Table 2.

Population PK-PG model parameter estimates and model description. Parameter estimates and 95% confidence intervals (CI) are shown for each PK parameter. Point estimates and 95% CI are shown for evaluated SNPs. SNPs were evaluated for their relative effects on the formation CL of M6G (CL₁₄) using the homozygous major SNP as the reference value. In this parameterization, a value of 1 indicates no difference from the reference. PG= (gHetero**Hetero(0/1)*(gMinor**hMinor(0/1). Next, The PG effect was added to the determination of CL₁₄ by the following equation: CL₁₄ = TVCL₁₄*PG. NA indicates that for the rs62296959 there were less than 5 subjects that expressed the homozygous minor SNP.

Parameter	Parameter Estimate	95% CI
Total morphine CL (L/h)	72.1	--
CL13 (L/h)	13.2	(10.4 , 16.0)
CL14 (L/h)	3.3	(2.6 , 3.9)
CL10 (L/h)	55.6	(48.2 , 62.9)
CL30 (L/h)	3.6	(2.9 , 4.2)
CL40 (L/h)	4.9	(4.0 , 5.9)
Q (L/h)	53.2	(41.9 , 64.4)
V1 (L)	22.9	(16.8 , 29.0)
V2 (L)	172.0	(158.6 , 185.5)
Estimated variance scale factor on shared eta $\left({\theta }_{{}^{\eta 2}}^{shared}\right)$	1.01	(0.97 , 1.1)
Effect of duration of stay on formation of M3G ${\left({\theta }_{C{L}_{13}}\right)}^{MV}$	0.67	(0.49 , 0.86)
Effect of duration of stay on formation of M6G ${\left({\theta }_{C{L}_{14}}\right)}^{MV}$	0.93	(0.69 , 1.2)
Effect of duration of stay on M3G CL ${\left({\theta }_{C{L}_{30}}\right)}^{MV}$	0.66	(0.49 , 0.82)
Effect of duration of stay on M6G CL ${\left({\theta }_{C{L}_{40}}\right)}^{MV}$	0.88	(0.64 , 1.1)
V3 (L)	23.0 FIXED	--
V4 (L)	29.0 FIXED	--
F1, relative bioavailability	0.24 FIXED	--
TM50 UGT maturation (years)	1.04 FIXED	--
γ UGT maturation	3.92 FIXED	--
TM50 renal maturation (years)	0.92 FIXED	--
γ renal maturation	3.4 FIXED	--
Interindividual Variability in CL10	0.48	(0.28 , 0.68)
Interindividual Variability in CL13	0.63	(0.39 , 0.87)
Interindividual Variability in CL14	0.54	(0.31 , 0.77)
Interindividual Variability in Metabolite CL (CL30 + CL40)	0.49	(0.28 , 0.72)
Residual Variability for Morphine	0.22	(0.20 , 0.25)
Residual Variability for M3G	0.089	(0.082 , 0.096)
Residual Variability for M6G	0.11	(0.10 , 0.12)
Heterozygous SNP rs28375964	1.03	(0.92,1.14)
Homozygous SNP rs28375964	1.04	(0.83, 1.25)
Heterozygous SNP rs10006452	0.99	(0.92,1.14)
Homozygous SNP rs10006452	1.04	(0.83, 1.25)
Heterozygous SNP rs62296959	0.99	(0.77,1.29)
Homozygous SNP rs62296959	NA	NA

PK = pharmacokinetic; PG = pharmacogenomic; CI = confidence interval (lower bound, upper bound); M3G = morphine-3-glucuronide metabolite; M6G = morphine-6-glucuronide metabolite; WT= weight; TM₅₀ = time to reach 50% of a completely mature clearance; PMA = post-menstrual age; θ^MV = effect of mechanical ventilation greater than 10 days. Correlation for parameters of interindividual and residual variability random-effect matrices were in the range of (−46%, 99%) and (62%, 87%), respectively. SNP = single nucleotide polymorphism

$C{L}_{TOTAL}={\theta }_{C{L}_{10}}+{\theta }_{C{L}_{13}}+{\theta }_{C{L}_{14}}$

$C{L}_{10}={\theta }_{C{L}_{10}}\cdot {\left(\frac{WT}{70}\right)}^{0.75}$ $C{L}_{13}={\theta }_{C{L}_{13}}\cdot {\left(\frac{WT}{70}\right)}^{0.75}\cdot \frac{PM{A}^{{\gamma }_{UGT}}}{T{M}_{50,UGT}^{{\gamma }_{UGT}}+PM{A}^{{\gamma }_{UGT}}}\cdot {\left({\theta }_{CL13}\right)}^{MV}$ $C{L}_{14}={\theta }_{C{L}_{14}}\cdot {\left(\frac{WT}{70}\right)}^{0.75}\cdot \frac{PM{A}^{Hill}}{T{M}_{50}^{Hill}+PM{A}^{Hill}}\cdot {\left({\theta }_{CL14}\right)}^{MV}$

$C{L}_{30}={\theta }_{C{L}_{30}}\cdot {\left(\frac{WT}{70}\right)}^{0.75}\cdot \frac{PM{A}^{{\gamma }_{renal}}}{T{M}_{50,renal}^{{\gamma }_{renal}}+PM{A}^{{\gamma }_{renal}}}\cdot {\left({\theta }_{CL30}\right)}^{MV}$ $C{L}_{40}={\theta }_{C{L}_{40}}\cdot {\left(\frac{WT}{70}\right)}^{0.75}\cdot \frac{PM{A}^{{\gamma }_{renal}}}{T{M}_{50,renal}^{{\gamma }_{renal}}+PM{A}^{{\gamma }_{renal}}}\cdot {\left({\theta }_{CL40}\right)}^{MV}\cdot {\theta }_{\eta 2}^{Shared}$

$Q={\theta }_Q\cdot {\left(\frac{WT}{70}\right)}^{0.75}$

$V_1={\theta }_{V_1}\cdot {\left(\frac{WT}{70}\right)}^1$ $V_2={\theta }_{V_2}\cdot {\left(\frac{WT}{70}\right)}^1$ $V_3={\theta }_{V_3}\cdot {\left(\frac{WT}{70}\right)}^1$ $V_4={\theta }_{V_4}\cdot {\left(\frac{WT}{70}\right)}^1$