TABLE 1
Parameters used and determined in the construction of digoxin human transplacental PK model
| Parameter | Definition of parameter | Fixed or Fitted (coefficient of variation [CV] %) | Reference | Comments |
|---|---|---|---|---|
| Molecular weight | 780.94 | |||
| Parameters of perfusion experimental settings | ||||
| fu,meda | Unbound fraction of drug in medium of maternal and fetal circuits | 1 | Derewlany et al., 1991 | No protein was added in the perfusion medium |
| fu,tb | Unbound fraction of drug in syncytiotrophoblast | 0.20 | Rodgers et al., 2005 | |
| fu,np | Unbound fraction of drug in non-perfused placental tissue | 0.20 | Assumed to be the same as fu,t | |
| Cmr at start of digoxin perfusion (ng/mL) | Total drug concentration in the maternal reservoir | 5.5 | Derewlany et al., 1991 | |
| Vmr (mL) | Volume of maternal reservoir | 246 | Derewlany et al., 1991 | |
| Vma (mL) | Volume of sampling port for maternal artery | 0.30 | Derewlany et al., 1991 | |
| Vmv (mL) | Volume of sampling port for maternal vein | 0.30 | Derewlany et al., 1991 | |
| Vfa (mL) | Volume of sampling port for umbilical artery | 0.30 | Derewlany et al., 1991 | |
| Vfv (mL) | Volume of sampling port for umbilical vein | 0.30 | Derewlany et al., 1991 | |
| Vfr (mL) | Volume of fetal reservoir | 135 | Derewlany et al., 1991 | |
| Vch (mL) | Volume of the medium in the maternal chamber | 17.5 (0.005) | Fitting | |
| Qm (mL/min) | Perfusion flow rate in the maternal side | 13.9 | Derewlany et al., 1991 | |
| Qf (mL/min) | Perfusion flow rate in the fetal side | 2.93 | Derewlany et al., 1991 | |
| Physiologic parameters of human placental cotyledon | ||||
| Vfc (mL)c | Volume of fetal capillaries | 1.22 | Mayhew et al., 2008 | |
| Vmi (mL)c | Volume of maternal intervillous space | 5.55 | Mayhew et al., 2008 | |
| Vt (mL)c | Volume of syncytiotrophoblast | 2.49 | Mayhew et al., 2008 | |
| Transplacental PK parameters of digoxin | ||||
| PSMVM,act,inf (mL/min) | Active influx clearance at the MVM | 1.50 (0.034) | Fitting | |
| PSMVM,act,eff (mL/min) | Active efflux clearance at the MVM | 2.18 (0.031) | Fitting | |
| PSBM,act,eff (mL/min) | Active efflux clearance at the BM | 0.66 (0.021) | Fitting | |
| PSBM,act,inf (mL/min) | Active influx clearance at the BM | 0.78 (0.037) | Fitting | |
| Qnp (ml/min) | Intercompartmental clearance between maternal placenta and non-perfused placental tissue | 0.51 (0.0015) | Fitting | |
| Vnp (ml) | Volume of non-perfused tissue | 49.6 (0.0015) | Fitting | |
| PSMVM,diff (mL/min) | Passive clearance at the MVM | 0.69 | Zheng et al., 2015 | |
| PSBM,diff (mL/min) | Passive clearance at the BM | 0.12 | Zheng et al., 2015 | |
aCalculated using the following equation:
, n: number of binding sites, Pt: albumin concentration, Kd: dissociation constant.bThe estimation method of fu,t is described in the Supplemental Text.
cThe calculation method of perfused tissue volumes (Vfc, Vmi, and Vt) is described in the Supplemental Text. Vfc, Vmi, and Vt are expressed as volume of a single cotyledon unit in human placenta.
