TABLE 2.
Summary of parameter values used for prediction of garadacimab PK and interaction with FXIIa in humans
| Parameter | Description | Value | Source |
|---|---|---|---|
| Garadacimab pharmacokinetics | |||
| σ 1 | Vascular permeability coefficient for tight tissue | 0.98 | Same value as monkey |
| σ 2 | Vascular permeability coefficient for leaky tissue | 0.426 | Same value as monkey |
| CLp (ml/h/kg) | Plasma clearance of garadacimab | 0.137 | Allometric scaling with exponent 0.85 |
| F | s.c. bioavailability | 0.529 | Same value as monkey |
| ka (h−1) | First‐order s.c. absorption rate constant | 0.0107 | Allometric scaling with exponent −0.25 |
| FXIIa dynamics | |||
| FXIIaB (nmol/ml) | Baseline concentration of FXIIa | 0.395 | 17 |
| kon_FXII (ml/nmol/h) | Binding association constant | 3600 | Table S2 |
| k off_FXII (1/h) | Binding dissociation constant | 205 | Table S2 |
| kdeg_FXII (1/h) | Degradation rate constant | 0.017 | 17, 18 |
| k int (1/h) | Elimination rate constant of garadacimab‐FXII complex | 0.0031 | Allometric scaling with exponent 0.85, assuming elimination rate is the same as that of garadacimab |
| α | Exponent factor of FXIIa‐mediated kallikrein activity assay | 1.59 | Assuming the same assay‐specific parameter |
| aPTT assay | |||
| AAT | Slope | −0.259 | Assuming the same |
| AAI | Intercept | 28 | 19, 20 |
| Physiological parameter values 16 | |||
| ISF (ml/kg) | Total tissue interstitial fluid volume | 223 | |
| Kp | Available fraction of ISF for antibody distribution | 0.4 | |
| VP (ml/kg) | Plasma volume | 37.1 | |
| VL (ml/kg) | Lymph volume | 74.3 | |
| L (ml/h/kg) | Total lymph flow rate | 1.73 | |
Abbreviations: FXII(a), (activated) factor XII; PK, pharmacokinetic; SC, subcutaneous.