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Research ArticleArticle

Pharmacokinetic Modeling of Warfarin І – Model-Based Analysis of Warfarin Enantiomers with a Target Mediated Drug Disposition Model Reveals CYP2C9 Genotype-Dependent Drug-Drug Interactions of S-Warfarin

Shen Cheng, Darcy R. Flora, Allan E. Rettie, Richard C. Brundage and Timothy S. Tracy
Drug Metabolism and Disposition September 2022, 50 (9) 1287-1301; DOI: https://doi.org/10.1124/dmd.122.000876

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Study Design Diagram. Each subject went through 3 study periods (upper dark blue section). Period 1 (red box), single 10 mg dose of warfarin. Periods 2 and 3 in crossover (yellow box), each subject was pretreated with either 400 of mg fluconazole or 300 mg of rifampin once daily for 7 consecutive days, followed by a single 10 mg dose of warfarin and continuous treatment with either 400 mg of fluconazole or 300 mg of rifampin once daily through the sampling phase. Notes: q.d.: Once daily.

  • Fig. 2.
    Fig. 2.

    PK model structure for S- and R-warfarin. Notes: Periph: peripheral; Cent: central.

  • Fig. 3.
    Fig. 3.

    PK profiles for S-warfarin in plasma (A) and urine (B) and R-warfarin in plasma (C) and urine (D). All the PK profiles are stratified by co-treatments. Colors represent different CYP2C9 genotypes as shown in figure legends. Plots are on log scales. Points represent mean and error bars represent 95% confidence intervals.

  • Fig. 4.
    Fig. 4.

    VPCs for S-warfarin PK profiles in plasma (A) and urine (B). Blue dots represent the observations. Red solid lines represent the medians of model predicted concentrations. The upper and lower red dashed lines represent the 10th and 90th percentiles of the model predicted concentrations, respectively. The figure is stratified by genotypes and co-treatments. The black dashed lines represent the LLOQ for S-warfarin (0.67 ng/ml). No observations were collected from CYP2C9 *1B/*1B subjects and treated with warfarin plus fluconazole. Note: Warf: warfarin; Flu: fluconazole; Rif: rifampin; *1/*1: CYP2C9 *1/*1; *1B/*1B: CYP2C9 *1B/*1B; *1/*3: CYP2C9 *1/*3; *2/*3: CYP2C9 *2/*3; *3/*3: CYP2C9 *3/*3.

  • Fig. 5.
    Fig. 5.

    VPCs for R-warfarin PK profiles in plasma (A) and urine (B). Blue dots represent the observations. Red solid lines represent the medians of model predicted concentrations. The upper and lower red dashed lines represent the 10th and 90th percentiles of the model predicted concentrations, respectively. The figure is stratified by genotypes and co-treatments. The black dashed lines represent the LLOQ for R-warfarin (0.67 ng/ml). No observations were collected from CYP2C9 *1B/*1B subjects and treated with warfarin plus fluconazole. Note: Warf: warfarin; Flu: fluconazole; Rif: rifampin; *1/*1: CYP2C9 *1/*1; *1B/*1B: CYP2C9 *1B/*1B; *1/*3: CYP2C9 *1/*3; *2/*3: CYP2C9 *2/*3; *3/*3: CYP2C9 *3/*3.

  • Fig. 6.
    Fig. 6.

    Genotype-dependent CL changes of S-warfarin following the administration of fluconazole (A) and rifampin (B). The dots and error bars represent the typical values and 95% CIs, respectively. The 95% CIs are constructed with RSE as shown in Table 1 assuming a symmetric normal distribution.

