Supporting Information I

Utility of Physiologically-Based Absorption Modeling in Implementing Quality by Design in Drug Development

Xinyuan Zhang1, 2, Robert A. Lionberger1, 2, 3, Barbara M. Davit1, 2, Lawrence X. Yu1, 2

1 The views presented in this article by the authors do not necessarily reflect those of the Food and Drug Administration (FDA).

2 Office of Generic Drugs, Food and Drug Administration

3 To whom correspondence should be addressed. Mailing address: Office of Generic Drugs (OGD), Food and Drug Administration (FDA). E-mail: . Phone: 240-276-9315. Fax: 240-276-9327


Table S1: ACAT Physiological Model Parameters for Fasted Simulation

Compartment / ASF / pH / Transit Time (h) / Volume (mL) / Length (cm) / Radius (cm)
Stomach / 0.0 / 1.30 / 0.25 a / 50.00 / 30.00 / 10.00
Duodenum / 12.84 / 6.00 / 0.26 / 48.25 / 15.00 / 1.60
Jejunum 1 / 13.69 / 6.20 / 0.95 / 175.3 / 62.00 / 1.50
Jejunum 2 / 15.33 / 6.40 / 0.76 / 139.9 / 62.00 / 1.34
Ileum 1 / 17.41 / 6.60 / 0.59 / 108.5 / 62.00 / 1.18
Ileum 2 / 20.34 / 6.90 / 0.43 / 79.48 / 62.00 / 1.01
Ileum 3 / 24.17 / 7.40 / 0.31 / 56.29 / 62.00 / 0.85
Caecum / 0.484 / 6.40 / 4.50 / 52.92 / 13.75 / 3.50
Asc Colon / 0.678 / 6.80 / 36.00 / 56.99 / 29.02 / 2.50

a For IR suspension simulation under fasted state, 0.1 hour was used as stomach transit time

Table S2: ACAT Physiological Model Parameters for Fed Simulation

Compartment / ASF / pH / Transit Time (h) / Volume (mL) / Length (cm) / Radius (cm)
Stomach / 0.0 / 4.9 / 1.00 / 953.6 / 30.00 / 10.00
Duodenum / 12.84 / 5.40 / 0.26 / 48.25 / 15.00 / 1.60
Jejunum 1 / 13.69 / 5.40 / 0.95 / 175.3 / 62.00 / 1.50
Jejunum 2 / 15.33 / 6.00 / 0.76 / 139.9 / 62.00 / 1.34
Ileum 1 / 17.41 / 6.60 / 0.59 / 108.5 / 62.00 / 1.18
Ileum 2 / 20.34 / 6.90 / 0.43 / 79.48 / 62.00 / 1.01
Ileum 3 / 24.17 / 7.40 / 0.31 / 56.29 / 62.00 / 0.85
Caecum / 0.484 / 6.40 / 4.50 / 52.92 / 13.75 / 3.50
Asc Colon / 0.678 / 6.80 / 36.00 / 56.98 / 29.02 / 2.50


