BIOWAIVER APPROACH FOR BCS CLASS 3 USING IN SILICO MODELING

MATA | MIRANDA | NAMORO | QUILANG | RAMIREZ | SO

ANSWERS TO GUIDE QUESTIONS
1. What is the major site of absorption for metformin?
The major site of absorption for metformin is the proximal small intestine and the primary route of
elimination is via the kidneys. Studies have suggested that metformin is a substrate for organic cation
transporters (OCTs) in enterocytes, small intestine, and hepatocytes, although no specific transporter has
been identified.

2. What is a biowaiver?
A biowaiver approach allows, on the basis of comparative in vitro release studies, the approval of changes
to a drug product that are predicted not to affect in vivo performance, minimizing review burden on regulators
and avoiding unnecessary clinical studies, expense, and delay for the sponsor.

3. What are the 2 tools used to show bioequivalence?
Two approaches are commonly used to establish bioequivalence between two drug products, that is,
statistical comparison of clinical studies and statistical comparison between sets of in vitro dissolution profiles.

4. What are the advantages of using modeling for a biowaiver proposal?
For the specific case of metformin, in silico modeling and simulation is presented to offer a third approach of
equal validity as it includes all of the key parameters that fully define the absorption profile of this compound
(dissolution, permeability, and GI residence time).
In comparing an f2 calculation versus a modeling and simulation approach (BCS 3 compounds have limited
permeability) transit time becomes a critical factor to the total fraction dose absorbed. A model which includes GI
transit as well as dissolution and permeability should be more mechanistically accurate and a stronger tool for
making bioequivalence comparisons than dissolution alone.
It is based on this argument that the in silico model was considered to show that for a specific range of
dissolution rates, metformin products should be bioequivalent regardless of the results of the f2 test.

5. Data from the human BA clinical studies of metformin were used for what two purposes?
Data from the human bioavailability clinical studies were used in (1) the model development and (2) to
validate the models capability to predict human plasma concentrations following administration of a 500 mg oral
dose.

(1) Model development: Clinical studies B and C were used to build the model and then the model
was used to predict the AUC(0T) and Cmax for Study a (immediate release) and Study d (extended
release).

(2) Validation of model: This model was then used to simulate the plasma profiles for drug release
profiles ranging from 100% drug release in 5 min up to 100% drug release in 14 h.


6. Which parameters are important to set in conducting virtual trials using GastroPlus?
Parameter
Physical- chemical Dose
Log D
Physiology Permeability (Jejunum)
Absorption scale factors Duodenum
Jejunum 1, 2
Ileum 1, 2, 3
Cecum
Ascending Colon
Pharmacokinetic Clearance
Volume of Distribution
K
12
, K
21,
K
13,
K
31


7. Why was the Hixson-Crowell Cube Root Law equation not used for this drug?
The HixsonCrowell Cube Root Law was not used for these simulations as this equation is written to assume that
dissolution is primarily a function of the particle size and solubility of the drug. As metformin is highly soluble,
much greater than 100 mg/mL, particle size does not affect the dissolution rate within the range of particle
diameters that are used in the formulations.

8. Which result confirmed that the model accurately represented the gastrointestinal transit time and
permeability profile?

Table 3. Results of Model Simulations and Statistical Comparison of the Cmax and AUC(0 T)
to Clinical Data for Four 500 mg Metformin Products

Formulation Parameter Point Estimate Lower 90% CI Upper 90% CI
500 mg IR, fed (Study a)
a

AUC(0 T) (ngh/mL) 0.92 0.81 1.04

Cmax (ng/mL) 1.09 0.96 1.23
500 mg IR, fed (Study b) AUC(0 T) (ngh/mL) 0.95 0.82 1.08

Cmax (ng/mL) 0.91 0.80 1.05
500 mg IR, fed, (Study c) AUC(0 T) (ngh/mL) 1.00 0.89 1.13

Cmax (ng/mL) 0.91 0.80 1.03
500 mg SR, fasted, (Study d) AUC(0 T) (ngh/mL) 1.06 0.89 1.25

Cmax (ng/mL) 0.97 0.81 1.15
a
Study a are the results of model simulations and statistical comparison of the Cmax and
AUC(0 T) to clinical data for the metformin product exhibiting dissimilar in vitro dissolution
profiles (f2 = 42) and bioequivalent clinical data.


As presented in Table 3, the AUC (0 T) and the Cmax for studies a and d showed that the simulations were
bioequivalent to the observed clinical values (Studies B and C were used to build the model). It shows
that the model variance adequately represents the subject variability for each clinical group studied and
as the slow release dose is also well predicted, these results show that the model accurately represents
the permeability profile an d the transit times throughout the GIT.

9. Explain figure 6 and 7.


Figure 6. Model simulations versus clinical
data (circles) for metformin release profiles
ranging from 5 min to 14 h for 100% to be
released. Note that the model predictions were
bioequivalent to the clinical data.


Figures 6 and 7 show the AUC(0T) and Cmax plotted as geometric means and SD for the different release rates.
The symbols (circles) represent the clinical data (Table 3) corresponding to dissolution times observed for the
products tested. In each case, the simulations were bioequivalent to the clinical data, that is, the Cmax and AUC(0
T) fell within the 0.801.25 range for the 90% confidence intervals. On the basis of these simulations, release times
for metformin ranging from 5 min up to 2 h did not have a statistically significant effect on Cmax and AUC. Beyond
2 h, the Cmax and AUC(0T) decreased and were no longer bioequivalent.