. Author manuscript; available in PMC: 2020 Jul 1.

Published in final edited form as: J Pharm Sci. 2019 Feb 18;108(7):2465–2475. doi: 10.1016/j.xphs.2019.01.034

Table 2:

The list of parameters utilized to build the ‘dual’ cell-level PK-PD model for ADC.

Parameters	Description	Units	Value (CV%)	Source
SF	Scaling factor to convert the number of molecules to nanomoles	Unitless	$\frac{10^{9}}{6.023 \times 10^{23}}$	Fixed
MV, $V_{C e l l}^{N 87}$ , $V_{C e l l}^{M C F 7}$	Volumes of media, single N87 and MCF7 cell	μL, pL, pL	100, 3.12, 8.14	(14)
DT^N87, DT^MCF7	Doubling times for N87 and MCF7 cells	h	40.1, 33.6	(14, 17)
$T C_{N 87}^{M a x}$ , $T C_{M C F 7}^{M a x}$	Maximum achievable cell-count in a culture well for N87 and GFP-MCF7 cells	Number	80, 500, 105,00	(17)
Tub^Total	Total concentration of intracellular tubulin in each cell	nM	65	Previously estimated (12)
$K_{o n}^{T u b}$ , $K_{o f f}^{T u b}$	Second-order association and first-order dissociation rates of MMAE binding to tubulin	1/nM/h, 1/h	0.0183, 0.545	(13,38,39)
$K_{o n}^{A D C}$ , $K_{o f f}^{A D C}$	Second-order association and first-order dissociation rates of T-vc-MMAE binding to HER2	1/nM/h, 1/h	0.03, 0.014	(13, 14)
$K_{i n t}^{A D C}$	First-order net antibody-HER2 complex internalization rate	1/h	0.11	(13, 14)
$K_{d e g}^{A D C}$	First-order non-specific deconjugation rate of MMAE from ADC	1/h	~0	Previously estimated to a low value (14)
DAR	Initial drug: antibody ratio of T-vc-MMAE	Unitless	4.5	Experimentally measured (17)
$A g_{e x}^{N 87}$ , $A g_{e x}^{M C F 7}$	Number of HER2 receptors on N87 and GFP-MCF7 cells	Unitless	950,000, 52,000	Determined in-house (14)
$K_{d e g}^{A D C}$	First-order rate of proteases-induced intracellular ADC degradation and MMAE release	1/h	0.353	(14)
$K_{i n}^{M M A E}$ , $K_{o u t}^{M M A E}$	First-order influx and efflux rate constants for MMAE from extracellular space to intracellular space	1/h	8.33, 0.199	(14)
$K_{m a x}^{N 87}$ , $K_{m a x}^{M C F 7}$	First-order killing rates ofMMAE in N87and GFP-MCF7 cells	1/h	0.03 (12.3 %), 0.021 (4.1%)	Estimated
$K_{50}^{N 87}$ , $K_{50}^{M C F 7}$	Mean intracellular occupancy to tubulin ( $O c c_{T u b}^{c e l l}$ ) required to achieve 50% cytotoxicity	percentage	98.3 % (19.3%), 96.1% (5.5%)	Estimated
$W C V_{K C 50}^{N 87}$ , $W C V_{K C 50}^{M C F 7}$	Within-cell variability in KC₅₀ values associated with N87 and GFP-MCF7 cells	Percentage	19.2% (31%), 17.9 % (10.9%)	Estimated
τ^N87,τ^MCF7	Transit time parameter associated with the cell distribution model for N87 and GFP-MCF7 cells	h	0.32(18%), 5.0 (12.3%)	Estimated
γ^N87, γ^MCF7	Curve fitting parameter that determines the steepness of the occupancy-response relationship for each cell line	Unitless	1.1 (18.2%), 3.1(21.9%)	Estimated
$K C_{50}^{ƛ}$	Percentage improvement in occupancy (“ƛ”) that results in 50% of maximum bystander killing	Percentage	59% (12.6%)	Estimated
τ^ƛ	Transit time parameter associated with the delay between bystander killing signal and observed bystander effect response	h	37 (41%)	Estimated