Table 2.

Model parameter values for the systems PK/PD model in humans, monkeys, and rabbits

Parameter	Unit	Humans	Monkeys	Rabbits
Physiological parameters
Body weight	kg	70	3.5	2.9
Vp	L	2.6 (Cao et al., 2013)	0.157 (Zhao et al., 2015)	0.107 (Armin et al., 1952)
Visf	L	15.6 (Cao et al., 2013)	0.735 (Zhao et al., 2015)	0.764 (Pavlin et al., 1986)
Kp	-		0.4 (Cao et al., 2013)
Vl	L	5.2 (Cao et al., 2013)	a 0.314 (Zhao et al., 2015)	a 0.153 (Armin et al., 1952)
L	L·day−1	2.904 (Cao et al., 2013)	0.288 (Zhao et al., 2015)	0.144 (Zhao et al., 2015)
σ1	-		0.945 (Cao et al., 2013)
σ2	-		0.697 (Cao et al., 2013)
σl	-		0.2 (Cao et al., 2013)
Target parameters
kon	M−1·s−1		4.48×106 (Hilden et al., 2012)
koff	s−1		b 1.74×10−3
sTFPI_b	nM	1.6 (Hansen et al., 2014)	0.91 (Gu et al., 2017)	1.4 (Hansen et al., 2014)
kdegs	day−1	1.18 (Farrokhi et al., 2018)	c 2.50	c 2.62
mTFPI_b	nM	b 20.03	d 11.32	d 17.50
kdegm/kint	day−1	b 1.155	c 2.44	c 2.56
Endosome parameters
CLup	L·day−1	1.48 (Yuan et al., 2018)	e 0.045	e 0.0672
krec	day−1	124.7 (Hopkins and Trowbridge, 1983)
CLe	L·day−1	5.75 (Yuan et al., 2018)	c 0.61	c 0.53
Ve1	L	f 0.005% of body weight (Li et al., 2014)
Ve2	L
FcRn_b	nM	49800 (Shah and Betts, 2012)
k1on	M−1·s−1		g 2.41×105
k1off	s−1		g 0.162
SC absorption parameters
F	-	h 0.93	0.93 (Agerso et al., 2014)	-
ka	day−1	h 0231	0.231 (Agerso et al., 2014)	-

^aAssume equal to blood volume (Cao et al., 2013);

^bOptimized in the reduced PK/PD model;

^cScaled from human value using a scaling factor of −0.25 for rate constant and 0.75 for clearance based on body weight;

^dsTFPI and mTFPI are produced through alternative splicing of the same TFPI gene (Maroney et al., 2010). Based on the sTFPI baseline, monkeys and rabbits were calculated as $\mathit{\text{human }}mTFPI\_b\times \frac{\mathit{\text{animal\hspace{0.17em}}}sTFP{I}_{\_b}}{\mathit{\text{human\hspace{0.17em}}}sTFP{I}_{\_b}}$;

^eOptimized using PK data of antibodies that show linear clearance (Figure 4);

^fAssume the volume of endosome is 1% of cell volume and the total endothelial cell volume is 0.5% of total tissue volume (Li et al., 2014);

^gAssume equal to the binding affinity of adalimumab, a wild-type IgG₁, to human FcRn (Suzuki et al., 2010). The IgG isotype has a negligible influence on FcRn binding (Neuber et al., 2014; Vidarsson et al., 2014). Monkey FcRn and rabbit FcRn have been shown to bind human IgG with similar affinity as human FcRn (Szikora et al., 2017; Yeung et al., 2010);

^hAssume equal to monkey value.