Integration of biopredictive dissolution and PBPK

models for evaluation of GI locally acting products:

PART I
Advances in PBPK Modeling and its Regulatory Utility
for Oral Drug Product Development
Sherin Thomas, Ph.D.
Pharmacologist
DQMM | ORS | OGD | CDER | FDA
October 12, 2023
 Disclaimer

This presentation reflects the views of the presenter and

should not be construed to represent FDA’s views or policies.

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 GI Locally Acting Products
• Demonstrating BE for locally acting GI drug products is challenging because
these drug products reach the site of action before they enter systemic
circulation.
• Systemic exposure may not reflect drug concentrations at the site of action.
• BE recommendations of oral locally acting GI drug products are based on drug
product properties and mechanism of action.
• In addition, PBPK models may be used for exploring the correlation between
dissolution in GI tract and plasma concentration profiles and support BE
evaluation of such products.

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 Case Example: Mesalamine DR Tablet
• Case: PBPK Modeling to Support BE Evaluation of a GI Locally Acting Product.
• Question: Whether the slower release of Test product would significantly impact the
drug exposure compared to the reference listed drug (RLD).
• Background:
– Indication: Treatment of mildly to moderately active ulcerative colitis
– Mechanism of action: It appears to have a topical anti-inflammatory effect on the
colonic epithelial cells.
– Bioavailability: 21 – 22%
– Metabolism: The only major metabolite of mesalamine is N-acetyl-5-aminosalicylic
acid and is formed by N-acetyltransferase (NAT) activity in the liver and intestinal
mucosa cells, principally by NAT-1.
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 PSG Recommendation
Type of study Design

Fasting Single-dose, partially or

fully replicated crossover

Fed Single-dose, partially or

fully replicated crossover

In vitro Three stage dissolution

comparative with stage 3 at pH 6.5,
dissolution study 6.8, 7.2 and 7.5

The two products were found to be bioequivalent for

systemic PK under both fasting and fed conditions
www.fda.gov Draft Guidance on Mesalamine, revised June 2016, 5
https://www.accessdata.fda.gov/drugsatfda docs/psg/Mesalamine draft Oral%20tab%20DR RLD%2022000 RC06-16.pdf
 Dissolution data

• Three-stage dissolution data:

Stage 3 F2 value
o Stage 1: 0.1N HCl for 2 hours pH condition
o Stage 2: pH 6.4 phosphate buffer
6.5 < 50
for 1 hour
o Stage 3: pH 6.5, 6.8, 7.2 and 7.5 6.8 < 50
phosphate buffer for 8 hours 6.9 < 50
• The in vitro dissolution testing over a 7.0 > 50
range of pH serves as a surrogate of in
7.2 > 50
vivo drug release in the GI tract.
• In this case the test product showed 7.5 > 50
decreased release compared to RLD at
pH < 7.

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 PBPK Modeling Steps
Intravenous PK data obtained from the literature were used to estimate disposition
parameters.

The PBPK model was developed for DR tablet. The intestinal first pass effect was
optimized. Three stage dissolution data (with pH 6.8, pH 6.9, pH 7.0 and pH 7.2 as stage
3) were incorporated into PBPK model.

PBPK model was validated using dissolution and PK data obtained from additional
clinical BE studies.

1) Evaluate whether the dissolution data at certain pH is biopredictive; 2) Predict local

drug amount in the colon; 3) Population simulation to compare the predicted
percentage of drug absorbed in the colon for T/R and support BE assessment
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 Model Development
 IV bolus 250mg

Vree TB, et al. Liver and gut mucosa acetylation of mesalazine in healthy volunteers.
www.fda.gov 8
International Journal of Clinical Pharmacology and Therapeutics. 2000, 38(11): 514–22
 Model Development

 Delayed release (DR) tablet 1.2 g

 Three stage dissolution data with stage
3 at pH 7.2 was used as direct input
 Intestinal first pass effect (FPE) was
optimized
PK Parameter %PE
Cmax (ng/mL) -1.2
AUCinf (ng*h/mL) 20.7

www.fda.gov 9
NDA ClinPharm Review document available on drugs@FDA.
 Model Validation
 Tablet DR 1.2g PK data from literature  Additional internally available dissolution
and PK data sets were used for model
validation
PK Dataset - I
PK Parameter %PE
Cmax (ng/mL) -7.2
AUCinf (ng*h/mL) 3.3
AUCt (ng*h/mL) 0.5
AUC4-48 (ng*h/mL) -16.3
PK Dataset - II
PK Parameter %PE
PK Parameter %PE Cmax (ng/mL) 12.7
Cmax (ng/mL) -6.5 AUCinf (ng*h/mL) 0.3
AUCinf (ng*h/mL) -18.2 AUCt (ng*h/mL) -1.5
AUC4-48 (ng*h/mL) -14.5

