Supplement Materials

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 Peffconverted 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]
Vsspredicted 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]
GFR (L/h) / 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]
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 Peffconverted 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]
Vsspredicted by PBPK (L) / 643
Gut FPE (%) / 0
Hepatic CL (L/h) / 4.2 / Route of elimination 30% excreted unchanged in urine based on drugbank: URL:
Renal CL (L/h) / 6.9 / Route of elimination 70% excreted unchanged in urine based on drugbank: URL:
GFR (L/h) / 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]
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
ADME Parameters
Solubility in water (mg/mL) / 0.024 / drugbank.ca;
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]
Vsspredicted 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]
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
ADME Parameters
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 (= metoprololPeff= 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
Vsspredicted by PBPK (L) / 198 / Poulin and Theil’s equation under-predicted Kp in tissues and therefore Vssis initially under-predicted. A scaling factor of 5 was then applied to optimize all Kp values in 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]
GFR (L/h) / 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

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.

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.

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.

References

1.Song, N.N., Q.S. Li, and C.X. Liu, Intestinal permeability of metformin using single-pass intestinal perfusion in rats. World Journal of Gastroenterology, 2006. 12(25): p. 4064-4070.

2.Tucker, G.T., et al., Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J ClinPharmacol, 1981. 12(2): p. 235-46.

3.Eyal, S., et al., Pharmacokinetics of metformin during pregnancy. Drug MetabDispos, 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. ClinPharmacolTher, 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 ClinPharmacol. 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. ClinPharmacolTher. 1976 Sep;20(3):253-9.

9.Tolle-Sander, S., et al., Midazolam exhibits characteristics of a highly permeable P-glycoprotein 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 MetabDispos, 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. ClinPharmacokinet. Jun 1;51(6):365-96.