Tables

  • TABLE 1

    Summary of population PK parameter estimations for S-warfarin

    ParametersDefinitionsEstimates (RSE)SIR medians (95% CIs)IIV/IOV Estimates (RSE)IIV/IOV SIR medians (95% CIs)ShrinkageUnitsSource
    KaAbsorption rate constant2/hourFixed
    CLClearance for subjects with CYP2C9 *1/*1 when warfarin is administered alone0.260 (8%)0.261 (0.221,0.301)22.9% (19%)22.7% (17.5%, 27.8%)1%L/hourEstimated by plasma model
    VCCentral compartment volume of distribution for subjects with CYP2C9 *1/*1, *1B/*1B, *1/*3 and *3/*35.00 (8%)5.01 (4.42, 5.64)21.4% (12%)21.3% (15.8%, 26.1%)6%LEstimated by plasma model
    CLDDistribution clearance1.25 (18%)1.23 (0.94, 1.56)21.7% (37%)22.3% (5.8%, 34.8%)41%L/hourEstimated by plasma model
    VPPeripheral compartment volume of distribution3.81 (8%)3.80 (3.32, 4.24)12.9% (54%)13.5% (4.5%, 20.8%)32%LEstimated by plasma model
    KonAssociation rate constant between drug and receptor for subjects with CYP2C9 *1/*1, *1B/*1B and *1/*30.00494 (10%)0.00500 (0.00402, 0.00590)28.9% (44%)30.5% (11.9%, 46.9%)36%L /(µg*hour)Estimated by plasma model
    KoffDissociation rate constant for drug-receptor complex0.0405/hourFixed (Levy et al., 2003)
    RBLBaseline receptor level for subjects with CYP2C9 *1/*1, *1B/*1B and *1/*3.182 (10%)181 (155, 212)18.9% (26%) (IIV)19.6% (8.7%, 26.7%)30%µg/LEstimated by plasma model
    19.5% (18%) (IOV)19.5% (14.1%, 24.6%)32% (Period1)
    42% (Period2)
    40% (Period3)
    CLRRenal clearance0.00369 (5%)0.00368 (0.00337, 0.00401)20.1% (19%)22.5% (15.5%, 29.2%)11%L/hourEstimated by urine model
    BL_P2Period 2 baseline concentration in central compartment3.65 (18%)3.66 (2.53, 4.96)106% (15%)108% (74%, 153%)9%µg/LEstimated by plasma model
    BL_P3Period 3 baseline concentration in central compartment3.85 (29%)3.89 (2.18,5.97)174% (40%)172% (97%, 354%)22%µg/LEstimated by plasma model
    BLP_P2Period 2 baseline concentration in peripheral compartment1µg/LFixed
    BLP_P3Period 3 baseline concentration in peripheral compartment1µg/LFixed
    CL_Geno2% CL for subjects with CYP2C9 *1B/*1B (reference CYP2C9 *1/*1)88.5% (13%)88.8% (69.0%, 112.0%)Estimated by plasma model
    CL_Geno3% CL for subjects with CYP2C9 *1/*3 (reference CYP2C9 *1/*1)60.7% (11%)61.0% (49.0%, 75.6%)Estimated by plasma model
    CL_Geno4% CL for subjects with CYP2C9 *2/*3 (reference CYP2C9 *1/*1)27.7% (16%)27.8% (19.6%, 35.8%)Estimated by plasma model
    CL_Geno5% CL for subjects with CYP2C9 *3/*3 (reference CYP2C9 *1/*1)21.5% (14%)21.7% (16.3%, 27.4%)Estimated by plasma model
    CL_Flu_Geno1% of CL when administered with fluconazole for subjects with CYP2C9 *1/*130.5% (5%)30.5% (27.8%, 33.4%)12.5% (41%)12.7% (8.2%, 18.4%)25%Estimated by plasma model
    CL_Flu_Geno3% of CL when administered with fluconazole for subjects with CYP2C9 *1/*335.2% (5%)35.3% (32.1%, 38.4%)Estimated by plasma model
    CL_Flu_Geno4% of CL when administered with fluconazole for subjects with CYP2C9 *2/*340.3% (8%)40.4% (34.8%, 46.5%)Estimated by plasma model
    CL_Flu_Geno5% of CL when administered with fluconazole for subjects with CYP2C9 *3/*352.2% (7%)52.4% (44.8%, 59.3%)Estimated by plasma model
    CL_Rif_Geno1% of CL when administered with rifampin for subjects with CYP2C9 *1/*1215% (4%)215% (198%, 232%)11.0% (20%)11.3% (8.5%, 14.2%)8%Estimated by plasma model
    CL_Rif_Geno2% of CL when administered with rifampin for subjects with CYP2C9 *1B/*1B211% (5%)212% (190%, 233%)Estimated by plasma model
    CL_Rif_Geno3% of CL when administered with rifampin for subjects with CYP2C9 *1/*3219% (4%)218% (203%, 235%)Estimated by plasma model
    CL_Rif_Geno4% of CL when administered with rifampin for subjects with CYP2C9 *2/*3298% (8%)299% (253%, 347%)Estimated by plasma model
    CL_Rif_Geno5% of CL when administered with rifampin for subjects with CYP2C9 *3/*3293% (6%)294% (261%, 330%)Estimated by plasma model
    Vc_Geno4% VC for subjects with CYP2C9 *2/*3 (reference all other genotypes)55.6% (23%)56.0% (37.0%, 76.3%)Estimated by plasma model
    Kon_Geno4% Kon for subjects with CYP2C9 *2/*3 (reference *1/*1, *1B/*1B, *1/*3)83.7% (26%)86.3% (49.1%, 131.3%)Estimated by plasma model
    Kon_Geno5% Kon for subjects with CYP2C9 *3/*3 (reference *1/*1, *1B/*1B, *1/*3)51.8% (30%)54.0% (29.9%, 83.1%)Estimated by plasma model
    RBL_Geno4% RBL for subjects with CYP2C9 *2/*3 (reference *1/*1, *1B/*1B, *1/*3)251% (29%)255% (152%, 385%)Estimated by plasma model
    RBL_Geno5% RBL for subjects with CYP2C9 *3/*3 (reference *1/*1, *1B/*1B, *1/*3)189% (17%)193% (134%, 258%)Estimated by plasma model
    CLR_Flu% CLR when administered with fluconazole84.7% (5%)85.4% (77.8%, 93.2%)12.6% (48%)17.2% (9.0%, 24.5%)47%Estimated by urine model
    CLR_Rif% CLR when administered with rifampin130% (6%)132% (117%, 148%)23.4 (25%)27.4% (17.5%, 37.3%)27%Estimated by urine model
    σwarfRUV for warfarin alone period plasma7.40% (5%)7.43% (6.84%, 7.95%)Estimated by plasma model
    σwarf_FluRUV for warfarin + fluconazole period plasma5.44% (5%)5.49% (4.99%, 5.92%)Estimated by plasma model
    σwarf_RifRUV for warfarin + rifampin period plasma9.20% (5%)9.21% (8.54%, 9.93%)Estimated by plasma model
    σwarf_URUV for warfarin alone period urine26.0% (8%)27.8% (24.1%, 31.7%)Estimated by urine model
    σwarf_Flu_URUV for warfarin + fluconazole period urine29.8% (10%)29.9% (25.6%, 34.9%)Estimated by urine model
    σwarf_Rif_URUV for warfarin + rifampin period urine26.0% (10%)26.5% (22.4%, 31.4%)Estimated by urine model

