Pharmacokinetic Modeling of Warfarin ІI - Model-based Analysis of Warfarin Metabolites following Warfarin Administered either Alone or Together with Fluconazole or Rifampin.

The objective of this study is to conduct a population pharmacokinetic (PK) model-based analysis on 10 warfarin metabolites (4'-, 6-, 7-, 8- and 10-hydroxylated (OH)-S- and R- warfarin), when warfarin is administered alone or together with either fluconazole or rifampin. One or two compartment PK models expanded from target mediated drug disposition (TMDD) models developed previously for warfarin enantiomers were able to sufficiently characterize the PK profiles of 10 warfarin metabolites in plasma and urine under different conditions. Model-based analysis shows CYP2C9 mediated metabolic elimination pathways are more inhibitable by fluconazole (% formation CL (CLf) of 6- and 7-OH-S-warfarin decrease: 73.2% and 74.8%) but less inducible by rifampin (% CLf of 6- and 7-OH-S-warfarin increase: 85% and 75%), compared with non-CYP2C9 mediated elimination pathways (% CLf of 10-OH-S-warfarin and CLR of S-warfarin decrease in the presence of fluconazole: 65.0% and 15.3%; % CLf of 4'- 8- and 10-OH-S-warfarin increase in the presence of rifampin: 260%, 127% and 355%), which potentially explains the CYP2C9 genotype-dependent DDIs exhibited by S-warfarin, when warfarin is administrated together with fluconazole or rifampin. Additionally, for subjects with CYP2C9 *2 and *3 variants, a model-based analysis of warfarin metabolite profiles in subjects with various CYP2C9 genotypes demonstrates CYP2C9 mediated elimination is less important and non-CYP2C9 mediated elimination is more important, compared with subjects without these variants. To our knowledge, this is so far one of the most comprehensive population-based PK analyses of warfarin metabolites in subjects with various CYP2C9 genotypes under different co-medications. Significance Statement The studies we wish to publish are potentially impactful. The need for a TMDD pharmacokinetic model and the demonstration of genotyped-dependent drug interactions may explain the extensive variability in dose-response relationships that are seen in the clinical dose adjustments of warfarin.