# Presentation: 691383

## EXUBERA® (Insulin Oral Inhalation)Clinical Pharmacology and Biopharmaceutics Issues 

- Advisory Committee Presentation
- September 8, 2005
- Sayed (Sam) Al Habet R. Ph., Ph.D.
- Hae-Young Ahn Ph.D.

## Issues

-  What is the effect of respiratory conditions on the systemic exposure of Inhaled Insulin?
-  Effect of Chronic Obstructive Pulmonary Disease (COPD)
-  Effect of Asthma
-  Effect of Smoking
-  Is there interchangeability between 1 x 3 mg and 3 x 1 Blister Strengths?
-  What is the variability associated with inhaled insulin?

## What is the Effect of Respiratory Conditions on the Exposure of Inhaled Insulin?

- Effect of Smoking:
-  Effect of chronic smoking
-  Effect of passive smoking

## What is the Effect of Chronic Smoking?

- Effect on AUC				Effect on Cmax
- Source: Study # 217-016

## What is the Effect of Cessation and Resumption of Smoking? 

- Effect on AUC				Effect on Cmax
- Source: Study # 217-1020

## What is the Effect of Passive Smoking?

- Design: Crossover in 28 healthy subjects as follows:
- Group A (n=14): 3 mg with 2 hours exposure to passive smoke
- Group B (n=14): 3 mg in absence of exposure to passive smoke
- Source: Study # A217-1057 (submitted August 10, 2005)

**~20-30%**

**+ Smoke**

**Control**

## What is the Effect of COPD on the PK of Inhaled Insulin?

-  Dose:
-  3 mg inhaled insulin 30 min before or after 2 puffs of albuterol inhaler.
-  9 U SC regular insulin
-  Healthy normal subjects (n=12):
-  Patients with COPD who are no longer smokers suffering from Emphysema (n=12) and chronic bronchitis (n=12)
-  Excluded Subjects:
-  4 due to high carbohydrate intake
-  2 outliers

## What is the Effect of COPD on the PK of Inhaled Insulin?

- 	 **AUC 0-360 min ****	****	****	****	****   Cmax**
- Source: Study # A217-1005

## What is the Effect of Asthma on the PK of Inhaled Insulin?

- 		AUC				Cmax
- Source: Study # 217-009

## What is the Effect of Rhinovirus Infection on the PK of Inhaled Insulin?n= 4 (control) n= 20 (active)

- 		AUC				Cmax
- Day 1: pre-Inoculation; Days 3 and 4 (Post-inoculation)
- Source: Study # 217-010

## What is the Effect of Albuterol on the PK of Inhaled Insulin in Asthma? 

- Study design:
-  	Four Treatments: 48 subjects with mild 	or moderate asthma
-  	Two treatments: 12 healthy subjects in 	crossover design
-  	Dose: 3 mg inhaled insulin alone or 30 	minutes after inhaled albuterol

## Compiled Cmax and AUC Data in Healthy and Asthmatic (Mild and Moderate) Subjects Before and After Albuterol

-  There was 25% and 30% increase in insulin exposure when administered 30 min after albuterol in subjects with mild to moderate asthma, respectively.
- Overall exposure is lower in asthmatic subjects than in healthy subjects.
- 		AUC				Cmax
- Source: Study # A217-1056

## What are the Issues of the Titration Process? 

-  Issue # 1: Switching between strengths as follows:
-  From 2 mg (2 x 1 mg) to 3 mg (1 x 3 mg)
-  From 3 mg (1 x 3 mg) to 4 mg ( 1 x 1 mg + 1 x 3 mg
-  From 4 mg  (1 x 1 mg + 1 x 3 mg) to 5 mg (2 x 1 mg + 1 x 3 mg)
- From 5 mg (2 x 1 mg + 1 x 3 mg) to 6 mg (2 x 3 mg)
-  Issue # 2: Switching from SC to inhalation
- Issue # 3: Variability within patients

## Is there Interchangeability between 1 x 3 mg and 3 x 1 mg Blister Strengths?

| Parameter | 3 x 1 mg | 1 x 3 mg | Ratio/
Difference
(%) | 90% CI |
| --- | --- | --- | --- | --- |
| AUC0-360
(μU.min/mL) | 2599 | 1859 | 140% | 117%,167% |
| Cmax
(μU/mL) | 31.02 | 24.51 | 127% | 108%,148% |
| F (%) | 5.80 | 4.15 | 140% |  |
| Tmax (min) | 44.4 | 42.0 |  |  |

## Average Exposure for Each Proposed Dosing Regimen(Study # 217-012)

## What is the Variability in PK Data for Inhaled Insulin?  

- In some studies, % CV is >100%.
-  In almost all studies the % CV is >50%.
-  Examples:
-  In the dose proportionality study (Study # A217-1012) the AUC ranged as follows:
-  1 mg (1 x 1 mg) = 45-9730 μU.min/ml
-  2 mg (2 x 1 mg) = 1270-11000 μU.min/ml
-  3 mg (1 x 3 mg) = 1070-13800 μU.min/ml
-  4 mg (1 x1 mg + 1 x 3 mg) = 4440-19300 μU.min/ml
-  6 mg (2 x 3 mg) = 934-32400 μU.min/ml
- The same trend for intra-subject variability as seen from the replicate dosing within the same subjects throughout the NDA.

## Cross Study Variability in AUC(Inhaled vs SC CV) 

- Residual Plot (Difference in % CV of Inhaled and in %CV SC Insulin) (each data point represents one study)

## Overall Summary of Exubera Clinical Pharmacology and Biopharmaceutics Issues 

- Respiratory Issues (1)
-  	The pathology of the lung as well as other 	exogenous factors play critical roles in the 	absorption, delivery and systemic exposure of 	inhaled insulin.
-  	The following conditions effect the exposure to 	inhaled insulin:
- Smoking		Increase by ~ 2-5 fold
- Passive smoking		Decrease by 20-30%
- COPD			Increase by ~ 50%
- Asthma			Decrease by 20-30%
- Rhinovirus infection

## Overall Summary of Exubera Clinical Pharmacology and Biopharmaceutics Issues

- Variability and Interchangeability:
-  	Inhaled insulin can be highly variable. 	The % CV can be 50% to 100%.
-  	There is lack of dosage form 	equivalency between 1 mg and 3 mg 	strengths.