TABLE 4.

Pharmacokinetic parameter estimates for the final models and Bootstrap results.

Parameters	Final model			Bootstrap		Bias (%)
	Estimate	RSE (%)	95%CI	Median	95%CI
Theory-based compartmental model
Ka (h−1)	4.48 fixed	—	—	4.48 fixed	—	—
CLPl/F (L h−1)	234	45.7	24.28–443.72	231.12	203.96–283.56	−0.23
θDDmax	3.51	55.8	0.332–7.352	3.51	3.09–4.39	0
θDD50	2.44	25	1.244–3.636	2.45	1.43–3.95	1.14
θAST	(−0.216)	19.8	(−0.3)-(-0.312)	(-0.211)	(−0.299)-(−0.139)	−2.31
θVRCZ	(−0.575)	17	(−0.766)-(−0.384)	(−0.571)	(−0.871)-(−0.312)	−0.69
θCYP3A5*1	0.168	37.1	0.046–0.29	0.167	0.056–0.299	−0.59
VPl/F (L)	11000	10.8	8,667.6–13332.4	10822.2	8,696.0–13072.5	−1.62
θPOD	0.887	12.3	0.673–1.101	0.886	0.727–1.159	−0.11
Between subject variability
ωCLpl/F (%)	29.7	8.2	—	29.2	24.5–34.4	−1.68
ωVpl/F (%)	59.2	11.5	—	59.1	39.3–71.3	−0.17
Residual unexplained error
δ1 (%)	30.8	7.7	—	30.7	28.2–32.9	−0.32
MM model
Vm (mg day−1)	6.62	5.2	5.952–7.288	6.63	6.03–7.50	0.15
Km (ng ml−1)	6.46	14	4.686–8.234	6.45	4.90–8.73	−0.15
θPOD	0.277	22.6	0.154–0.4	0.272	0.152–0.404	−1.80
θHCT	1.16	22.8	0.641–1.679	1.14	0.598–1.685	−1.72
θTBIL	0.286	23	0.157–0.415	0.281	0.156–0.429	−1.75
θCYP3A5*1	(-0.365)	19.4	(−0.504)–(−0.226)	(−0.362)	(−0.500)–(−0.210)	−0.82
θVRCZ	2.15	42.3	0.368–3.932	2.13	0.554–4.417	−0.93
Between subject variability
ωKm	65.3%	7.8	—	64.7%	55.3%–74.1%	−0.92
Residual unexplained error
δ1 (%)	20.4	10.5	—	20.2	14.4–24.4	−0.098
δ2 (mg day−1)	0.568	10.2	—	0.559	0.436–0.699	−1.58

CL_Pl/F, the apparent plasma clearance; V_Pl/F, the apparent plasma volume of distribution; Ka, absorption rate constant; V_m, the maximum dose rate (daily dose) at the steady state; K_m, the Michaelis constant which denotes the steady-state trough concentration at half-maximal dose rate; ω, between subject variability; δ₁, proportional residual error; δ₂, additive residual error; θ, the coefficient of the included covariates on the parameters; CI, confidence interval; RSE, relative standard error; CYP3A5*1, CYP3A5*1*3 and CYP3A5*1*1 expresser; MM, Michaelis-Menten; Bias, prediction error.

$\mathrm{B}\mathrm{i}\mathrm{a}\mathrm{s}\%=\frac{\mathrm{B}\mathrm{o}\mathrm{o}\mathrm{t}\mathrm{s}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{p}-\mathrm{N}\mathrm{O}\mathrm{N}\mathrm{M}\mathrm{E}\mathrm{M}}{\mathrm{N}\mathrm{O}\mathrm{N}\mathrm{M}\mathrm{E}\mathrm{M}}\times 100\%$

Where NONMEM, represents the PK, parameters estimates of the final model and Bootstrap represents the PK, parameters median values obtained from the nonparametric bootstrap procedure.