TABLE 2.
Summary of population PK parameter estimations for R-warfarin
| Parameters | Definitions | Estimates (RSE) | SIR medians (95% CIs) | IIV/IOV Estimates (RSE) | IIV/IOV SIR medians (95% CIs) | Shrinkage | Units | Source |
|---|---|---|---|---|---|---|---|---|
| Ka | Absorption rate constant | 2 | /hour | Fixed | ||||
| CL | Clearance when warfarin is administered alone | 0.119 (5%) | 0.119 (0.108, 0.131) | 28.3% (12%) | 29.1% (23.1%, 35.1%) | 0% | L/hour | Estimated by plasma model |
| VC | Central 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% | L | Estimated by plasma model |
| CLD | Distribution clearance | 2.49 (2%) | 2.46 (2.36, 2.56) | L/hour | Estimated by plasma model | |||
| VP | Peripheral compartment volume of distribution | 4.79 (1%) | 4.79 (4.65, 4.93) | L | Estimated by plasma model | |||
| Kon | Association rate constant between drug and receptor | 0.00137 (10%) | 0.00139 (0.00116, 0.00163) | 23.1% (64%) | 29.1% (10.1%, 46.1%) | 46% | L /(µg*hour) | Estimated by plasma model |
| Koff | Dissociation rate constant for drug-receptor complex | 0.0405 | /hour | Fixed (Levy et al., 2003) | ||||
| RBL | Baseline 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/L | Estimated by plasma model |
| 36.0% (23%) (IOV) | 37.1% (27.1%, 50.1%) | 29% (Period1) 44% (Period2) 45% (Period3) | ||||||
| CLR | Renal clearance | 0.00436 (5%) | 0.00433 (0.00396, 0.00480) | 24.8% (18%) | 27.4% (20.2%, 34.8%) | 8% | L/hour | Estimated by urine model |
| BL_P2 | Period 2 baseline concentration in central compartment | 2.75 (23%) | 2.82 (1.84, 4.01) | 106% (33%) | 121% (77%, 203%) | 26% | µg/L | Estimated by plasma model |
| BL_P3 | Period 3 baseline concentration in central compartment | 1.97 (13%) | 2.03 (1.57, 2.57) | 29.3% (64%) | 39.1% (20.1%, 63.1%) | 63% | µg/L | Estimated by plasma model |
| BLP_P2 | Period 2 baseline concentration in peripheral compartment | 1 | µg/L | Fixed | ||||
| BLP_P3 | Period 3 baseline concentration in peripheral compartment | 1 | µg/L | Fixed | ||||
| CL_Flu | % of CL when administered with fluconazole | 51.3% (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 fluconazole | 75.2% (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 rifampin | 143% (8%) | 143% (123%, 165%) | 34.1% (22%) | 39.5% (28.0%, 52.6%) | 18% | Estimated by urine model | |
| σwarf | RUV for warfarin alone period plasma | 7.37% (4%) | 7.39% (6.82%, 8.05%) | Estimated by plasma model | ||||
| σwarf_Flu | RUV for warfarin + fluconazole period plasma | 6.26% (5%) | 6.29% (5.73%, 6.88%) | Estimated by plasma model | ||||
| σwarf_Rif | RUV for warfarin + rifampin period plasma | 8.60% (5%) | 8.59% (7.85%, 9.39%) | Estimated by plasma model | ||||
| σwarf_U | RUV for warfarin alone period urine | 25.7% (8%) | 27.4% (24.1%, 30.7%) | Estimated by urine model | ||||
| σwarf_Flu_U | RUV for warfarin + fluconazole period urine | 31.1% (10%) | 31.1% (26.9%, 36.3%) | Estimated by urine model | ||||
| σwarf_Rif_U | RUV for warfarin + rifampin period urine | 26.8% (11%) | 27.8% (23.4%, 33.0%) | Estimated by urine model |
Notes: IIV and IOV terms are expressed as CV% (; RUV terms are expressed as CV% ().