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We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four‐way, crossover, single‐dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (p < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/min) vs. 2-2.25 (8.3 ± 0.6 mL/min; p=0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/min; p=0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (p=0.03). There was also a greater reduction in HR with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; p<0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; p=0.095). These data highlight linear trends between CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.