Pharmacokinetic Modeling of Warfarin ІI – Model-Based Analysis of Warfarin Metabolites after 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 Rwarfarin), 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. Modelbased 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'-8and 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 comedications.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with VariousCYP2C9Genotypes under Different Cotreatments

“…Subjects possessing the CYP2C9 *2 and *3 variants experience higher S-warfarin exposure following warfarin administration and require lower warfarin maintenance doses (Dean, 2012). In subjects with the CYP2C9 *2 and *3 variants, non-CYP2C9 mediated elimination pathways occupy a higher proportion of overall S-warfarin elimination (Cheng et al, 2022b). A differential effect of fluconazole inhibition and rifampin induction on different metabolic pathways of S-warfarin was also noted, potentially explaining our observation of CYP2C9 genotype-dependent DDIs on S-warfarin PK in our previous population PK analysis (Cheng et al, 2022a).…”

“…The hepatic intrinsic CL values for S-and R-warfarin were separated into five metabolic pathways (4'-, 6-, 7-, 8-, 10-monohydroxylated (OH)) pathways. The proportion of each metabolite as a function of the overall clearance was based on the results of our previous warfarin metabolites population PK modeling study (Cheng et al, 2022b). The metabolic elimination of S-and Rwarfarin was assumed to be completely mediated by these five metabolic pathways.…”

“…The fractions of warfarin metabolic clearance by each metabolic pathway. Fraction values are calculated based on literature (Cheng et al, 2022b). Notes: The metabolic fractions presented in the original study for each parent compound were summed and rescaled to 100% to calculate the new fractions of hepatic intrinsic CL mediated by the various metabolic pathways.…”

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention‐Deficit/Hyperactivity Disorder

“…Although the formation of 4-OH is the predominant ATX elimination pathway in CYP2D6 AS ≥ 0.5 patients, minor metabolic pathways dominate when CYP2D6 activity is compromised. 30,31 Frequently referred to as "shifting" or "shunting" in the literature, the issue is more related to loss of the quantitatively most important pathway. Consider a situation where CYP2D6, CYP2C19, and CYP2B6 are responsible for 75%, 15%, and 10% of the total clearance of a compound -in essence a "pie" of 100 units, with slices of 75, 15, and 10 units.…”

“…Additionally, our analysis found that the contribution of 4‐OH to the overall metabolic elimination pathway decreased as the CYP2D6 AS (functional CYP2D6 activity) decreases ( Figure ). Although the formation of 4‐OH is the predominant ATX elimination pathway in CYP2D6 AS ≥ 0.5 patients, minor metabolic pathways dominate when CYP2D6 activity is compromised 30,31 . Frequently referred to as “shifting” or “shunting” in the literature, the issue is more related to loss of the quantitatively most important pathway.…”