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

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

Parameter	Estimate	RSE (%)	BSV (CV%)	RSE (%)
Crenezumab
CL_el (L/day)	0.159	3.0	19.1	8.4
CL_int (L/day)	1.01	5.8	15.3	25
V_cent (L)	2.89	3.4	18.3	8.8
V_periph (L)	1.84	10	75.2	9.7
Q (L/day)	0.142	4.8	–	–
F_sc (%)	66.2	3.9	–	–
K_a (/day)	0.161	6.4	–	–
K_d Aβ(1–40) (nM)	12.0	3.0	13.6^a	12
K_d Aβ(1–42) (nM)	9.37	2.5	13.6^a	12
BWT (kg) on CL_el	0.835	12	–	–
BWT (kg) on CL_int	0.474	42	–	–
BWT (kg) on V_cent	0.725	17	–	–
Aβ(1–40)
Baseline (pM)	142	1.3	8.3	10
K_deg (/day)	114	5.7	17.9^a	12
Q (L/day)	8.72	31	–	–
V_periph (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 K_deg^b	− 0.16	36
Aβ(1–42)
Baseline (pM)	5.98	1.7	13.8	9.9
K_deg (/day)	287	6.5	17.9^a	12
Q (L/day)	229	15	–	–
V_periph (L)	8.19	7.8	–	–
GFR (mL/min/1.73 m²) on baseline	− 0.0048	22
Sex (male) on K_deg^b	− 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 K_d and K_deg. ^bThe same coefficient was used on Aβ(1–40) and Aβ(1–42) for covariate effect of sex on K_deg. Abbreviations: Aβ beta-amyloid, BSV between-subject variability, BWT body weight, CL_el elimination clearance (of crenezumab), CL_int intrinsic clearance (of crenezumab–Aβ complex), CV coefficient of variation, F_SC subcutaneous bioavailability, GFR glomerular filtration rate, K_a absorption rate constant, K_d equilibrium constant governing antibody-ligand binding, K_deg degradation rate constant, PD pharmacodynamics, PK pharmacokinetics, Q inter-compartment clearance, RSE relative standard error, V_cent central volume of distribution, V_periph peripheral distribution volume

ISSN: 1758-9193