TABLE 3

Pharmacokinetic parameter estimates of HSP90 inhibitors by rapid binding approximation models in male Sprague-Dawley rats after a single intravenous administration

Precision of the estimates is expressed as standard error in parentheses. A1, B1, and C1 are low-affinity HSP90 inhibitors, whereas A2, B2, and C2 were their corresponding high-affinity inhibitors.

Model	V₁	k_el	k_pt	k_tp	R_total	HSP90 Inhibitor K_D, nM						OFV^{^a}
Model	V₁	k_el	k_pt	k_tp	R_total	A1	A2	B1	B2	C1	C2	OFV^{^a}
	l/kg	h^–1	h^–1	h^–1	nM
One-cmpt^{^b}	2.5	3.2	−	−	2380	447	6.3	710	3.0	832	3.4	1863
	(0.29)	(0.27)			(11)	(33)	(1.3)	(35)	(0.73)	(45)	(0.67)
Two-cmpt^{^c}	1.3	4.4	5.6	1.9	2710	−	5.8	−	1.0	−	1.4	1694
	(0.23)	(0.77)	(1.8)	(0.53)	(705)		(2.4)		(0.48)		(0.68)
Two-cmpt^{^d}	1.3	4.7	6.0	2.1	1540	21	11	30	2.5	23	3.5	1771
	(0.13)	(0.45)	(0.56)	(0.43)	(368)		(3.4)		(0.95)		(1.4)
Two-cmpt^{^e}	1.4	5.0	6.3	2.1	1370	210	11	300	3.4	230	4.9	1770
	(0.13)	(0.47)	(0.40)	(0.37)	(274)		(2.4)		(1.3)		(1.8)

–, Not applicable.
↵^a Objective function values estimated with NONMEM.
↵^b Rapid binding approximation model with a central compartment.
↵^c Rapid binding approximation model with central and peripheral compartments assuming no target-mediated drug disposition for A1, B1, and C1.
↵^d Rapid binding approximation model with central and peripheral compartments assuming in vivo K_D = K_{i,vitro,total} for A1, B1, and C1.
↵^e Rapid binding approximation model with central and peripheral compartments assuming in vivo K_D = 10 × K_{i,vitro,total} for A1, B1, and C1.