Supplement Materials
Table S1: Input parameters (with references) for four model drugs in non-pregnant PBPK
model
Parameters
Values
References
Metformin
Physicochemical Properties
Acid/Base
Base
MW (g/mol)
129.2
Log D at pH 7.4
-1.386
GastroPlus ADMET predictor
pKa
10.37
GastroPlus ADMET predictor
ADME Parameters
Solubility in water (mg/mL)
129
Effective permeability (10-4 cm/s)
0.25
rat Peff obtained from Song et al. 2006 [1];
Human Peff converted from rat Peff within GatroPlus
Fraction unbound in plasma (fup)
1
MetaglipTM drug labeling
Blood-to-plasma ratio
0.7
Tucker et al. 1981 [2]
Vss predicted by PBPK (L)
82.7
Gut FPE (%)
0
Hepatic CL (L/h)
N/A
Renal CL (L/h)
28.6
Eyal et al. 2010 [3]
9.9
Eyal et al. 2010 [3]
Filtration CL (L/h)
9.9
Eyal et al. 2010 [3]
Secretion CL (L/h)
18.7
Eyal et al. 2010 [3]
GFR (L/h)
Digoxin
Acid/Base
Neutral
MW (g/mol)
781
Log D at pH 7.4
-1.4
GastroPlus ADMET predictor
pKa
12.98
GastroPlus ADMET predictor
ADME Parameters
Solubility in water (mg/mL)
0.25
Effective permeability (10-4 cm/s)
1.02
Caco-2 Papp obtained from Troutman and Thakker 2003 [4];
Human Peff converted from Caco-2 Papp within GatroPlus
Fraction unbound in plasma (fup)
0.63
Hebert et al. 2008 [5]
Blood-to-plasma ratio
1.1
Hinderling 1984 [6]
Absolute Bioavailability (%)
70%
Average values from literature [7][8]
Vss predicted by PBPK (L)
Gut FPE (%)
643
0
6.9
Route of elimination 30% excreted unchanged in urine based
on drugbank: URL:http://www.drugbank.ca/drugs/DB00390
Route of elimination 70% excreted unchanged in urine based
on drugbank: URL:http://www.drugbank.ca/drugs/DB00390
7.4
Calculated using Eq. 2
Filtration CL (L/h)
4.6
Calculated using Eq. 3
Secretion CL (L/h)
2.3
Hebert et al. 2008 [5]
Hepatic CL (L/h)
Renal CL (L/h)
GFR (L/h)
4.2
Midazolam
Acid/Base
Base
MW (g/mol)
325.8
Log D at pH 7.4
3.56
GastroPlus ADMET predictor
pKa
5.5
GastroPlus ADMET predictor
Solubility in water (mg/mL)
0.024
drugbank.ca; http://www.drugbank.ca/drugs/DB00683
Effective permeability (10-4 cm/s)
6.28
Tolle-Sander et al. 2003 [9]
Fraction unbound in plasma (fup)
0.0061
Eyal et al. 2010 [3]
Blood-to-plasma ratio
0.55
Gertz et al. 2010 [10]
Vss predicted by PBPK (L)
85.8
Gut FPE (%)
40
Gertz et al. 2010 [10]
Hepatic CL (L/h)
24.5
Reported IV CL (23.7 – 28.2 L/h) Gertz et al. 2010 [10]
ADME Parameters
Emtricitabine
Acid/Base
Base
MW (g/mol)
247.3
Log D at pH 7.4
-0.43
EMTRIVA (emtricitabine) capsule prescribing information
pKa
2.65
EMTRIVA (emtricitabine) capsule prescribing information
Solubility in water (mg/mL)
112
EMTRIVA (emtricitabine) capsule prescribing information
Effective permeability (10-4 cm/s)
2.0
In vitro and in situ data unavailable; BCS Class I compound;
Assuming high Peff (= metoprolol Peff = 2.0 × 10-4 cm/s)
Fraction unbound in plasma (fup)
0.96
EMTRIVA (emtricitabine) capsule prescribing information
Blood-to-plasma ratio
1
EMTRIVA (emtricitabine) capsule prescribing information
Absolute Bioavailability (%)
93
EMTRIVA (emtricitabine) capsule prescribing information
Vss predicted by PBPK (L)
198
Poulin and Theil’s equation under-predicted Kp in tissues
and therefore Vss is initially under-predicted. A scaling
factor of 5 was then applied to optimize all K p values in
ADME Parameters
order to capture the observed Vd reported in Stek et al.
