Table 1.

Parameters Used for the Rat and Human PBPK Models

Parameters	Units	Clozapine	Norclozapine	Risperidone	Paliperidone
Parameter shared by both the rat and human modelsa
Molecular weight	g/mol	326.8	312.8	410.5	426.5
Log P		3.44100	3.07100	2.5101	2.4102
pKa1		3.69103	NA	3.11104	8.2102
pKa2		7.57103	NA	8.24104	NA
Vmax,pgp	nmol/min/nmol	2.1119	27b	2.8619	15b (10c)
Km,pgp	μM	5819	0.5b	12.419	12.4b
Kd,D2	nM	82105 (218.7818)d	165.9618	7.2418	6.1718
koff,D2	1/s	0.023105 (0.04218)d	0.04818	0.00518	0.00518
Rat model‐specific parameters
fu,plasma		0.06126	0.1126	0.118102	0.285102
t1/2,absorption	min	40 (87e)b	160b	15 (23e)b	15b
CLHepatic	ml/min/kg	35 (100%f)b	30b	25 (4%f)b	10b
CLRenal	ml/min/kg	10b	10b	15b	10b
Human model‐specific parameters
fu,plasma		0.0540	0.09740	0.1106	0.226106
Dissolution time/shape	Min	100/0.92b , g	NA	10/0.92104 , g	NA
CLHepatic	mL/min/kg	NA	4.6b	NA	1.04b
CLRenal	mL/min/kg	0	0	0	1.04b
CYP1A2,Vmax	pmol/min/pmol	4.4107	NA	NA	NA
CYP1A2,Km	μM	18107	NA	NA	NA
CYP2D6,Vmax	pmol/min/pmol	NA	NA	2.3108	NA
CYP2D6,Km	μM	NA	NA	1.1108	NA
CYP3A4,Vmax	pmol/min/pmol	5.4107	NA	15108	NA
CYP3A4,Km	μM	304107	NA	61108	NA
CYP3A5,Vmax	pmol/min/pmol	NA	NA	15108	NA
CYP3A5,Km	μM	NA	NA	200108	NA

CL_Hepatic, total plasma clearance in liver; CL_Renal, total plasma clearance in kidney; CYP, cytochrome P450; f_u,plasma, fraction unbound in plasma; K_d,D2, affinity (dissociation constant) at D2 receptor; k_off,D2, dissociation rate at D2 receptor; K_m,pgp, substrate concentration at which the transport rate is half of V_max,pgp; NA, not applicable; t_{1/2,absorption}: absorption half‐life after subcutaneous injection; V_max,pgp: maximum rate of the P‐gp mediated efflux transport at blood‐brain barrier administration.

^aThe rat model and the human model used the same parameter values unless specified.

^bValues were estimated in PK‐Sim.

^cV_max,pgp in the human model (10 nmol/min/nmol) was reduced to two‐third of those in the rat model (15 nmol/min/nmol). Further explanations on the V_max,pgp and K_m,pgp values are provided in Table S8.

^dThe K _d,D2R and k _off,D2R values, used in both the rat and human models, were provided by Sahlholm et al.18 The only exception was that for clozapine in the rat model the values were provided by Kapur and Seeman105 instead, which had improved the model prediction.

^eThe estimated t_{1/2,absorption} values could adequately capture the subcutaneous PK profiles in all rat studies except for those in the Cremers et al26 and Culot et al.27 For these two studies the absorption rate from the subcutaneous injection site was slower than the others and a higher t_{1/2,absorption} value was needed to adequately capture the observed plasma and brainECF PK profiles. Possibly, a distinct formulation and/or injection site was applied in these studies. Specifically, 20% cyclodextrin was used for the clozapine injection in Culot's study, and the strong complexation between the drug and cyclodextrin could have slowed down the absorption rate.109

^fThe percentage indicates the portion of total plasma clearance in liver (CL_Hepatic) of the parent drug that generates the metabolite norclozapine and paliperidone.

^gWeibull function, with dissolution time (50% dissolved) and a shape parameter as input, was used to simulate the dissolution of the oral tablet. The in vitro dissolution profile from Saibi et al104 was used as the input for risperidone tablet. For clozapine, in vitro tablet dissolution rate was not reported and thus it was estimated in PK‐Sim.