Table 2.

Model parameters of the final pharmacokinetic covariate model with dose

Parameter	Value	RSE (%)	Inter-individual variability CV (%)a	RSE (%)	Shrinkage (%)
CL/F (L/h)	1.24	3.19	25.1	9.23	10.2e
V/F (L)	34.3	2.12	21.0	16.5	34.7e
ka (1/h)	1.29	9.54	117	16.7	35.2e
θCL,age	− 0.418	20.5
θCL,bodyweight	0.75b	n.a.
θCL,standardized creatinine clearance	0.164	26.1
θCL,bilirubin	− 0.072	26.1
θV,bodyweight	1.00b	n.a.
θV,sex	0.850	4.09
θka,bodyweight	1.28	25.2
θka,albumin	2.37	26.1
θF,dose≤1.25 mg	1.08	2.62
θF,dose=5 mg	0.867	1.94
θF,dose=10 mg	0.793	2.60
Proportional error (%)	25.7c	4.21			8.4f
Additive error (µg/L)	7.27d	14.9			8.4f

CL/F apparent clearance, CV coefficient of variation, F estimate of absolute bioavailability dependent on dose size, k_a absorption rate constant, RSE relative standard error, V/F apparent volume of distribution

^aThe CV% is calculated by SQRT[EXP(OMEGA²)−1] × 100

^bFixed value

^cThe CV is calculated by SQRT(SIGMA²) × 100

^dThe standard deviation is calculated by SQRT(SIGMA²)

^eETA shrinkage is calculated by 100% × [1 − SD(ETA)/SQRT(OMEGA²)]

^fEpsilon shrinkage is calculated by 100% × [1−SD(IWRES)]

Parameter covariate relations were described as:

$\begin{array}{c}F=\left\{\begin{array}{c}1.08,\text{Dose}\le 1.25\text{mg}\\ 1,\text{Dose}=2.5\text{mg}\\ 0.867,\text{Dose}\le 5\text{mg}\\ 0.793,\text{Dose}\le 10\text{mg}\\ \end{array}\right)\\ \frac{\text{CL}}{F}=1.24\times {\left(\frac{\text{Age}}{68}\right)}^{-0.418}\times {\left(\frac{\text{Bilirubin}}{0.6}\right)}^{-0.075}\times {\left(\frac{{\text{CL}}_{\text{Cr,st}}}{100}\right)}^{0.164}\times {\left(\frac{\text{Weight}}{70}\right)}^{3/4}\\ \frac{V}{F}=3.43\times \text{SEX}\times \left(\frac{\mathit{Weight}}{70}\right),\text{with}\text{SEX}=\left\{\begin{array}{c}1,\text{male}\\ 0.850,\text{female}\\ \end{array}\right)\\ k_{\text{a}}=1.29\times {\left(\frac{\text{Albumin}}{4.0}\right)}^{2.37}\times {\left(\frac{\text{Weight}}{70}\right)}^{1.28}\\ \end{array}$