Table 2.

Parameter estimates of the final PopPK model

Parameter	Description	Estimate	95% CI
CL (L/h)	Apparent clearance	8.52	7.70–9.64
V0 (L)	Apparent volume of distribution at baseline	565	468–686
MTT (h)	Mean transit time	0.367	0.34–0.39
VLmax (fraction)	Maximum fraction of volume decrease	0.805	0.771–0.839
VLA50 (μg)	Amount in the central compartment resulting in 50% of the maximum volume decrease	3.36	2.16–5.21
Ntr	Number of transit compartments	5.81	4.29–7.26
Kgut (1/h)	Gut extraction rate constant	1.89	1.16–2.88
Kout (1/h)	Gut extraction degradation rate constant	0.00205	(Fixed)
S	Scaling factor for the effect of Aa on Kout	22.0	13.8–30.5
WTV0	Effect of body weight on V0	1.00	(Fixed)
FOODMTT	Effect of food on MTT	3.39	(Fixed)
RUVearly	Maximum value of time-varying RUV immediately after dosing	1.20	0.811–1.77
RUVlate	Minimum value of time-varying RUV	0.216	0.201֪–0.232
RUVrate (1/h)	RUV decrease rate	1.32	0.992–1.670
RUVadd	Additive RUV component	0.000625a	(Fixed)
AGEslope	Slope in the CL–age maturation function	0.267	0.106–0.447
AGE50 (years)	Age where 50% of adult CL/F is reached	5.34	1.36–6.89
IIVCL	Variance on CL/F	0.150b	0.120–0.177
IIVV0	Variance on V0	0.0944b	0.0628–0.1320
IIVMTT	Variance on MTT	0.0423b	0.0232–0.0661

95% CI calculated from a 500-sample bootstrap, with 457 successful minimizations

The time-varying (proportional) RUV model was implemented as $RU{V}_{\mathit{prop}}=RU{V}_{\mathit{early}}-(RU{V}_{\mathit{early}}-RU{V}_{\mathit{late}})\times (1-e^{{\mathit{RUV}}_{\mathit{rate}}\times TAD})$, where RUV_prop is the proportional RUV component and TAD is time after dosing

^aThe additive RUV component was fixed to a value equivalent to 0.025 ng/mL standard deviation, corresponding to 50% of the assay lower limit of quantitation

^bIIV values are reported as variance estimates in the log-normal distribution. Coefficient of variation was 39% for IIV_CL, 31% for IIV_V0 and 21% for IIV_MTT. Shrinkage was 4.5% for IIV_CL, 17.4% for IIV_V0, and 40.8% for IIV_MTT