Table 2. Final model pharmacokinetic parameter estimates and SIR results.

	Morphine		M3G§		M6G§
Parameter	Estimate	SIR* 95% CI	Estimate	SIR* 95% CI	Estimate	SIR* 95% CI
Cl, l/h#	0.899	0.797–0.985	0.456	0.424–0.492	1.73	1.61–1.87
V, l#	8.88	7.87–9.92	0.264	0.089–0.384	4.53	3.64–5.39
PNA on Cl; %/h	0.420	0.297–0.582	NA	NA	NA	NA
GA on Cl; %/d	1.66	1.30–1.94	NA	NA	NA	NA
TEMP on Cl; %/°C	6.89	5.37–8.41	4.91$	3.53–6.22$	4.91$	3.53–6.22$
Interindividual variability
Cl, variance (rsd)	0.224 (47.3%)	0.185–0.276	0.291$ (53.9%)	0.240–0.356$	0.291$ (53.9%)	0.240–0.356$
V, variance (rsd)	0.464 (68.1%)	0.364–0.602	NA	NA	NA	NA
Covariance interindividual variability Clmorphine/Clmetabolites
Covariance (correlation coefficient)	0.117 (46.0%)	0.0799–0.161
Residual variability
Proportional, variance (rsd)	0.0498 (22.3%)	0.0437–0.0574	0.0914 (30.2%)	0.0798–0.105	0.101 (31.8%)	0.0888–0.115

Final model

Cl_MORPHINE = 0.899 x (BW/3.5)^0.75 x (1 + 0.0042 x PNA) x (1 + 0.0166 x (GA-280)) x (1 + 0.0689 x (TEMP-36.5))

V_MORPHINE = 8.88 x (BW/3.5)¹

Cl_M3G/F_M3G = 0.456 x (BW/3.5)^0.75 x (1 + 0.0491 x (TEMP-36.5)

V_M3G/F_M3G = 0.264 x (BW/3.5)¹

Cl_M6G/F_M6G = 1.73 x (BW/3.5)^0.75 x (1 + 0.0491 x (TEMP-36.5)

V_M6G/F_M6G = 4.53 x (BW/3.5)¹

^§All metabolite estimates are relative to formation fraction F_M3G and F_M6G, resp.

*Ten iterations; no. of samples 1000,1000,1000,1000,1000,1000,2000,2000,2000,2000; no. of resamples 200,200,400,400,500,500,1000,1000,1000,1000

^#Estimates for neonate with BW 3.5 kg, GA 280 days, PNA 0h and TEMP 36.5°C

^$Single estimate for both metabolites

V = volume of distribution, Cl = clearance, PNA = postnatal age, GA = gestational age, TEMP = body temperature, M3G = morphine-3-glucuronide, M6G = morphine-6-glucuronide, SIR = sampling importance resampling, BW = birth weight, NA = not applicable, rsd = relative standard deviation