# Presentation: 138609

## Axcan Public Presentation for the FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee MeetingJuly 23, 2008

**Axcan Public Presentation for ****the FDA Pharmaceutical Science ****and Clinical Pharmacology ****Advisory Committee Meeting****July 23, 2008**

## Bioequivalence testing serves to confirm therapeutic equivalence to assure comparable (substitutable) safety and effectiveness  in patients 

**Bioequivalence testing serves to confirm therapeutic equivalence to assure comparable (substitutable) safety and effectiveness  in patients**

## Mesalamine Suppository Release Characteristics are Multifactorial and Unique

| Oral
Prodrug | Oral
Drug | Enema Suspension
Drug | Suppository
Drug | Substance Category | Product Release
Characteristics |
| --- | --- | --- | --- | --- | --- |
| X |  |  |  | Low solubility | Metabolic |
|  | X |  |  | Low solubility | Immediate |
|  |  | X |  | Low solubility | “Immediate” |
|  |  |  | X | Low solubility | “Non-Immediate” |

** ****Variability with suppository**
** ****Melting in the rectal cavity**
** ****Post-melting dispersion and dissolution**
** ****Drug partitions between the lipophilic base and the present fluid**
** ****Distribution equilibrium between the base and fluid can occur rather than complete dissolution**
** ****Presence of fecal material, blood and mucous**
** ****Systemic exposure is a post effect-site phenomenon that can involve variable absorption across rectal mucosa**

## Scientific and Regulatory points to considerfor Locally Acting Rectal Suppositories (1)

**Scientific and Regulatory points to consider****for Locally Acting Rectal Suppositories ****(1)**

- Axcan supports the FDA “Draft *Guidance on Mesalamine *” for rectally administered suppositories, published in May 2007.
- The FDA Draft Guidance recommends that *in vivo *bioequivalence be demonstrated with:
- “Bioequivalence study with clinical endpoints” and
- “Bioequivalence studies with pharmacokinetic endpoints (fasting)”

## Scientific and Regulatory points to consider for Locally Acting Rectal Suppositories (2)

**Scientific and Regulatory points to consider**** for Locally Acting Rectal Suppositories ****(2)**

**There is no scientifically agreed upon methodology to establish the bioequivalence of locally acting mesalamine suppositories**
- FDA recognizes the lack of agreed upon methodologies for certain products and route of administration and is seeking input via the FDA Critical Path Initiative and Advisory Committee meetings.
- FDA Critical Path Opportunities*
- “*In vivo* Drug Release for GI Acting Products: Direct comparison of *in vivo* drug release (perfusion, tissue sampling, or imaging) could be used to validate dissolution tests as a bioequivalence method for modified release products.”
- “For locally acting drugs that are absorbed and can be detected in plasma, the rate of absorption could be related to the local concentrations in the GI tract.”
- “Imaging and PK studies could establish the correlation between the drug delivered to the site of action and the measured plasma concentration.”
- *Critical Path Opportunities for Generic Drugs, Office of Generic Drugs,
- Office of Pharmaceutical Science. Center for Drug Evaluation and Research. May 1, 2007

## Scientific and Regulatory points to consider for Locally Acting Rectal Suppositories (3)

**Scientific and Regulatory points to consider**** ****for Locally Acting Rectal Suppositories ****(3)**

_***In vitro***_** and **_***in vivo ***_**methodologies have not been agreed upon to establish bioequivalence of mesalamine delivered by locally acting rectal suppositories.**
- "...it is challenging to find a standard method to test *in vitro* drug release from lipophilic suppositories“*
- "However, no simulated rectal fluid exists at the moment to simulate the *in vivo* dissolution of suppositories“*
- *International Journal of Pharmaceutics, Volume 328, Issue 1,
- 2 January 2007, Pages 12-21

## Scientific and Regulatory points to consider for Locally Acting Rectal Suppositories (4)

**Scientific and Regulatory points to consider**** ****for Locally Acting Rectal Suppositories ****(4)**

- Factors leading to the high variability of systemic blood levels of mesalamine limit the potential for systemic PK being a surrogate or biomarker for effect-site bioavailability.  These include:
- Suppository location within the rectum
- Retention time within the rectum
- Limited volume within the rectum
- Limited water within the rectum
- Variable presence of fecal material, blood and mucous
- Degree of damage to the rectal mucosa = inflammation of tissue.
- Allen LV.  Chapter 4: Pharmaceutic, biopharmaceutic and pharmacokinetic factors involving suppositories. In: Suppositories. 2008. pp. 51-75.

## Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in

|  | Single dose CV% | Multiple dose CV % |
| --- | --- | --- |
| Cmax (ng/mL) | 53.33 | 166.29 |
| AUC 0-T | 78.4 | NC |
| AUC inf | 96.3 | NC |
| AUC 0-8 | NC | 64.7 |
| AUC 0-12 | NC | 67.9 |

**Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in**
_**healthy volunteers.**_

*From NDA Biopharm Review:* Table 1.  Summary of Pharmacokinetic Parameters of 5-ASA in Patients with Ulcerative Colitis and Healthy Subjects Treated with Mesalamine 500 mg Rectal Suppositories as a Single Dose and on the Last Day of Multiple Dose Administration Every Eight Hours for Six Days.

## Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in

|  | Single dose CV% | Multiple dose CV % |
| --- | --- | --- |
| Cmax (ng/mL) | 56.48 | 66.68 |
| AUC 0-T | 65.36 | NC |
| AUC inf | 60.96 | NC |
| AUC 0-8 | NC | 65.2 |
| AUC 0-12 | NC | 63.0 |

**Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in**
_**ulcerative proctitis patients.**_

*From NDA Biopharm Review:* Table 1.  Summary of Pharmacokinetic Parameters of 5-ASA in Patients with Ulcerative Colitis and Healthy Subjects Treated with Mesalamine 500 mg Rectal Suppositories as a Single Dose and on the Last Day of Multiple Dose Administration Every Eight Hours for Six Days.

## Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable inulcerative proctitis patients. 

**Systemic blood levels of mesalamine upon administration of mesalamine suppository are highly variable in**_**ulcerative proctitis patients.**_** **

*“**Based on these data, following rectal administration of mesalamine (FIV-ASA®) 500 mg suppository to subjects with ulcerative colitis, *_*systemic drug exposure is highly variable between individuals*_* as evidenced by high variability in AUC and C**max**. This could be related** **to *_*variability in bioavailability secondary to differences between individuals*_* in suppository location and/or retention time in the rectum.”*
- Excerpt from the FDA Biopharm Review of Mesalamine Suppository NDA 21-252: Ulcerative Proctitis

## Standard pharmacokinetic parameters observed upon rectal administration of mesalamine suppositories “bear little relationship to clinical efficacy.”

**Standard pharmacokinetic parameters observed upon rectal administration of mesalamine suppositories “bear little relationship to clinical efficacy.”**

*“**Since the therapeutic efficacy of mesalamine is thought to result from a predominately topical effect, *_*standard pharmacokinetic parameters bear little relationship to clinical efficacy*_*.  However, pharmacokinetics and bioavailability data may contribute to the characterization of safety.” *
- Excerpt from the FDA Medical Review of Mesalamine Suppository NDA 21-252: Ulcerative Proctitis
- Mahmud N *et al*. Ir J Med Sc 1999; 168: 228-32.

## Current State of Dissolution Testing

**Current State of Dissolution Testing**

**Release of a drug from lipophilic suppositories is multifactorial**
- _Melting_ in the rectal cavity
- _Drug partitions_ between the lipophilic base and the present fluid
- _Distribution equilibrium_ between the base and fluid can occur rather than complete dissolution
**There is no *****in vivo*****/*****in vitro***** correlation for an *****in vitro***** dissolution test for a “hard fat” mesalamine suppository.**
- The dissolution test for mesalamine suppositories was developed as a quality control test and was not constrained by a desire to mimic In Vivo conditions.
- “FIP/AAPS Guidelines to Dissolution/in Vitro Release Testing of Novel/Special Dosage Forms” Siewert  M *et al*. AAPS PharmSciTech 2003; 4 (1) Article 7.

## Summary of Scientific and Regulatory Considerations

**Summary of Scientific and Regulatory Considerations**

- There is no scientifically agreed upon methodology to establish the bioequivalence of locally acting mesalamine suppositories.
*In vitro and in vivo* methodologies have not been agreed upon to establish bioequivalence of locally acting mesalamine suppositories.
- High variability in blood levels from rectal mesalamine suppositories limit the use of systemic PK as a surrogate (biomarker) for effect-site bioavailability to confirm clinical effectiveness.
- Systemic blood levels of mesalamine  suppositories are highly variable in healthy volunteers and in ulcerative proctitis patients .
- Standard PK parameters observed upon rectal administration of mesalamine suppositories “bear little relationship to clinical efficacy.”
- Release of a drug from lipophilic suppositories is multifactorial.
- There is no *in vivo*/*in vitro* correlation for an *in vitro *dissolution test for a “hard fat” mesalamine suppository.

## ConclusionThe currently available data support:

**Conclusion****The currently available data support:**

- The FDA “Draft *Guidance on Mesalamine”  *for  rectally administered suppositories, published in May 2007.
- The FDA Draft Guidance recommends that *in vivo* bioequivalence be demonstrated with:
-  “Bioequivalence study with clinical endpoints” and
- “Bioequivalence studies with pharmacokinetic endpoints (fasting)”
- The FDA approach of treating  the bioequivalence testing required for locally acting mesalamine products that use different release mechanisms or routes of administration on a case-by-case  basis.*
- *Docket no. 2005P-0146