    • Notes: IIV and IOV terms are expressed as CV% (Embedded Image; RUV terms are expressed as CV% (Embedded Image).

  • TABLE 2

    Summary of population PK parameter estimations for R-warfarin

    ParametersDefinitionsEstimates (RSE)SIR medians (95% CIs)IIV/IOV Estimates (RSE)IIV/IOV SIR medians (95% CIs)ShrinkageUnitsSource
    KaAbsorption rate constant2/hourFixed
    CLClearance when warfarin is administered alone0.119 (5%)0.119 (0.108, 0.131)28.3% (12%)29.1% (23.1%, 35.1%)0%L/hourEstimated by plasma model
    VCCentral compartment volume of distribution for subjects with CYP2C9 *1/*1, *1B/*1B and *1/*3.3.18 (8%)3.19 (2.75, 3.65)35.1% (11%)38.1% (30.1%, 45.1%)3%LEstimated by plasma model
    CLDDistribution clearance2.49 (2%)2.46 (2.36, 2.56)L/hourEstimated by plasma model
    VPPeripheral compartment volume of distribution4.79 (1%)4.79 (4.65, 4.93)LEstimated by plasma model
    KonAssociation rate constant between drug and receptor0.00137 (10%)0.00139 (0.00116, 0.00163)23.1% (64%)29.1% (10.1%, 46.1%)46%L /(µg*hour)Estimated by plasma model
    KoffDissociation rate constant for drug-receptor complex0.0405/hourFixed (Levy et al., 2003)
    RBLBaseline receptor level for subjects with CYP2C9 *1/*1, *1B/*1B..188 (13%)188 (154, 230)15.6% (77%) (IIV)23.1% (7.1%, 36.1%)57%µg/LEstimated by plasma model
    36.0% (23%) (IOV)37.1% (27.1%, 50.1%)29% (Period1) 44% (Period2) 45% (Period3)
    CLRRenal clearance0.00436 (5%)0.00433 (0.00396, 0.00480)24.8% (18%)27.4% (20.2%, 34.8%)8%L/hourEstimated by urine model
    BL_P2Period 2 baseline concentration in central compartment2.75 (23%)2.82 (1.84, 4.01)106% (33%)121% (77%, 203%)26%µg/LEstimated by plasma model
    BL_P3Period 3 baseline concentration in central compartment1.97 (13%)2.03 (1.57, 2.57)29.3% (64%)39.1% (20.1%, 63.1%)63%µg/LEstimated by plasma model
    BLP_P2Period 2 baseline concentration in peripheral compartment1µg/LFixed
    BLP_P3Period 3 baseline concentration in peripheral compartment1µg/LFixed
    CL_Flu% of CL when administered with fluconazole51.3% (4%)51.1% (48.1%, 55.1%)18.3% (13%)19.1% (15.1%, 23.1%)12%Estimated by plasma model
    CL_Rif% of CL when administered with rifampin for subjects with CYP2C9 *1/*1, *1B/*1B, *2/*3 and *3/*3.268% (3%)268% (254%, 282%)13.5% (14%)14.1% (11.1%, 17.1%)5%Estimated by plasma model
    CL_Rif_Geno4% of CL when administered with rifampin for subjects with CYP2C9 *2/*3.377% (10%)380% (316%, 451%)Estimated by plasma model
    Vc_Geno4% VC for subjects with CYP2C9 *2/*3 (reference *1/*1, *1B/*1B, *1/*3)71.1% (22%)73.1% (48.1%, 104.1%)Estimated by plasma model
    Vc_Geno5% VC for subjects with CYP2C9 *3/*3 (reference *1/*1, *1B/*1B, *1/*3)169% (19%)175% (121%, 236%)Estimated by plasma model
    RBL_Geno3% RBL for subjects with CYP2C9 *1/*3 (reference *1/*1, *1B/*1B)47.9% (17%)49.1% (36.1%, 65.1%)Estimated by plasma model
    RBL_Geno4% RBL for subjects with CYP2C9 *2/*3 (reference *1/*1, *1B/*1B)50.6% (22%)52.1% (31.1%, 74.1%)Estimated by plasma model
    RBL_Geno5% RBL for subjects with CYP2C9 *3/*3 (reference *1/*1, *1B/*1B)21.0% (22%)21.1% (14.1%, 30.1%)Estimated by plasma model
    CLR_Flu% of CLR when administered with fluconazole75.2% (5%)75.6% (67.8%, 83.1%)14.8% (58%)20.5% (11.2%, 31.2%)42%Estimated by urine model
    CLR_Rif% of CLR when administered with rifampin143% (8%)143% (123%, 165%)34.1% (22%)39.5% (28.0%, 52.6%)18%Estimated by urine model
    σwarfRUV for warfarin alone period plasma7.37% (4%)7.39% (6.82%, 8.05%)Estimated by plasma model
    σwarf_FluRUV for warfarin + fluconazole period plasma6.26% (5%)6.29% (5.73%, 6.88%)Estimated by plasma model
    σwarf_RifRUV for warfarin + rifampin period plasma8.60% (5%)8.59% (7.85%, 9.39%)Estimated by plasma model
    σwarf_URUV for warfarin alone period urine25.7% (8%)27.4% (24.1%, 30.7%)Estimated by urine model
    σwarf_Flu_URUV for warfarin + fluconazole period urine31.1% (10%)31.1% (26.9%, 36.3%)Estimated by urine model
    σwarf_Rif_URUV for warfarin + rifampin period urine26.8% (11%)27.8% (23.4%, 33.0%)Estimated by urine model

