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 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 clearance (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 renal clearance 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 drug-drug interactions 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.

SIGNIFICANCE STATEMENT The present study conducted population model-based analyses of 10 warfarin metabolites after racemic warfarin is administered either alone or together with metabolic inhibitors or inducers. The differential inhibition and induction of various elimination pathways of warfarin potentially explains the CYP2C9 genotype-dependent drug-drug interactions of S-warfarin. The analysis also facilitates a deeper understanding of warfarin disposition.

This manuscript was funded by National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM069753] (T.S.T.) and [Grant P01-GM032165] (T.S.T.).

↵1 Current affiliation: Metrum Research Group, Tariffville, Connecticut.

↵2 Current affiliation: GRYT Health Inc., Rochester, New York.

↵3 Current affiliation: Tracy Consultants, Huntsville, Alabama.

This work is part of the Ph.D. thesis of S.C.

Citation of meeting abstracts: Cheng S., Flora D.R., Tracy T. S., Rettie A.E., Brundage R.C. Genotype-Dependent Changes in Warfarin Clearance upon Co-administration of an Inhibitor (fluconazole) and an inducer (rifampin): A Model-based Analysis. American Conference of Pharmacometrics (ACOP) 11

The authors declare no conflict of interest.

dx.doi.org/10.1124/dmd.122.000877.

↵This article has supplemental material available at dmd.aspetjournals.org.