2011 [11]
Gut FPE (%)
0
Hepatic CL (L/h)
0
Renal CL (L/h)
19.1
CL/F reported in Stek et al. 2011 [11]
6.84
Generic value reported by Abduljalil et al. [12]
Filtration CL (L/h)
6.56
Calculated using Eq. 2
Secretion CL (L/h)
12.54
Calculated using Eq. 3
GFR (L/h)
Figure S1. Physiological parameters (tissue volume and perfusion rate) of metformin p-PBPK
model for (A) non-pregnant subjects (weight 97 kg), (B) late pregnant women (weight 117.8
kg) based on model 1, and (C) late pregnant women (weight 117.8 kg) based on model 2.
A
B
C
Figure S2 Physiological parameters (tissue volume and perfusion rate) of digoxin and
midazolam p-PBPK model (same patient population for both studies) for (A) non-pregnant
subjects (weight 71.6 kg), (B) late pregnant women (weight 84 kg) based on model 1, and (C)
late pregnant women (weight 84 kg) based on model 2.
A
B
C
Figure S3 Physiological parameters (tissue volume and perfusion rate) of emtricitabine p-PBPK
model for (A) non-pregnant subjects (weight 75.7 kg), (B) late pregnant women (weight 92.3
kg) based on model 1, and (C) late pregnant women (weight 92.3 kg) based on model 2.
A
B
C
References
1.
Song, N.N., Q.S. Li, and C.X. Liu, Intestinal permeability of metformin using singlepass intestinal perfusion in rats. World Journal of Gastroenterology, 2006. 12(25): p. 40644070.
2.
Tucker, G.T., et al., Metformin kinetics in healthy subjects and in patients with diabetes
mellitus. Br J Clin Pharmacol, 1981. 12(2): p. 235-46.
3.
Eyal, S., et al., Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos,
2010. 38(5): p. 833-40.
4.
Troutman, M.D. and D.R. Thakker, Efflux ratio cannot assess P-glycoprotein-mediated
attenuation of absorptive transport: asymmetric effect of P-glycoprotein on absorptive and
secretory transport across Caco-2 cell monolayers. Pharm Res, 2003. 20(8): p. 1200-9.
5.
Hebert, M.F., et al., Effects of pregnancy on CYP3A and P-glycoprotein activities as
measured by disposition of midazolam and digoxin: a University of Washington specialized
center of research study. Clin Pharmacol Ther, 2008. 84(2): p. 248-53.
6.
Hinderling, P.H., Kinetics of partitioning and binding of digoxin and its analogues in
the subcompartments of blood. J Pharm Sci, 1984. 73(8): p. 1042-53.
7.
Binnion PF. A comparison of the bioavailability of digoxin in capsule, tablet, and
solution taken orally with intravenous digoxin. J Clin Pharmacol. 1976 Oct;16(10 Pt 1):461-7.
8.
Marcus FI, Dickerson J, Pippin S, Stafford M, Bressler R. Digoxin bioavailability:
formulations and rates of infusions. Clin Pharmacol Ther. 1976 Sep;20(3):253-9.
9.
Tolle-Sander, S., et al., Midazolam exhibits characteristics of a highly permeable Pglycoprotein substrate. Pharm Res, 2003. 20(5): p. 757-64.
10.
Gertz, M., et al., Prediction of human intestinal first-pass metabolism of 25 CYP3A
substrates from in vitro clearance and permeability data. Drug Metab Dispos, 2010. 38(7): p.
1147-58.
11.
Stek, A.M., et al., Effect of pregnancy on emtricitabine pharmacokinetics. HIV Med,
2012. 13(4): p. 226-35.
12.
Abduljalil K, Furness P, Johnson TN, Rostami-Hodjegan A, Soltani H. Anatomical,
physiological and metabolic changes with gestational age during normal pregnancy: a database
for parameters required in physiologically based pharmacokinetic modelling. Clin
Pharmacokinet. Jun 1;51(6):365-96.