www.fda.gov Alex Yu et al. Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine 10
Formulations in Regions of the Human Gastrointestinal Tract. Mol. Pharmaceutics 2017, 14, 345−358.
 Model Application
 Evaluate whether the dissolution data at certain pH is biopredictive
– Dissolution profiles at both pH 7.0 and pH 7.2 (as stage 3) is
biorelevant/biopredictive to the PK profiles with %PE < 22%.

Stage 3 pH 7.2 Stage 3 pH 6.9

PK Parameter %PE PK Parameter %PE
Cmax (ng/mL) 20.5 Cmax (ng/mL) 20.1
AUCinf (ng*h/mL) 11.3 AUCinf (ng*h/mL) 17.6
AUCt (ng*h/mL) 11.3 AUCt (ng*h/mL) 17.6
AUC4-48 (ng*h/mL) 2.4 AUC4-48 (ng*h/mL) 0.2
Stage 3 pH 7.0 Stage 3 pH 6.8
PK Parameter %PE PK Parameter %PE
Cmax (ng/mL) 19.9 Cmax (ng/mL) 34.5
AUCinf (ng*h/mL) 12.7 AUCinf (ng*h/mL) 30.6
AUCt (ng*h/mL) 12.7 AUCt (ng*h/mL) 30.6
AUC4-48 (ng*h/mL) 1.8 AUC4-48 (ng*h/mL) 10.7

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 Model Application
 Predict local drug amount in the colon and percentage of drug
absorbed in the colon
– The simulation results using biopredictive pH at Stage 3 Predicted for Predicted for
Dissolution PK Parameter Colon for RLD Colon for Test
dissolution data suggest that the local amount
Cmax (mg) 157.7 152.4
in colon is similar between RLD and test 7.2 AUCt (mg*h) 2592 2609
product. Cmax (mg) 156.6 153.6
7 AUCt (mg*h) 2580 2567
Cmax (mg) 157 153.2
6.9 AUCt (mg*h) 2521 2422

– Population simulations (n=25) showed that the Stage 3 pH T/R Ratio 90% CI lower 90% CI upper
percentage of drug absorbed in the colon is
pH 7.2 99.71 99.21 100.20
similar between the RLD and test product with
the 90% CI of the T/R ratio falling within 80- pH 7.0 101.58 98.06 105.10
125%.
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 Summary

• PBPK model developed by the reviewers to predict local drug amount in the
colon by incorporating dissolution data at different pH conditions supported
that:
– The three-stage dissolution profiles at both pH 7.0 and pH 7.2 (as stage 3) may be
biopredictive/biorelevant to the local and systemic exposure.
– The percentage of drug absorbed in the colon is similar between the RLD and test
product.
– The predicted amount of mesalamine in colon is similar between RLD and test product.
• Totality of evidence based on dissolution data, formulation differences, gut
physiology considerations along with PBPK modeling results was used to
conclude that the test product was low risk for bioinequivalence at site of
action.
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 Ongoing GDUFA Funded Research
Research focused on improving in vitro bioequivalence (BE) methods and
developing predictive in silico models. The following ongoing projects intend
to develop in vitro biopharmaceutic data including solubility and dissolution
data will be generated for locally acting GI drug products. Using the
generated in vitro biopharmaceutics data, model-based virtual BE evaluation
will be simulated in healthy and patient population.
• Title: Development of Physiologically Based Biopharmaceutics Modeling (PBBM)
Framework to Support an Assessment of Bioequivalence for Locally-Acting Drugs in
the Gastrointestinal Tract in Healthy Subjects and Patients. (Grant #1U01FD007660-
01; University of Bath)
• Title: Development and Verification of In Vitro Integrated Mechanistic Population-
Based PBPK Model Framework Towards Virtual Bioequivalence Assessment of Locally
Acting Drug Products in the GI Tract. (Grant # 1U01FD007662; University of Florida)

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 Acknowledgment
OGD/ORS/Division of Quantitative Methods and Modeling
Dr. Fang Wu
Drs. Yi-Hsien Cheng, Arindom Pal
Drs. Lanyan (Lucy) Fang, Liang Zhao
OGD/ORS/IO
Drs. Lei Zhang and Robert Lionberger

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