TABLE 2.

Pharmacokinetic parameter estimates from the final joint model and bootstrap results.

Parameter	Final model		Bootstrap		Bias %
	Estimate	SE (%)	Median	95% CI
F	0.895	Fix	—	—	—
Ka (h−1)	1.1	Fix	—	—	—
V1 (L)	207.29	33.76	213.82	71.52–356.12	3.15
CL1 (L/h)	1.91	26.68	1.99	0.67–3.33	4.19
V2(L)	10.01	28.78	9.37	3.18–14.82	−6.39
Vmax (mg/h)	18.80	17.00	17.65	11.73–23.45	−6.12
Km	1.15	Fix	—	—	—
CL2 (L/h)	4.65	16.45	4.46	3.73–5.15	−4.09
Imax	0.75	Fix	—	—	—
IC50(mg/L)	14.6	Fix	—	—	—
θNM	0	Fix	—	—	—
θIM	−0.31	42.10	−0.30	−0.47 to −0.13	3.23
θPM	−0.61	28.37	−0.63	−1.19 to −0.06	−3.28
Interindividual variability
ωV1 (%)	240.77	27.57	264.06	119.14–408.98	9.67
ωCL1 (%)	6.02	21.10	5.97	3.38–8.56	−0.83
ωCL2 (%)	25.57	24.25	24.15	12.31–35.99	−5.55
ωVmax (%)	21.13	14.78	20.69	10.85–30.53	−2.08
Residual variability
VCZ-σ(%)	46.97	9.40	46.92	38.20–54.19	−0.11
VNO-σ(%)	27.93	6.16	27.91	22.95–33.49	−0.07

SE, standard error; F, oral bioavailability; Ka, absorption rate constant; V1, volume of distribution in the central compartment; CL1, the clearance of VCZ, other than the metabolic pathway converting to VNO; V2, volume of distribution in the metabolite compartment; Vmax, maximum elimination rate; Km, Michaelis-Menten constant; CL2, the clearance of VNO; ωV1, ωCL1, ωCL2, ωVmax: square root of interindividual variance for pharmacokinetic parameters; σ, residual variability.

^a $V_{\max }=18.80\times \exp \left({\theta }_{CYP2C19}\right)$ , θ_CYP2C19 is equal to θ_NM, θIM, or $C_2=\frac{A_2}{V_2}$ .

^bBias = (median estimate from bootstrap analysis–estimate from the final model)/estimate from the final model.