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Table 2 Estimated PK/PD parameters determined using nonlinear mixed-effects modeling

From: Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer’s disease

ParameterEstimateRSE (%)BSV (CV%)RSE (%)
 CLel (L/day)0.1593.019.18.4
 CLint (L/day)1.015.815.325
Vcent (L)2.893.418.38.8
Vperiph (L)1.841075.29.7
Q (L/day)0.1424.8
Fsc (%)66.23.9
Ka (/day)0.1616.4
Kd Aβ(1–40) (nM)
Kd Aβ(1–42) (nM)9.372.513.6a12
 BWT (kg) on CLel0.83512
 BWT (kg) on CLint0.47442
 BWT (kg) on Vcent0.72517
 Baseline (pM)1421.38.310
Kdeg (/day)1145.717.9a12
Q (L/day)8.7231
Vperiph (L)3.7711
 Age (year) on baseline0.003727  
 GFR (mL/min/1.73 m2) on baseline− 0.003520  
 Sex (male) on Kdegb− 0.1636  
 Baseline (pM)5.981.713.89.9
Kdeg (/day)2876.517.9a12
Q (L/day)22915
Vperiph (L)8.197.8
 GFR (mL/min/1.73 m2) on baseline− 0.004822  
 Sex (male) on Kdegb− 0.1636  
  1. 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