Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics

Table 1 Parameter estimates of final population pharmacokinetic model

			Bootstrap analysis Median [5-95th percentiles]
Parameters	Estimates (RSE%)	BAV (RSE%)	Estimates	BAV
Clozapine
CL_clo/F (L/min)	0.5(20.3)		0.463[0.358-0.661]
V_clo-p/F (L)	19.4(40.3)		18.9[5.43-31.59]
Ka_clo (1/min)	0.00801(14.7)		0.00815[0.0051-0.0095]
Q_clo/F (L/min)	2.01(40.8)	0.193(33.6)	2.08[0.58-3.43]	0.2[0.07-0.29]
V_clo-b/F (L)	0.214 FIXED
Ktr1 (1/min)	0.0125(9.4)	0.05 (48.9)	0.0129[0.011-0.015]	0.047[0.0033-0.069]
F_clo	1 FIXED	0.259(37.1)		0.243[0.062-0.35]
Norclozapine
Cl_clo-met/F (L/min)	0.055(24.8)		0.0584[0.04-0.0855]
CL_met/F (L/min)	0.419(18.8)	0.111(74.8)	0.43[0.33-0.61]	0.08[0.0038-0.18]
V_met-p/F (L)	2.95(38.6)	0.168(51.1)	3.02[1.91-5.55]	0.149[0.000047-0.27]
Ka_met (1/min)	0.00277(31)	0.371(44.2)	0.00296[0.0015-0.0047]	0.319[0.065-0.54]
Q_met/F (L/min)	0.388(45)		0.386[0.229-0.768]
V_met-b/F (L)	0.25 FIXED
Ktr2 (1/min)	0.00517(12.3)		0.00521[0.0045-0.0064]
F_met	1 FIXED
Residual error (proportional)
Parent-plasma	0.109(70)		0.084[0.029-0.19]
Parent-brain	0.0367(27)		0.0371[0.023-0.055]
Metabolite-plasma	0.0762(24.1)		0.0714[0.051-0.11]
Metabolite-brain	0.014(18)		0.0133[0.0095-0.017]

Clo (Clozapine): CL_clo/F (L/min) = apparent clearance of clozapine; V_clo-p/F (L) = apparent volume of distribution of clozapine in plasma; Ka_clo (1/min) = absorption rate of clozapine; Q_clo/F (L/min) = apparent intercompartmental clearance of clozapine;
V_clo-b/F (L) = apparent volume of distribution of clozapine in brain; Ktr1 (1/min) = transit rate constant of clozapine.
Met (Norclozapine): CL_clo-met/F (L/min) = apparent clearance of clozapine to norclozapine; CL_met/F (L/min) = apparent clearance of norclozapine; V_met-p/F (L) = apparent volume of distribution of norclozapine in plasma; Ka_met (1/min) = absorption rate of norclozapine; Q_met/F (L/min) = apparent intercompartmental clearance of norclozapine; V_met-b/F (L) = apparent volume of distribution of norclozapine in brain; Ktr2 (1/min) = transit rate constant of norclozapine.
BAV = between animal variability.
RSE% = percent relative standard error.

ISSN: 1479-5876