    • Notes: IIV and IOV terms are expressed as CV% (Embedded Image; RUV terms are expressed as CV% (Embedded Image).

Additional Files

  • Data Supplement

    • Supplemental Data -

      Supplemental Material 1:  R-warfarin urine PK model NONMEM code

    • Supplemental Data -

      Supplemental Material 2:  R-warfarin urine PK model NONMEM code


    • Supplemental Data -

      Supplemental Material 3:   S-warfarin plasma PK model NONMEM code

    • Supplemental Data -

      Supplemental Material 4:   S-warfarin urine PK model NONMEM code

    • Supplemental Data -

      Supplemental Table S1: Demographics for subjects with various CYP2C9 genotypes.

      Supplemental Table S2: Table for illustrating the general process of model development for S- and R-warfarin TMDD model.

      Supplemental Figure S1: CWRES vs TIME plots when modeling S-warfarin plasma PK profiles using a linear compartmental model.

      Supplemental Figure S2: CL_Flu and CL_Rif vs CYP2C9 genotypes plots.

      Supplemental Figure S3: Diagnostic plots for S-warfarin plasma stratified by co-treatments.

      Supplemental Figure S4: Diagnostic plots for S-warfarin plasma stratified by CYP2C9 genotypes.

      Supplemental Figure S5: Diagnostic plots for S-warfarin urine stratified by co-treatments.

      Supplemental Figure S6: Diagnostic plots for S-warfarin urine stratified by CYP2C9 genotypes.

      Supplemental Figure S7: Individual prediction checks for S-warfarin plasma and urine PK profiles.

      Supplemental Figure S8: Diagnostic plots for R-warfarin plasma stratified by co-treatments.

      Supplemental Figure S9: Diagnostic plots for R-warfarin plasma stratified by CYP2C9 genotypes.

      Supplemental Figure S10: Diagnostic plots for R-warfarin urine stratified by co-treatments.

      Supplemental Figure S11: Diagnostic plots for R-warfarin urine stratified by CYP2C9 genotypes.

      Supplemental Figure S12: Individual prediction checks for R-warfarin plasma and urine PK profiles.
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Interaction between CYP2C9 Genotypes and S-Warfarin DDIs

Shen Cheng, Darcy R. Flora, Allan E. Rettie, Richard C. Brundage and Timothy S. Tracy
Drug Metabolism and Disposition September 1, 2022, 50 (9) 1287-1301; DOI: https://doi.org/10.1124/dmd.122.000876
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