Table 2.

Final model parameter estimates

Model parameter	Parameter estimate	Bootstrap median	Bootstrap 95% CI
Risperidone (parent)
Fixed effects
Absorption rate constant (ka) (h−1)	2.01 (fix)a
Volume of distribution (V/F) (L)	333	317	177, 586
Clearance (CL/F) (L/h)
Base	4.2	4.2	3.6, 4.9
CYP2D6*1	23.2	22.5	15.4, 31.6
CYP2D6 allele (fraction of CYP2D6*1)
*2-rs5758550G	0.66	0.66	0.50, 0.85
*35	0.57	0.57	0.28, 0.90
*2-rs5758550A	0.30	0.31	0.17, 0.49
*9	0.39	0.40	0.20, 0.68
*10	0.32	0.33	0.15, 0.56
*41	0.15	0.16	0.08, 0.26
*3-*6	0 (fix)	-	-
NFIB allele (fraction of NFIB-T)
NFIB-C	1.41	1.41	1.15, 1.73
Age breaking point (years)	34	34	28, 38
Reduction per year (≥ breaking point)	− 0.9%	− 0.9%	− 1.2%, − 0.5%
Random effects
BSV CL/F (% CV)	86%	84%	69%, 103%
Residual error, proportional (%)	58%	58%	53%, 62%
Residual error, additive (ng/mL)	0.06	0.06	0.04, 0.15
9-hydroxyrisperidone (metabolite)
Fixed effects
Volume of distribution (Vmet/F × fmet)	96	97	77, 127
Clearance (CLmet/F × fmet)	8.0	8.0	7.5, 8.6
Age breaking point (years)	39	39	30, 48
Reduction per year (≥ breaking point)	− 1.3%	− 1.3%	− 1.6%, − 1.0%
Random effects
BSV CLmet/fmet (% CV)	49%	49%	43%, 55%
Residual error, proportional	38%	38%	35%, 41%
Correlation with BSV CL/F	0.43	0.41	0.25, 0.52

Bootstrap-derived values are based on 5000 non-parametric bootstrap replicates. Final clearance functions: CL_risperidone = (CL_base + [CL_{CYP2D6, allele1} + CL_{CYP2D6, allele2}] × CL_NFIB [if CC or CT]) × (1–CL_age × [Age–Age_BP]) [if Age ≥ Age_BP]; CL_{9-hydroxyrisperidone} = CL × (1–CL_age × [Age– Age_BP]) [if Age ≥ Age_BP] where each parameter refers to corresponding parameters in the table; Age is patient age, Age_BP is the age breaking point, and CL_age is the estimated reduction per year

CL clearance, V volume of distribution, F bioavailability, f_met fraction metabolized, BSV between-subject variability, CV coefficient of variation

^aFixed to value from literature [31]