Rtot (nM) | Baseline ASGPR density in mouse liver | 633.4 | Bon et al., 2017 |
kdeg (h−1) | Degradation rate constant for ASGPR | 0.04 | Bon et al., 2017 |
ksyn (nM/h) | Synthesis rate for ASGPR | 27.9 | Calculated (ksyn = Rtot · kdeg) |
koff (h−1) | Dissociation rate constant for GalNAc to ASGPR | 1.32 | Estimated (Sato et al., 2002) |
kon (nM−1·h−1) | Association rate constant for GalNAc to ASGPR | 0.53 | Calculateda (kon = koff / KD ) |
kint (h−1) | Internalization rate constant for bound ASGPR | 2.4 | Estimated (Sato et al., 2002) |
krec (h−1) | ASGPR recycling constant | 13.8 | Schwartz et al., 1982 |
kdeg,R (h−1) | Degradation rate constant for endosomal ASGPR | 1.53 | Schwartz et al., 1982 |
kcle (h−1) | Rate constant for GalNAc cleavage from siRNA | 1.32 | Prakash et al., 2014 |
ka (h−1) | Subcutaneous absorption rate constant | 0.7 | 6.5 |
F (%) | Apparent subcutaneous bioavailability | 33 | 5.0 |
fu,p | Plasma fraction unbound | 0.15 | Humphreys et al., 2019 |
PS (ml/h) | Kidney permeability flow rate | 49.6 | 31.9 |
fu,k | Kidney fraction unbound | 0.07 | 15.6 |
kass,kid (h−1) | Kidney association rate constant for binding | 9.9 | 14.2 |
kdis,kid (h−1) | Kidney dissociation rate constant for binding | 0.026 | 13.8 |
CLup,liv_in (ml/h) | Liver uptake clearance | 207.2 | 8.5 |
CLup,liv_eff (ml/h) | Liver release clearance | 0.0025 | 23.9 |
kass,liv (h−1) | Liver association rate constant for binding | 0.0032 | 63.2 |
kdis,liv (h−1) | Liver dissociation rate constant for binding | 0.0034 | 24.4 |
KP,rest | Partition coefficient for remaining organs | 0.1 | Fixed |
fesc | Fraction siRNA in endosome escaping into cytosol | 0.01 | Gilleron et al., 2013 |
kdeg,d (h−1) | Rate constant for endosomal siRNA degradation | 0.012 | 3.0 |
kon,RISC (nM−1·h−1) | Association rate constant of siRNA to RISC | 0.00023 | 22.6 |
koff,RISC (h−1) | Dissociation rate constant of siRNA from RISC | 10−7 | Fixed (Bartlett and Davis, 2006) |
RISCtot (nM) | Total RISC concentration in hepatocytes | 30 | Wang et al., 2012 |
kDR (h−1) | Degradation rate constant for loaded RISC | 0.005 | 21.0 |
kdeg,c (h−1) | Degradation rate constant for free cytosolic siRNA | 0.1 | Fixed (sensitivity analysis) |
kdeg,m (h−1) | Degradation rate constant for AT mRNA | 0.06 | 41.3 |
kdeg,p (h−1) | Degradation rate constant for AT protein | 0.05 | 25.0 |
Smax | Maximal stimulation of target mRNA degradation | 14.2 | Fixed (calculated) |
SC50 (ng/M) | Bound RISC at half maximal effect | 2.4 | 6.5 |
γ | Gamma coefficient for mRNA-protein translation | 1.5 | 5.6 |