TABLE 3

Population pharmacokinetic model parameters (fixed and random effects) for models 9 and 11

Parameter (units)	Definition	Model 9		Model 11
Parameter (units)	Definition	Value	IIV	Value	IIV
			%		%
Cli (l/h)	Intrinsic blood clearance in hepatocytes	0.31	91	N.E.
K_m = K_{m_e} (mg/l)	Michaelis-Menten constant of metabolic process in liver and enterocyte	72.0	N.E.	148	N.E.
k₁₂ (h⁻¹)	Intercompartmental rate constant	2.80^{^a}	N.E.	2.31^{^a}	N.E.
k₂₁ (h⁻¹)	Intercompartmental rate constant	1.14^{^a}	37^{^a}	0.63^{^a}	71^{^a}
V_c (l)	Volume of distribution in central compartment	0.24^{^a}	73^{^a}	0.38^{^a}	60^{^a}
k_B (l/mg · h)	Protein-binding rate constant	1.12 × 10⁻⁶	40^{^a}
k_U (h⁻¹)	Protein-unbinding rate constant	0.20	78^{^a}
QMA (mg)	Maximum binding capacity of the proteins for SQV	21,700	51^{^a}
k_{a_IP} (h⁻¹)	Absorption rate constant for intraperitoneal administration	1.09^{^a}	166^{^a}	0.38^{^a}	N.E.
BIO_IP	Fraction of amount absorbed by intraperitoneal route	1^{^a}	N.E.	1^{^a}	N.E.
FR_(G8)	Fraction of dose that precipitate after intraperitoneal administration in group 8	0.97^{^a}	N.E.	0.87^{^a}	N.E.
FR_(G7) = (1 + FR_(G8))/2	Fraction of dose that precipitated after intraperitoneal administration in group 7	0.98^{^a}		0.93^{^a}
k_{D (G7)} (h⁻¹)	Dissolution rate constant for group 7	0.04^{^a}		0.04^{^a}
k_{D (G8)} (h⁻¹)	Dissolution rate constant for group 8	0.48^{^a}	N.E.	4.46^{^a}	N.E.
K_a₁ (h⁻¹)	Absorption rate constant for oral administration from intestinal compartment 1	0.24	56	0.24	1.5
k_T (h⁻¹)	Intestinal transit rate constant	0.58	61	0.12	126
Q_h (l/h)	Hepatic flow	1.15^{^b}	6.5^{^b}	1.15^{^b}	6.5^{^b}
V_h (l)	Volume of distribution in hepatocyte compartment	0.01^{^b}		0.01^{^b}
V_e (l)	Volume of distribution in enterocyte compartment	0.006^{^b}		0.006^{^b}
Cli_e (l/h)	Intrinsic blood clearance due to metabolism in enterocytes	4.35	92	2.35	113
Cli_se (l/h)	Intrinsic blood clearance of intestinal secretion	2.83 × 10⁻⁶	6.9
K_{m_e} (mg/l)	Michaelis-Menten constant of enterocyte secretion process	0.02
K_a₂ (h⁻¹)	Absorption rate constant after oral administration from intestinal compartment 2	0.17	59
FK_{m (G9)}	Factor that modified the Michaelis-Menten constant for group 9	5.16		5.05
FK_{m (G10)}	Factor that modified the Michaelis-Menten constant for group 10	10.2		38
σ1 (CV %)	Residual variability; exponential component	12.2		24
σ2 (mg/l)	Residual variability; additive error	0.29		0.23

N.E., not estimated; CV, coefficient of variation.
↵a Parameters fixed to the estimated values obtained in previous steps.
↵b Parameters fixed to physiological values from the literature.