Abstract Number: PB0949
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: While hemophilia A treatment goals are evolving towards functional cures and health equity (Skinner, Haemophilia. 2019), FVIII products that achieve optimal bleed protection with weekly dosing remain an unmet need. BIVV001, a new class of FVIII replacement, circulates independently of endogenous von Willebrand factor (VWF) and provides high sustained FVIII activity (Konkle, Blood. 2018; Lissitchkov, Blood. 2019).
Aims: To develop a population model that characterizes BIVV001 PK and to identify factors that determine BIVV001 PK variability in adults with severe hemophilia A.
Methods: FVIII activity measured via a one-stage clotting assay during two clinical trials (NCT03205163, N=15; EudraCT: 2018-001535-51, N=24) was used to assess BIVV001 PK. Population PK was evaluated by maximum likelihood nonlinear mixed-effects modeling. Forward inclusion and backward elimination processes evaluated covariate effects. Diagnostic plots and objective function evaluation guided model building and goodness-of-fit assessment.
Results: BIVV001 population PK was best fitted with a one-compartment model with two covariates: body weight on clearance and body weight and hematocrit on central volume. VWF concentration was not a covariate, consistent with BIVV001 clearance being endogenous VWF-independent. Error models included interindividual variability in clearance and central volume, correlation between both, and proportional and additive residual errors (Table 1).
| Parameter | Estimate (95% CI) |
| Clearance, dL/hour Volume (central compartment), dL Allometric exponent of body weight on clearance Allometric exponent of body weight on central volume Exponent of hematocrit (fraction) on central volume |
0.434 (0.396, 0.476) 27.6 (26.0, 29.3) 0.703 (0.416, 0.990) 0.513 (0.322, 0.704) -0.568 (-0.974, -0.162) |
| Interindividual variability | |
| Interindividual variability clearance (%) Interindividual variability on central volume (%) Correlation of inter-individual variability clearance on central volume |
21.3 (15.1, 27.7) 15.1 (8.81, 21.5) 0.741 (0.541, 0.942) |
| Residual variability | |
| Proportional error (fraction) Additive error, IU/dL |
0.152 (0.140, 0.164) 0.196 (0.115, 0.277) |
| aPTT, activated partial thromboplastin time; CI, confidence interval; PK, pharmacokinetic. aBased on the one-stage (aPTT) clotting assay. |
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[Table 1. Parameter estimates for the BIVV001 population PK modela]
Clinical trial simulations were conducted for various BIVV001 regimens to support Phase 3 prophylactic BIVV001 dose selection (once-weekly 50 IU/kg). BIVV001 PK modeling demonstrated high sustained geometric mean FVIII activity in the normal to near-normal range (≥40%) for 3.2 days, ≥20% for 5.0 days, and ~10% for 7 days post dose (Table 2).
| FVIII activity | Time (hours)b | Time (days)b |
| 10% | 162.75 (148.43, 178.46) | 6.78 (6.18, 7.44) |
| 15% | 137.48 (124.97, 151.25) | 5.73 (5.21, 6.30) |
| 20% | 119.54 (108.22, 132.04) | 4.98 (4.51, 5.50) |
| 40% | 76.18 (67.22, 86.35) | 3.17 (2.80, 3.60) |
| aPTT, activated partial thromboplastin time; FVIII, factor VIII. aBased on the one-stage (aPTT) clotting assay. bValues are geometric mean (95% confidence interval). |
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[Table 2. Estimated time to FVIII activity levels at 50 IU/kg BIVV001 steady state in adult subjects with severe hemophilia A (n=9)a]
Conclusions: Population PK analyses provided comprehensive quantitative characterization of BIVV001 activity-time profiles in adults with severe hemophilia A. Population PK modeling predicts high sustained FVIII activity in the normal to near-normal range for the first 3-4 days post dose to ~10% for one week after 50 IU/kg BIVV001.
To cite this abstract in AMA style:
Katragadda S, Denney WS, Willemze A, Benson C, Wong N. Population Pharmacokinetic (PK) Analysis of BIVV001 (Rfviiifc-VWF-XTEN), a New Class of Factor VIII (FVIII) Replacement [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/population-pharmacokinetic-pk-analysis-of-bivv001-rfviiifc-vwf-xten-a-new-class-of-factor-viii-fviii-replacement/. Accessed October 1, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/population-pharmacokinetic-pk-analysis-of-bivv001-rfviiifc-vwf-xten-a-new-class-of-factor-viii-fviii-replacement/