TABLE 2.

Parameter values for the translational QSP model in mice, NHPs, and humans.

Parameter	Description	Unit	Mice (28 g) (%RSE)	NHP (5 kg) (%RSE)	Human (71 kg) (%RSE)
${\mathrm{k}}_{\text{in},\text{endo}}$	Rate of endocytosis for LNP, sgRNA, and mRNA	1/h	0.14 a	0.039 (43)	0.007 (1.44)
${\mathrm{k}}_{\text{out},\text{exo}}$	Rate of exocytosis for LNP, sgRNA, and mRNA	1/h	6.84 (13.4)	2,690 (65.4)	775 (0.602)
${\mathrm{k}}_{\mathrm{deg},\text{DR}}$	Rate of degradation for the LNP-LDL complex	1/h	2.04 b	2.04 (12)	5.15 (6.47)
${\text{LDL}}_{\text{tot}}$	LDL concentration	ug/mL	539 b	539 (66.2)	84.5 (0.508)
${\mathrm{k}}_{\text{dis}}$	Rate of dissociation from opsonins	1/h	0.47 c	8.64 (39)	0.186 (27.2)
${\mathrm{k}}_{\text{ass}}$	Rate of association from opsonins	1/h	1,550.34 c	5.06 (14.5)	56.8 (16)
${\mathrm{k}}_{\text{release}}$	Rate of release of mRNA and sgRNA from LNPs	1/h	0.0056 (Miyazawa et al., 2024)	0.634 (5.31)	0.0056 (Miyazawa et al., 2024)
${\mathrm{k}}_{\mathrm{deg},\text{LNP}}$	Rate of degradation of unbound LNP	1/h	1.6486 (Miyazawa et al., 2024)	1.6486 (Miyazawa et al., 2024)	0.101 (35.9)
${\mathrm{k}}_{\text{el}}$	Rate of elimination of the LDL receptor	1/h	0.231 d (Harwood and Pellarin, 1997)	0.231 d (Harwood and Pellarin, 1997)	0.009 (44.7)
${\mathrm{k}}_{\mathrm{deg},\text{sgRNA}}$	Rate of degradation of sgRNA	1/h	0.378 e	2.01 c	2.01 c
${\mathrm{k}}_{\mathrm{deg},\text{mRNA}}$	Rate of degradation of mRNA	1/h	0.378 (46.5)	0.1232 (Miyazawa et al., 2024)	0.1232 (Miyazawa et al., 2024)
${\mathrm{k}}_{\text{on},\text{RNP}}$	Rate of association for the formation of the RNP complex	ug/mL/h	Calculated ${\mathrm{k}}_{\text{on}}=\frac{\text{koff}}{{\mathrm{K}}_{\mathrm{D}}}$	Calculated ${\mathrm{k}}_{\text{on}}=\frac{\text{koff}}{{\mathrm{K}}_{\mathrm{D}}}$	Calculated ${\mathrm{k}}_{\text{on}}=\frac{\text{koff}}{{\mathrm{K}}_{\mathrm{D}}}$
${\mathrm{k}}_{\text{off},\text{RNP}}$	Rate of dissociation for the RNP complex	1/h	0.00188 c	0.00188 c	0.00188 c
${\mathrm{K}}_{\mathrm{D}}$	Equilibrium dissociation constant	nM	0.49 (Sternberg et al., 2014)	0.49 (Sternberg et al., 2014)	0.49 (Sternberg et al., 2014)
${\mathrm{k}}_{\mathrm{int}}$	Rate constant for phagocytosis into the mononuclear phagocytosis system	1/h	0.9063 (Miyazawa et al., 2024)	0.9063 (Miyazawa et al., 2024)	0.9063 (Miyazawa et al., 2024)
${\mathrm{k}}_{\text{on},\text{LNP}}$	Rate of association of the LNP-LDL complex	ug/mL/h	0.18 (Harwood and Pellarin, 1997)	0.18 (Harwood and Pellarin, 1997)	0.18 (Harwood and Pellarin, 1997)
${\mathrm{k}}_{\text{off},\text{LNP}}$	Rate of dissociation of the LNP-LDL complex	1/h	33.12 (Harwood and Pellarin, 1997)	33.12 (Harwood and Pellarin, 1997)	33.12 (Harwood and Pellarin, 1997)
${\mathrm{f}}_{\mathrm{u}}$	Plasma free fraction of LNPs	—	0.002 f (Mager et al., 2012)	0.002 f (Mager et al., 2012)	0.002 f (Mager et al., 2012)
${\mathrm{k}}_{\text{trans}}$	Rate of translation from mRNA to Cas	1/h	0.36 c	0.36 c	0.36 c
${\mathrm{f}}_{\mathrm{u}}$	Plasma free fraction of RNA (sgRNA and mRNA)	—	0.15 (Ayyar et al., 2021)	0.15 (Ayyar et al., 2021)	0.15 (Ayyar et al., 2021)
${\text{TTR}}_0$	Baseline TTR concentration	%	—	100 (fixed)	100 (fixed)
${\mathrm{k}}_{\text{out},\text{TTR}}$	First-order rate constant for the degradation of the TTR protein	1/d	—	0.493 (15)	0.247 (17.5)
${\mathrm{I}}_{\max }$	Maximum inhibition for TTR	—	—	0.961 (0.625)	0.959 (6.55)
$\mathrm{I}{\mathrm{C}}_{50}$	RNP concentration at 50% of inhibition for TTR	ug/mL	—	4.77 (11.5)	0.3 (0.02)
$\mathrm{\gamma }$	Gamma coefficient for TTR	—	—	0.31 (13.3)	—
$\text{PCSK}{9}_0$	Baseline PCSK9 in serum	%	—	100 (Fixed)	—
$\text{MTT}$	Mean transit time for PCSK9	day	—	14.5 (0.563)	—
${\mathrm{I}}_{\max }$	Maximum inhibition for PCSK9	—	—	0.771 (14.2)	—
$\mathrm{I}{\mathrm{C}}_{50}$	RNP concentration at 50% inhibition for PCSK9	ug/mL	—	21.5 (0.994)	—
$\mathrm{\gamma }$	Gamma coefficient for PCSK9	—	—	1.1 (Fixed)	—
$\mathrm{\Gamma }$	Gamma coefficient for LDL cholesterol	—	—	0.672 (18.5)	—
${\mathrm{k}}_{\mathrm{deg},\text{LDL}}$	Rate of degradation for LDL cholesterol	1/d	—	4.66 (67.4)	—

TTR, transthyretin; PCSK9, proprotein convertase subtilisin/kexin type 9; LNP, lipid nanoparticle; mRNA, messenger mRNA; sgRNA, single guide RNA; LDL, low-density lipoprotein.

^a Fixed and scaled from NHPs at an allometric coefficient of −0.25.

^b Fixed and assumed the same as NHPs.

^c Fixed from the mechanistic model.

^d Calculated from the half-life of the LDL receptor (Harwood and Pellarin, 1997).

^e Assumed to be the same as for mRNA degradation.

^f Calculated from the renal clearance of mice (Mager et al., 2012).