Table S3: Distribution of Parameters Used in Virtual BE Studies

Parameters / Lower Limit / Upper Limit / CV% / Distribution
Fraction of colon fluid volume in fated state (%) / 7.4082 / 13.499 / 10 / Log-Normal
Fraction of SI fluid volume in fasted state (%) / 29.633 / 53.994 / 10 / Log-Normal
Caecum Length (cm) / 10.186 / 18.561 / 10 / Log-Normal
Colon Length (cm) / 21.499 / 39.173 / 10 / Log-Normal
Caecum Radius (cm) / 2.5929 / 4.7254 / 10 / Log-Normal
Colon Radius (cm) / 1.852 / 3.3746 / 10 / Log-Normal
Caecum Transit Time (h) / 2.4697 / 8.1995 / 20 / Log-Normal
Colon Transit Time (h) / 19.757 / 65.596 / 20 / Log-Normal
Stomach pH / 0.907 / 1.8633 / 12 / Log-Normal
Deodenum ASF / 9.5113 / 17.331 / 10 / Log-Normal
Duodenum pH / 5.4836 / 6.565 / 3 / Log-Normal
Jejunum 1 ASF / 10.145 / 18.486 / 10 / Log-Normal
Jejunum 1 pH / 5.6664 / 6.7839 / 3 / Log-Normal
Jejunum 2 ASF / 11.357 / 20.693 / 10 / Log-Normal
Ileum 1 ASF / 12.897 / 23.499 / 10 / Log-Normal
Ileum 2 ASF / 15.067 / 27.455 / 10 / Log-Normal
Ileum 3 ASF / 17.904 / 32.623 / 10 / Log-Normal
Caecum ASF / 0.3589 / 0.654 / 10 / Log-Normal
Caecum pH / 5.8492 / 7.0027 / 3 / Log-Normal
Asc Colon ASF / 0.5025 / 0.9156 / 10 / Log-Normal
Asc Colon pH / 6.2147 / 7.4404 / 3 / Log-Normal
Hepatic Perfusion (L/min) / 0.6099 / 3.6894 / 30 / Log-Normal
Subject Weight (kg) / 51.857 / 94.49 / 10 / Log-Normal
Specific Central Compartment Volume (L/kg) / 0.4614 / 1.5319 / 20 / Log-Normal
Distribution Constant Central to Peripheral K12 (1/h) / 0.0187 / 0.0621 / 20 / Log-Normal
Distribution Constant Peripheral to Central K21 (1/h) / 0.132 / 0.4384 / 20 / Log-Normal
Specific Systemic Clearance (L/h/kg) / 0.0082 / 0.0274 / 20 / Log-Normal
Primary Permeability (cm/sec ×104) / 2.3599 / 7.8351 / 20 / Log-Normal
Refernce Solubility (mg/mL) / 0.0268 / 0.5378 / 50 / Log-Normal
Stomach Transit Time (h) / 0.1372 / 0.4555 / 20 / Log-Normal


Table S4: Comparison of predicted PK parameters using CR: Integral Tablet versus CR: Dispersed for XR tablet.

Method / Obs. / CR: Integral Tablet * / CR: Dispersed **
Weibull
(Max, %) / Fasted / N.A. / 79.46 / 97.26
Fed / N.A. / 79.46 / 97.54
Weibull
(Tlag, hr) / Fasted / N.A. / 0 / 0.479
Fed / N.A. / 0 / 0.888
Weibull (a) / Fasted / N.A. / 20.61 / 19.31
Fed / N.A. / 20.61 / 12.72
Weubll (b) / Fasted / N.A / 1.528 / 1.524
Fed / N.A. / 1.528 / 1.134
Cmax
(ng/mL) / Fasted / 3005.2 / 3105.2 / 3430.3
Fed / 3329.9 / 3786.6 / 3859.5
AUCt
(µg×h/mL) / Fasted / 270.4 / 263.7 / 299.1
Fed / 286.1 / 288.6 / 321.0
AUCinf
(µg×h/mL) / Fasted / 285.8 / 272.2 / 308.9
Fed / 304.7 / 297.5 / 331.3
Tmax
(hr) / Fasted / 24 / 28.9 / 31.3
Fed / 24 / 16.4 / 20.5
POT20
(hr) / Fasted / [10,42] / [13,44] / [13, 47]
Fed / [8.1,42] / [10,34] / [11, 41]
Fa (%) / Fasted / N.A. / 71.6 / 81.3
Fed / N.A. / 78.2 / 87.1
Correlation Coefficient (R2) / Fasted / N.A. / 0.974 / 0.965
Fed / N.A. / 0.954 / 0.933

* The Weibull function parameters were obtained by fitting an in vitro dissolution profile. This was used as the baseline simulation in current study. Simulations were performed under CR: Integral Tablet dosage form.

** The Weibull function parameters were obtained by deconvolution of observed mean PK profiles under CR: Dispersed dosage form. Simulations were performed under CR: Dispersed dosage form as well.
Figure S1. Comparison of in vivo dissolution after oral administration of IR formulations and XR tablet with in vitro dissolution. Simulation performed for fasted state used the same solubility (0.32mg/mL) as for fed state. (A) suspension; (B) tablet; (C) XR tablet


Figure S2: Predicted PK profiles for XR tablet using CR: Dispersed in (A) fasted; (B) fed conditions.

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