. Author manuscript; available in PMC: 2023 Jun 1.

Published in final edited form as: Br J Clin Pharmacol. 2022 Jan 27;88(6):2863–2874. doi: 10.1111/bcp.15218

Table 3.

Estimated PK Parameters.

Base Model		Covariate Models
Entire Cohort (N=363)			Entire Cohort (N=363)		Reduced Cohort (N=223)
Extracted Last-Dose Time			Extracted Last-Dose Time	Assumed Last-Dose Time	Extracted Last-Dose Time	Assumed Last-Dose Time
Objective Function	10368	Objective Function	10169	10209	6441	6486
Parameter	Estimate (SE) [95% CI]	Parameter	Estimate (SE) [95% CI]
		*CL_ij=θ₁ × SNP^θ2 × (age_ij/47) ^θ3 × (alb_ij/4.1) ^θ4 × (hgb_ij/12.5) ^θ5*
CL	32.5 (0.93) [30.7, 34.4]	θ₁	26.2 (0.7) [24.8, 27.6]	26.5 (0.7) [25.1, 27.9]	24.7 (0.8) [23.1, 26.2]	25.0 (0.8) [23.4, 26.6]
		θ₂	0.71 (0.05) [0.61, 0.81]	0.72 (0.05) [0.62, 0.82]	0.75 (0.07) [0.61, 0.89]	0.76 (0.07) [0.62, 0.90]
		θ₃	−0.26 (0.08) [−0.42, −0.1]	−0.26 (0.07) [−0.40, −0.12]	−0.25 (0.10) [−0.45, −0.05]	−0.25 (0.10) [−0.45, −0.05]
		θ₄	0.35 (0.12) [0.11, 0.59]	0.38 (0.12) [0.14, 0.62]	0.31 (0.14) [0.04, 0.58]	0.34 (0.15) [0.05, 0.63]
		θ₅	−0.29 (0.09) [−0.47, −0.11]	−0.30 (0.09) [−0.48, −0.12]	−0.26 (0.11) [−0.48, −0.04]	−0.26 (0.10) [−0.46, −0.06]
		V_i= θ₆
V	4463 (524) [3436, 5490]	θ₆	3726 (844) [2072, 5379]	4140 (407) [3341, 4938]	3329 (510) [2329, 4329]	3725 (359) [3020, 4429]
ω_CL (%CV)	52.8 (2.1) [48.6, 56.9]	ω_CL (%CV)	40.8 (1.9) [37.1, 44.5]	41.3 (1.6) [38.1, 44.4]	40.1 (2.0) [36.1, 44.1]	40.6 (2.0) [36.8, 44.5]
ω_V (%CV)	65.5 (6.1) [53.7, 77.4]	ω_V (%CV)	65.3 (22.2) [21.7, 108.9]	59.2 (6.8) [45.8, 72.5]	74.4 (6.4) [60.8, 86.0]	69.9 (5.8) [58.6, 81.3]
σ_prop (%CV)	32.2 (1.6) [29.0, 35.4]	σ_prop (%CV)	31.8 (1.2) [29.4, 34.2]	32.1 (1.3) [29.6, 34.5]	31.2 (1.6) [28.0, 34.4]	31.6 (1.6) [28.4, 34.8]
σ_add (ng/ml)	0.36 (0.79) [0.00, 1.91]	σ_add (ng/ml)	0.52 (0.38) [0, 1.26]	0.56 (0.35) [0, 1.25]	0.38 (0.65) [0, 1.65]	0.39 (0.64) [0, 1.64]

Pharmacokinetic (PK) parameter estimates for both the entire and reduced datasets either with extracted or assumed last-dose times. Estimates are presented as mean (standard error) [Wald 95% confidence interval]. SNP is coded continuously as 1, 2, 3 for 0, 1, and 2 mutations, respectively. The age_ij, alb_ij, and hgb_ij represent covariate values for subject i at time j. CL and V are population PK parameters for clearance and volume of distribution in the base model. The ω _CL and ω _V are the between-subject variance components for clearance and volume of distribution, respectively, presented as %CV. The σ_prop and σ_add represent the proportional and additive residual errors in the combined residual error model, presented as %CV and the standard deviation, respectively. The θs denote model parameters as typically used in statistical models.