Table 2.

Parameter estimates for the final model of paracetamol and its metabolites in neonates^a

Parameter	Model fit			Bootstrap median [95 % CI]b
	Estimatea	BSV, as %CV	Shrinkage (%)	Estimatea	BSV, as %CV
CLfG (L/h)	0.049	62	0	0.049 [0.038 to 0.062]	60 [45–77]
Effect of weightc	2.0			2.0 [1.7 to 2.5]
Effect of PNAc	0.37			0.40 [0.097 to 0.79]
CLfS (L/h)	0.21	33	1	0.21 [0.17 to 0.24]	32 [24–39]
Effect of weightc	0.90			0.89 [0.71 to 1.1]
CLfO (L/h)	0.058	72	0	0.056 [0.044 to 0.078]	69 [55–85]
Effect of weightc	1.7			1.8 [1.4 to 2.1]
Effect of PNAc	0.69			0.67 [0.25 to 1.0]
VP(l)	2.7	11	4	2.7 [2.6 to 3.2]	12 [7.7–23]
Effect of weightc	0.90			0.90 [0.83 to 1.0]
VG (L)	1.2	48	4	1.2 [0.91 to 1.4]	47 [30–65]
Effect of weightc	1.1			1.1 [0.73 to 1.3]
VS (L)	0.98	36	8	0.97 [0.77 to 1.2]	36 [23–50]
Effect of weightc	1.2			1.2 [0.88 to 1.4]
VO (L)	3.0	67	3	2.9 [2.1 to 4.6]	62 [23–110]
Effect of weightc	1.5			1.5 [1.3 to 1.9]
CLRP (L/h)	0.016	30	6	0.016 [0.012 to 0.024]	30 [18–43]
Effect of weightc	0.64			0.62 [0.37 to 1.0]
Effect of urine flow rated	0.060			0.059 [0.044 to 0.080]
Effect of postoperative indicatione	−0.57			−0.57 [−0.76 to −0.34]
CLRG (L/h)	0.10	37	1	0.10 [0.079 to 0.12]	37 [21–47]
Effect of weightc	1.1			1.1 [0.76 to 1.3]
Effect of urine flow rated	0.015			0.016 [0.0020 to 0.029]
CLRS (L/h)	0.12	54	1	0.12 [0.085 to 0.14]	54 [38–70]
Effect of weightc	1.4			1.4 [0.99 to 1.7]
Effect of urine flow rated	0.015			0.016 [0.0027 to 0.031]
CLRO (L/h)	0.17	43	1	0.18 [0.14 to 0.21]	44 [26–62]
Effect of weightc	1.3			1.3 [1.1 to 1.6]
Effect of urine flow rated	0.032			0.032 [0.015 to 0.042]

Parameter	Model fit		Bootstrap median [95 % CI]b
	RUV, as %CV	Shrinkage (%)	RUV, as %CV
Proportional RUV
Plasma paracetamol	27	5	26 [21–32]
Plasma paracetamol-glucuronide	27	5	27 [23–33]
Plasma paracetamol-sulfate	23	5	24 [17–30]
Plasma oxidative pathway metabolites	35	5	34 [27–43]
Urinary paracetamol	49	3	49 [42–55]
Urinary paracetamol-glucuronide	68	3	68 [59–76]
Urinary paracetamol-sulfate	70	3	69 [60–77]
Urinary oxidative pathway metabolites	61	3	62 [53–70]

Parameter	Model fit		Bootstrap median [95 % CI]b
	RUV, as SD (mg/L)	Shrinkage (%)	RUV, as SD (mg/L)
Additive RUV
Plasma paracetamol-sulfate	1.1	5	1.1 [0.028–2.0]
Urinary paracetamolf	1.3	3	1.2 [0.029–1.8]
Urinary paracetamol-sulfateg	14	3	14 [0.16–35]

BSV between-subject variability, CI confidence interval, CV coefficient of variation, PNA postnatal age, RUV residual unexplained variability, SD standard deviation. CL_fG, CL_fS, and CL_fO represent, respectively, formation (hepatic) clearances for paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites; V_P, V_G, V_S, and V_O represent, respectively, volumes of distribution for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites; CL_RP, CL_RG, CL_RS, and CL_RO represent, respectively, renal clearances for unchanged paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites

^aPharmacokinetic parameter estimates are typical values for patients with a procedural indication at the mean current body weight (2.3 kg), mean PNA (7.5 days), and median urine flow rate (6.5 mL/h)

^bBootstrap success rate was 77 % (n = 153 out of 200)

^cExponent on mean-centered weight or mean-centered PNA (i.e., the covariate effect, θ_cov, in Eq. 3)

^dCoefficient on median-centered urine flow rate in the exponential covariate function (i.e., the covariate effect, θ_cov, in Eq. 4)

^eProportional change in CL_RP for patients with a postoperative indication (i.e., the covariate effect, θ_cov, in Eq. 2)

^fThe mean urinary paracetamol concentration was 14.2 mg/L (SD 11.4)

^gThe mean urinary paracetamol-sulfate concentration was 184 mg paracetamol equivalents/L (SD 174)