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

Abstract

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 (CL_f) of 6- and 7-OH-S-warfarin decrease: 73.2% and 74.8%) but less inducible by rifampin (% CL_f of 6- and 7-OH-S-warfarin increase: 85% and 75%), compared with non-CYP2C9 mediated elimination pathways (% CL_f of 10-OH-S-warfarin and CL_R of S-warfarin decrease in the presence of fluconazole: 65.0% and 15.3%; % CL_f 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.

Keywords: drug-drug interactions; genetic polymorphism; pharmacokinetic modeling.

Fig. 1.

PK model structures for warfarin parent and metabolites. Dark blue frames: S-warfarin parent compound and metabolites models; dark red frames: R-warfarin parent compound and metabolites models. Cent, central; DR, drug-receptor complexes; M-Cent, metabolite central compartment; M-periph, metabolite peripheral compartment; M-urine, metabolite urine compartment; Periph, peripheral; R, receptors.

Fig. 2.

Plasma PK profiles for S-warfarin metabolites [left, 4’-(A), 6-(C), 7-(E), 8-(G), and 10-(I) OH-S-warfarin] and R-warfarin metabolites [right, 4’-(B), 6-(D), 7-(F), 8-(H), and 10-(J) OH-R-warfarin]. Colors represent subjects’ CYP2C9 genotypes. Plots are on log scales.

Fig. 3.

Urine PK profiles for S-warfarin metabolites [left, 4’-(A), 6-(C), 7-(E), 8-(G), and 10-(I) OH-S-warfarin] and R-warfarin metabolites (right, 4’-(B), 6-(D), 7-(F), 8-(H), and 10-(J) OH-R-warfarin]. Colors represent subjects’ CYP2C9 genotypes. Plots are on log scales.

Fig. 4.

Percentage changes in CL_f or CL_R of S-warfarin metabolites (A and B) and R-warfarin metabolites (C and D) after the administration of fluconazole (A and C) or rifampin (B and D). Colors represent the fluconazole and rifampin introduced inhibition and induction, respectively, as shown in the figure legend. Error bars represent 95% confidence intervals constructed with relative standard error (RSE) estimated from covariance steps assuming a symmetrical normal distribution.

Fig. 5.

S-warfarin metabolic profiles in subjects with different CYP2C9 genotypes after the administration of warfarin alone (A) and warfarin together with fluconazole (B) or rifampin (C). Color represents different elimination pathway as shown in the figure legend.

Fig. 6.

R-warfarin metabolic profiles in subjects with different CYP2C9 genotypes after the administration of warfarin alone (A) and warfarin together with fluconazole (B) or rifampin (C). Color represents different elimination pathway as shown in the figure legend.