Table 3.

Parameters used in enoxaparin PBPK model development

Parameter	Enoxaparin	Source
Physicochemical properties
Units of anti‐Xa per 1 mg enoxaparin (IU/mL)	100	FDA label 1
Molecular weight (g/mol)	4,500	FDA label 1
pKa value	3.00	Wang et al. 48
Lipophilicity	−10.0	Drug Bank
Solubility (mg/mL)	200	Drug Bank
Blood to plasma ratio	0.85	Calculated valuea
Binding
Antithrombin plasma concentration (μM)b	25	Wajima et al. 44
K D (μM)b	2.5	Wajima et al. 44
k off (1/hour)	2	Optimized
Distribution
Partition coefficients	PK‐Sim Standard	Willmann et al. 49 , 50
Cellular permeabilities	PK‐Sim Standard	Willmann et al. 49 , 50
k a (1/hour)	0.60	Optimized
Metabolism
Heparinase
CLspec (1/minute)c	0.096	Optimized
Excretion
GFR fractiond	1.00	FDA label 1
f e,urine	40%	FDA label 1

CL_spec, specific clearance; FDA, US Food and Drug Administration; f _e,urine, fraction of dose excreted in urine; k _a, absorption rate constant; GFR, glomerular filtration rate; IU, international unit; K _D, equilibrium dissociation constant; k _off, rate of unbinding; PBPK, physiologically‐based pharmacokinetic; pKa, negative log of the acid dissociation constant.

^a $\left[\left(f_{{\mathrm{water}}_{\mathrm{rbc}}}+f_{{\mathrm{lipids}}_{\mathrm{rbc}}}\ast {10}^{\log P}+f_{{\mathrm{proteins}}_{\mathrm{rbc}}}\ast \mathrm{KProt}\right)\ast f_u\ast \mathrm{HCT}\right]‐\mathrm{HCT}+1$; where f _{water_rbc} is the fractional volume content of water in blood cells, f _{lipids_rbc} is the fractional volume content of lipid in blood cells, logP is the lipophilicity measure, f _{proteins_rbc} is the fractional volume content of protein in blood cells, KProt is partition coefficient of water to protein, f_u is the fraction unbound, and HCT is the hematocrit. ⁴⁹ , ^{50 b}A sensitivity analysis found that of all the PBPK model parameters, antithrombin concentration and K _D had the largest impact on anti‐Xa 4‐hour concentration. However, neither of these parameters resulted in a ≥ 10% increase or decrease in 4‐hour concentration when increased by 10%, indicating that the PBPK model is not overly sensitive to them. ^cCL_spec is a PK‐Sim software‐specific term that is calculated by ${\mathrm{CL}}_{\mathrm{spec}}=\frac{{\mathrm{CL}}_{\mathrm{int}}}{V\ast f_{\mathrm{cell}}}$; where CL_int is the scaled intrinsic clearance (mL/minute), V is the volume of the liver, and f _cell is the fraction intracellular in the liver. ^dGFR fraction is a PK‐Sim software‐specific term that describes what fraction of the virtual participant’s GFR contributes to renal clearance. A GFR fraction of 1.0 indicates no tubular secretion or reabsorption is included.