Table 4.
Parameter Estimates of the Population PK (VWF:RCo) and PK/PD (FVIII) Models
| Parameter | rVWF Model | pdVWF/FVIII Model | ||
|---|---|---|---|---|
| Point Estimate | RSE (%)a | Point Estimate | RSE (%) | |
| VWF:RCo PK model | ||||
| CL, dL/h | 2.10 | 8.10 | 4.14 | 12.7 |
| Vc, dL | 43.5 | 4.98 | 47.0 | 16.7 |
| Q, dL/h | 2.29 | 12.2 | 4.47 | 12.3 |
| Vp, dL | 15.8 | 4.47 | 19.3 | 3.12 |
| EVWF, VWD type 3, IU/dL | 0.500 | (FIX) | 0.500 | (FIX) |
| WT effect on CL and Q | 0.750 | (FIX) | 0.750 | (FIX) |
| WT effect on Vc and Vp | 1.00 | (FIX) | 1.00 | (FIX) |
| Hematocrit effect on Vc | −0.334 | 37.5 | −0.334 | (FIX) |
| IIV CL, CVb | 0.401 | 9.88 | 0.235 | 38.3 |
| IIV Vc, CVb | 0.292 | 10.7 | 0.373 | 51.7 |
| Proportional RUV, CVb | 0.138 | 1.26 | 0.0479 | 14.1 |
| Additive RUV, IU/dLb | 2.80 | 2.08 | 1.48 | 12.4 |
| FVIII PK/PD model | ||||
| Baseline FVIII, IU/dLc,d | 0.500 | – | 0.500 | (FIX) |
| kout, h−1 c | 15.9 | – | 15.9 | (FIX) |
| Imax | 0.998 | – | 0.994 | 0.0378 |
| IC50, IU/dL | 0.0658 | – | 0.0577 | 20.4 |
| Hematocrit effect on baseline FVIII | −0.571 | – | −0.571 | (FIX) |
| FVIII V, dL | – | – | 32.9 | 1.65 |
| IIV baseline FVIII, CV | 0.296 | – | 0.215 | 44.4 |
| IIV IC50, CV | 0.588 | – | 0.542 | 29.4 |
| Proportional RUV, CV | 0.190 | – | 0.172 | 2.50 |
| Additive RUV, IU/dL | 1.55 | – | 2.91 | 15.5 |
Notes: aThe precision in parameter estimates for the rVWF PK/PD model was estimated using a bootstrap method, which showed that the population estimates of the final model were within the 2.5th to 97.5th percentile obtained from the bootstrap analysis (data not shown). bRSE reported on the approximate standard deviation scale. cParameter was fixed in the pdVWF/FVIII model. dThe estimated baseline FVIII:C represents the theoretical baseline FVIII:C assuming that no VWF is affecting kout.
Abbreviations: CL, clearance; CV, coefficient of variation; EVWF, endogenous von Willebrand factor; FVIII, factor VIII; FVIII:C, FVIII activity; IC50, activity level at half maximum inhibition; IIV, interindividual variability; Imax, maximum inhibition; kout, first-order removal; PD, pharmacodynamic; pdVWF/FVIII, plasma-derived von Willebrand factor/FVIII; PK, pharmacokinetic; Q, intercompartmental clearance; RSE, relative standard error; RUV, residual unexplained variability; rVWF, recombinant von Willebrand factor; Vc, central volume of distribution; Vp, peripheral volume of distribution; FVIII V, volume of distribution for FVIII; VWD, von Willebrand disease; VWF:RCo, von Willebrand factor:ristocetin cofactor; WT, weight.