TABLE 1

Pharmacokinetic parameters for inhibitors

Parameters	Units	Values	Sources
For ICZ
Bioavailability		0.55	Thummel et al., 2011
CL_tot (plasma)	l/h	21.4	Thummel et al., 2011
CL_tot (blood)	l/h	36.9	CL_tot (plasma) / R_b
f_e		< 0.01	Thummel et al., 2011
CL_h (blood)	l/h	36.9	Assuming CL_r = 0
F_h		0.575	1-CL_h/Q_h
F_aF_g		0.957	Bioavailability / F_h
f_p		0.002	Thummel et al., 2011
R_b		0.58	Kato et al., 2008
cLogP		6.05	Calculated by using ChemDraw Ultra 7.0
K_p		6.67	Eq. 14
f_h		0.000300	Eq. 13
Dose	μg	100,000	Niemi et al., 2003a
k_a	h⁻¹	0.121 ± 0.037	^*
V_b	l	59.2 ± 36.2	^*
CL_int	l/h	14,700 ± 2,600	^*
C_b,0	μg/l	98	Jaakkola et al., 2005
C_h,0	μg/l	1,131	Assuming C_h,0 = C_b,0 × K_p / R_b
For GEM
Bioavailability		0.98	Thummel et al., 2011
CL_tot (plasma)	l/h	7.14	Thummel et al., 2011
CL_tot (blood)	l/h	12.9	CL_tot (plasma) / R_b
f_e		< 0.01	Thummel et al., 2011
CL_h (blood)	l/h	12.9	Assuming CL_r = 0
F_h		0.85	1-CL_h/Q_h
F_aF_g		1	Bioavailability > F_h
f_p		0.0065	Shitara et al., 2004
f_b		0.012	f_p / R_b
R_b		0.55	Kilford et al., 2009
f_h		0.013	Eq. 13
Dose	μg	600,000	Niemi et al., 2003a
k_a	h⁻¹	3.13 ± 0.36	^*
Lag	h	0.25	Estimated to fit the blood concentration profile of GEM
V_b	l	13.3 ± 8.6	^*
CL_int1	l/h	199 ± 506	^*
CL_int2	l/h	32.6	CL_i_nt,gem1 / CL_int,gem2 = 6.1
PS_inf	l/h	8,470	CL_int,all × 10
PS_eff	l/h	2,010 ± 5,110	^*
For GEM-glu
f_p		0.115	Shitara et al., 2004
f_b		0.209	f_p / R_b
R_b		0.55	Assumed to be the same as GEM
f_h		0.206	Eq. 13
V_b	l	5.2	Blood volume
CL_NH	l/h	1.57	Glomerular filtration rate × f_b,glu
CL_int,h	l/h	12.5 ± 2.7	^*
PS_inf	l/h	469	Assuming f_b·PS_inf,gem = f_b·PS_inf,glu
PS_eff	l/h	100 ± 20	^*

↵* Optimized by fitting analysis.