Table 2.
Estimated PK/PD parameters determined using nonlinear mixed-effects modeling
| Parameter | Estimate | RSE (%) | BSV (CV%) | RSE (%) |
|---|---|---|---|---|
| Crenezumab | ||||
| CLel (L/day) | 0.159 | 3.0 | 19.1 | 8.4 |
| CLint (L/day) | 1.01 | 5.8 | 15.3 | 25 |
| Vcent (L) | 2.89 | 3.4 | 18.3 | 8.8 |
| Vperiph (L) | 1.84 | 10 | 75.2 | 9.7 |
| Q (L/day) | 0.142 | 4.8 | – | – |
| Fsc (%) | 66.2 | 3.9 | – | – |
| Ka (/day) | 0.161 | 6.4 | – | – |
| Kd Aβ(1–40) (nM) | 12.0 | 3.0 | 13.6a | 12 |
| Kd Aβ(1–42) (nM) | 9.37 | 2.5 | 13.6a | 12 |
| BWT (kg) on CLel | 0.835 | 12 | – | – |
| BWT (kg) on CLint | 0.474 | 42 | – | – |
| BWT (kg) on Vcent | 0.725 | 17 | – | – |
| Aβ(1–40) | ||||
| Baseline (pM) | 142 | 1.3 | 8.3 | 10 |
| Kdeg (/day) | 114 | 5.7 | 17.9a | 12 |
| Q (L/day) | 8.72 | 31 | – | – |
| Vperiph (L) | 3.77 | 11 | – | – |
| Age (year) on baseline | 0.0037 | 27 | ||
| GFR (mL/min/1.73 m2) on baseline | − 0.0035 | 20 | ||
| Sex (male) on Kdegb | − 0.16 | 36 | ||
| Aβ(1–42) | ||||
| Baseline (pM) | 5.98 | 1.7 | 13.8 | 9.9 |
| Kdeg (/day) | 287 | 6.5 | 17.9a | 12 |
| Q (L/day) | 229 | 15 | – | – |
| Vperiph (L) | 8.19 | 7.8 | – | – |
| GFR (mL/min/1.73 m2) on baseline | − 0.0048 | 22 | ||
| Sex (male) on Kdegb | − 0.16 | 36 | ||
Patient factors are incorporated as the exponential and linear form on the parameters for crenezumab and Aβ, respectively. aSame BSV was used on Aβ(1–40) and Aβ(1–42) for Kd and Kdeg. bThe same coefficient was used on Aβ(1–40) and Aβ(1–42) for covariate effect of sex on Kdeg. Abbreviations: Aβ beta-amyloid, BSV between-subject variability, BWT body weight, CLel elimination clearance (of crenezumab), CLint intrinsic clearance (of crenezumab–Aβ complex), CV coefficient of variation, FSC subcutaneous bioavailability, GFR glomerular filtration rate, Ka absorption rate constant, Kd equilibrium constant governing antibody-ligand binding, Kdeg degradation rate constant, PD pharmacodynamics, PK pharmacokinetics, Q inter-compartment clearance, RSE relative standard error, Vcent central volume of distribution, Vperiph peripheral distribution volume