrial fibrillation.

• 

  Figure 4. Conditional weighted residuals (CWRES) vs. time plot for PO administration (left) and IV administration (right). Values of CWRES were approximately N (0, 1) and hence concentrated between y = −2 and y = +2. Values significantly above 3 or below −3 should be suspected and may indicate a lack of fit and/or model misspecification. Inspection of the figure indicates that data were evenly distributed about zero and that the trends (as given by the blue line and the red line with its negative reflection) did not show any fanning, thus indicating no bias in the structural model.

• 

  Figure 5. Logarithmic plots of observed quinidine plasma concentrations vs. individual predictions (IPRED) (upper) and population predictions (PRED) (bottom) after PO (left plots) and IV (right plots) administrations.

• 

  Figure 6. Visual predictive check of observations vs. time after PO administration (left) and IV administration (right). The observed and predicted 10th and 90th percentiles are indicated using solid black and red lines, respectively. The observed and predicted 50th percentiles (median) are indicated using black and red dotted lines, respectively. Blue dots represent individual raw data.

• 

  Figure 7. The predicted quinidine concentrations for 5,000 simulated horses based on Monte Carlo simulations after PO administration of quinidine sulfate dihydrate 22 mg/kg (18.24 mg/kg as QND base) q 2 h (left) and q 6 h (right). The predicted concentrations for 10, 50% (median), and 90% of the populations are indicated using red, black and blue lines, respectively. The green area indicates the therapeutic range (2.0–3.8 μg/mL).

• 

  Figure 8. The predicted quinidine concentration for 5,000 simulated horses based on Monte Carlo simulations after PO administration of quinidine sulfate dihydrate 30 mg/kg (24.87 mg/kg as QND base) as loading dose and 6 mg/kg (4.97 mg/kg as QND base) q 2 h (left), and 45 mg/kg (37.31 mg/kg as QND base) as loading dose and 9 mg/kg (7.46 mg/kg as QND base) q 2 h (right). The predicted concentrations for 10, 50% (median), and 90% of the populations are indicated using red, black and blue lines, respectively. The green area indicates the therapeutic range (2.0–3.8 μg/mL).

• 

  Figure 9. The predicted quinidine concentration for 5,000 simulated horses based on Monte Carlo simulations after administration of quinidine sulfate dihydrate 15 mg/kg (12.44 mg/kg as QND base) as loading dose and 3 mg/kg (2.49 mg/kg as QND base) q 2 h three times as maintenance dose on first day, 30 mg/kg (24.87 mg/kg as QND base) as loading dose and 6.5 mg/kg (4.97 mg/kg as QND base) q 2 h three times on second day, and 40 mg/kg (33.16 mg/kg as QND base) as loading dose and 9 mg/kg (7.46 mg/kg as QND base) q 2 h three times on third day. The predicted concentrations for 10, 50% (median), and 90% of the populations are indicated using red, black and blue lines, respectively. The green area indicates the therapeutic range (2.0–3.8 μg/mL).