TABLE 4

Compound-specific parameters, in vivo PK, and predicted Vuss of 13 protein kinase inhibitors

Physicochemical parameters were predicted using ADMET Predictor (Simulations Plus Inc.). Unbound fraction in plasma and blood-to-plasma concentration ratios were measured experimentally. In vivo Vss was obtained from literature or in vivo PK studies. The amount of intracellular drug located in lysosomes (% in lysosomes) was calculated according to eq. 1.

Compound	pK_a	Log P	fu^{^a}	B:P^{^a}	Vss exp.^{^b}	Vuss exp.^{^c}	Vuss pred.^{^d}	% in Lyososomes
					l/kg	l/kg	l/kg
Afatinib	8.4, 3.9	3.8	0.11	2.6	16	152	224	54
Bosutinib	8.4, 4.1	4.1	0.09	1.1	15	177	93	51
Cediranib	9.1, 3.4	4.1	0.14	1.6	5.5	41	90	54
Crizotinib	9.7, 4.1	3.6	0.04	0.94	2.9	82	130	57
Dasatinib	6.9, 3.9	4.0	0.05	1.1	6.3	140	245	31
Gefitinib	6.9, 4.1	3.8	0.04	0.8	9.2	259	142	31
Imatinib	8.2, 4.5	4.4	0.02	0.86	2.6	165	288	60
Lapatinib	6.5, 4.1	4.6	0.003	0.48	1.8	551	1085	20
Masitinib	8.1, 4.2	5.0	0.03	0.83	6.2	236	411	55
Saracatinib	8.1, 5.0	3.2	0.10	1.7	10	97	130	69
Sunitinib	9.0	2.9	0.03	1.6	5.5	171	375	53
Tandutinib	8.9, 4.6	4.3	0.37	2.8	47	127	76	62
Vandetanib	8.8, 4.2	4.5	0.14	2.3	27	189	157	57

↵^a Sources: bosutinib, FDA (2012); dasatinib, Kamath et al. (2008); gefitinib, EMA (2008a); imatinib, O’Brien and Fallah Moghaddam (2013); lapatinib, O’Brien and Fallah Moghaddam (2013); sunitinib, EMA (2006).
↵^b Sources: afatinib, EMA (2013); bosutinib, FDA (2012); crizotinib, PMDA (2012); dasatinib, Lombardo et al. (2004); gefitinib, McKillop et al. (2004); lapatinib, EMA (2008b); saracatinib, Hennequin et al. (2006); sunitinib, EMA (2006); vandetanib, TGA (2013).
↵^c Calculated from experimental volume of distribution and fraction unbound in plasma.
↵^d Detailed prediction results (i.e., Kpu of tissues) are summarized in Supplemental Table 5.