# Presentation: 275432

## Bioequivalence of Poorly Soluble Locally Acting GI Drugs 

- Robert Lionberger
- Office of Generic Drugs
- ACPS-CP Meeting
- July 23, 2008

## BE for Locally Acting Drugs

- Define low solubility
- Role of PK studies
- Examples
- Steps toward use of biorelevant media

## Why Does Solubility Matter?

- In vivo dissolution controls delivery to the site of action
- For high solubility drugs, equivalent in vitro dissolution in buffer (pH 1.2, 4.5, 6.8) ensures in equivalent vivo dissolution and supports biowaivers

##   Example

**Drug X; Highly soluble, IR tablet**
**The test and reference list drug products have the same formulations, qualitatively and quantitatively**

-   Example

## What is Low Solubility?

- When the highest strength does not dissolve in 250 ml of aqueous media at any pH between 1 and 7.5
- Very conservative
- Categories of low solubility drugs
- Weak acid  (only low solubility at low pH)
- Weak base (only low solubility at high pH)
- Reasonable solubility in vivo fluids
- Truly poor solubility
- Solubility limited absorption
- Reduction in fraction absorbed with dose
- Novel formulation technologies may be used

## Pharmacokinetics/Absorption

- GI acting drugs may or may not have significant absorption
- Many can be detected systemically
- Pharmacokinetic (PK) studies may be requested for safety

- Rate of absorption is related to local GI concentration
- in vivo formulation performance
- Location of drug after release from IR dosage form is governed by GI transit

- S. Willmann, W. Schmitt, J. Keldenich,
- and J. B. Dressman *Pharm Res, ****20****, 1766, 2003*

## BE for Locally Acting Drugs

- Systemic action: drug in plasma -> BE
- Local action: drug in plasma ->“side effect”

## Introduction to Examples

- For high solubility drugs, in vitro dissolution in buffer (pH 1.2, 4.5, 6.8) ensures in vivo dissolution and supports biowaivers
- Low solubility drugs are more challenging
- Ionization effects
- Increased solubility in micellar solutions
- Solubility and dissolution in in vivo fluid generally much larger than aqueous solubility
- Does the in vitro test predict in vivo performance for low solubility drugs?

## Example One

- Drugs P (prodrug) and A (active)
- A has site of action in colon
- A is rapidly absorbed from intestine
- Can be measured in plasma
- Extensively metabolized in gut wall
- Delivered to colon as a prodrug (P)
- P is cleaved in the colon to form A
- 12-35% of A is absorbed
- <5% of P is absorbed

## Solubility

- Prodrug Solubility

- Active Drug Solubility

## Prodrug Dissolution

## Potential Bioequivalence Methods

- OGD Working Group considered
- Dissolution
- PK study (as a surrogate for local delivery)
- Clinical end-point studies
- Actions
- Laboratory studies of dissolution
- Simulations of GI transit, drug release, absorption, PK
- Individual review and discussion of each product
- BE recommendation
- Dissolution of prodrug; fed and fasting PK of prodrug and active

## BE Recommendations

- P released from
- formulation
**Dissolution measured**

- Some P absorbed
**PK of P measured**

- Remaining P transits
- small intestine

- In colon, bacteria
- convert P to A

- A absorption fromcolon (site of action)
**PK of A**
**measured**

## P and A (Simulation)

- Simulations illustrate GI concentration/plasma concentration correlations for IR products

- Prodrug

- Active

## Reflection

- Is there a dissolution test that would eliminate the need for multiple PK studies?
- For this product, dissolution was questioned because it lacked sequential exposure to low pH
- Combination of dissolution and PK addressed this concern

## Sequential Exposure

- Dissolution at pH 4.5

- 30 min at pH 1.2
- Dissolution at pH 4.5

## Example Two

- Drug B
- Solubility (pKa of 5.81)
- < 0.1 mg/mL in 0.1 N HCl
- 33-100 mg/mL in 0.1 N NaOH
- ~33% of dose is absorbed
- Absorbed drug may not reach local site of action
- AUC increases supra-linearly with dose
- Tablet and suspension formulations marketed and compared in clinical, PK and dissolution studies

## Product Comparison

| Form | Clinical
Endpoint 1 | Clinical
Endpoint 2 | PK AUC
(μg*h/mL)  | Dissolution
(30 min) |
| --- | --- | --- | --- | --- |
| Tablet | 96%  | 85% | 52 | ~70% |
| Susp | 87% | 83% | 36 | ~85% |
| Placebo | 43% | 44% |  |  |

## Dissolution

- Tablet Dissolution pH 7.5
- 6% of various surfactants

- Suspension Dissolution pH 7.5
- 6% of surfactant

- Regulatory methods (release tests)  use non-physiological pH and surfactant concentrations

## PK comparison (metabolite)

- PK profiles indicate drug is released from formulation
- and available for absorption in small intestine
- Suggests drug may be soluble in biorelevant media

## Potential BE Approaches

- Fed and fasted PK studies
- Which dissolution media?
- pH range and surfactant concentration range to provide most sensitive formulation comparison or
- Biorelevant media

## Reflection

- What is the value of dissolution in 6% surfactant?
- Role of inactive ingredients in suspension formulation
- Detected in PK study
- No significant clinical effect
- Role of particle size
- Detected in other PK studies

## Current State to Next Step

- For a particular product: in vitro dissolution + in vivo studies provided demonstration of BE (local delivery) for a low solubility drug
- PK study: evidence of in vivo release
**Next**: How do we generalize this to other products?
- High aqueous solubility in limited pH range
- High solubility in biorelevant media
- No high solubility in vivo

## Next Step

- High aqueous solubility in limited pH range
- Recommend dissolution in aqueous buffers and PK or other study to confirm in vivo release
- Contingent on site of action
- Drug only soluble in biorelevant media
- Recommend dissolution in biorelevant media and PK or other study to confirm in vivo release
- Contingent on site of action
- Drug not soluble in biorelevant media
- Investigate mechanism for local availability

## Desired State 

- Biorelevant dissolution to eliminate need for additional in vivo studies.
- In vivo dissolution directly determines local GI concentration
- Equivalent dissolution over the physiological range ensure BE over patient population.
- Q1 and Q2 differences may lead to additional studies

## How will we know when biorelevant dissolution is ready?

- When biorelevant dissolution predicts in vivo dissolution (as assessed by drug absorption or imaging studies), then it is ready.
- When biorelevant dissolution is used in  QbD approaches to design the formulation of low solubility drugs, then it is ready.

## Questions

- What role should biorelevant dissolution play in developing BE recommendations for low solubility locally acting drugs that treat GI conditions?
- What role should systemic pharmacokinetics play in developing BE recommendation for low solubility locally acting drugs that treat GI conditions?