application of eu guidelines for pk studies of orally ... · • hv studies potentially more...

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Safeguarding public health

Application of EU Guidelines for PK studies of

Orally Inhaled Products

Dr S.Dissanayake

Medicines and Healthcare products Regulatory Agency, UK

29th March 2010

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Revision of OIP guideline

• Inter alia driven by recognition of assay sensitivity issues

• Requirements for clinical documentation for orally inhaled products

(OIP) including the requirements for demonstration of therapeutic

equivalence between two inhaled products for use in the treatment of

Asthma and Chronic Obstructive Pulmonary Disease (COPD) in adults

and for use in the treatment of asthma in children and adolescents

(CPMP/EWP/4151/00 Rev. 1)

• Known as ‘OIP guideline’. August 2009

http://www.ema.europa.eu/htms/human/humanguidelines/efficacy.htm

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Revised OIP Guideline – Principal features

• Stepwise approach to demonstrate equivalence

• Step 1. In vitro data

• Step 2. Lung deposition models (PK / scintigraphy)

• Step 3. Therapeutic effect / pharmacodynamic models

If equivalence confirmed at steps 1 or 2, may be no need for further data

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OIP Guideline – PK studies

• Very significant change to guideline

• Relatively little detail re PK study design

• Read in conjunction with revised EU bioequivalence guidance (August 2010) and literature

http://www.ema.europa.eu/htms/human/humanguidelines/efficacy.htm

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Study population

• Guideline advocates patient studies

• However, most studies demonstrate greater pulmonary deposition in healthy subjects vs. patients (asthma/COPD)

• Lesser deposition due to bronchoconstriction

• In asthma deposition appears related to extent obstruction

• In COPD relationship less clear – influenced by obliterative bronchiolitis / parenchymal destruction?

• ? Excess mucus production clearance (chronic bronchitis) also relevant

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Study population

• Overall greater exposure in HVs

• HV studies potentially more discriminative, less

confounded (↓ period-period variability), greater power

• HV studies accepted in EU

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Requisite PK parameters

• Cmax, AUC0-t, AUC0-inf

• AUC0-initial where rapid onset relevant

• Justify AUC0-initial interval on clinical grounds

- onset clinically relevant effect [e.g., time to FEV1↑ ≥15%]

• E.g, for formoterol AUC0-10 or AUC0-15 reasonable

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Requisite PK parameters - Prodrugs

• Difficult issue

• BDP, ciclesonide - both inactive prodrugs

• BE guideline advocates prodrug PK (even where inactive) assuming

levels quantifiable

• Rationale for prodrug PK:

- Limit confounding influence of downstream variability

- More sensitive to differentiate formulations

• If use metabolite PK, clear justification re rapid prodrug elimination &

bioanalytical sensitivity

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Confidence intervals & intra-subject variability

• Standard limits (80-125%) apply for Cmax & AUC

• Widening of Cmax limits for highly variable drugs

- Define a priori

- Must be no potential clinical implications

- Confirm variability in pivotal replicate study

- Limits scaled per reference variability:

◦ ISV 30% → CIs 80-125%

◦ ISV 35% → CIs 77-129%....., etc.

◦ ISV ≥ 50% → CIs 70-143%

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Intra-subject variability

• Few studies have specifically evaluated ISV of OIPs with replicate

designs

• Most show low ISV 6-16%

• Surprising given;

- Variability of respiratory manoeuvres

- Variable interaction of aerosol cloud with patients geometry

- Variations in dose to dose delivery

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Drug Device Intrasubject coefficient of variation

(%)

Salbutamol Evohaler MDI1

8.2%

Evohaler MDI2

6.1%

Evohaler MDI3

10.1%

Easibreathe breath actuated MDI3

7.1%

Easyhaler DPI4

15.6%

Budesonide Turbuhaler DPI4

12.4%

Flexhaler DPI / Turbuhaler DPI5

14.9%§*

1. Hindle, Br J Clin Pharm 1992,

2. Hindle, Thorax 1994

3. Tomlinson, Br J Clin Pharm 2003

4. Lähelmä, Br J Clin Pharm 2004

5. Persson, Curr Med Res Opin 2008

§Mean intrasubject CV for the two devices

*ISV = residual unidentified variability

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• Contrast with Aswania, J Aerosol Med 2004

• 5 salbutamol devices, replicate design (x 5 periods each, 26

visits/subject)

• Training only once per inhaler

Drug Device Intrasubject coefficient of variation

(%)

Salbutamol Evohaler MDI 52.0%

Evohaler MDI + Volumatic 31.8%

Easibreathe breath-actuated MDI 35.9%

Accuhaler DPI 40.4%

Turbuhaler DPI 42.4%

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Confidence intervals & intra-subject variability

• Not obvious how feasible widening will be. May be limited potential.

• Limited public data re ISV of several OIPs

• Assurance re consistency of subject inhalation manoeuvres important

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Narrowing confidence intervals

Narrowing limits

• Narrow CIs for narrow therapeutic index (NTI) drugs

• E.g., 90-111%, 80-111%

• However, OIPs do not exhibit features of NTI drugs:

- Plasma level / biochemical monitoring required

- Steep dose response for safety

- Fine dose titration

• → Little justification to narrow limits for OIPs

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Measurement of inspiratory flow rate

• Drug delivery from MDIs/several DPIs flow rate dependent

• Mx inspiratory flow rate common in scintigraphic studies,

less so in PK studies

• Controls for / allows for evaluation of major potential

confounding influence

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• Individual data for 8 subjects (of 52) with highest and lowest

salmeterol T/R AUC0-t ratios

Subject

Individual T/R AUC0-t ratio

Salmeterol Fluticasone

Highest

1 390% 368%

2 374% 194%

3 342% 109%

4 285% 153%

Lowest

5 53% 31%

6 51% 34%

7 49% 44%

8 41% 32%

Generic salmeterol-fluticasone MDI data

Correlation coefficient = 0.89

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Measurement of inspiratory flow rate

• Measure IFR e.g., with inhalation profile recorder

• May ↓ variability

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MDIs and spacer data

• Generic OIPs should be fully substitutable for reference

inhalers

• For MDI therefore, spacer data is required

• In vitro allowed, but unlikely to confirm equivalence

• PK spacer study likely to be required

• Use in vitro data to inform model; avoid biased selection

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MDIs and spacer data

0

2

4

6

8

10

12

FP

M (

mcg

)

MDI alone + Volumatic + Volumatic (2s

delay)

+ Volumatic (deep

breathing)

+ Volumatic (tidal

breathing)

Test

Reference

Salmeterol test / reference MDI data under varying conditions of device use

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DPIs and flow rate consideration

• Generic OIPs should be fully substitutable for reference

inhalers

• DPIs resistance / flow rate dependence varies

• Where at least one of the DPIs exhibits substantial flow

rate dependency, comparison at a particular flow rate

impacts BE comparison

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0

5

10

15

20

25

30

35

40

45

50

30 40 50 60 70 80 90 100

Flow rate (L/min)

FP

M (

mc

g)

Reference

Test


Example of test/reference DPI differences across flow rates

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• Historically DPIs often compared at ‘optimal’ / ‘half-optimal’

IFRs

• Do not convey information as to feasibility of attainment of

these IFRs

• Flow rate studies provide this data

• Younger children, elderly, acute asthma exacerbation,

COPD of particular interest

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• Evaluation of corresponding flow rates for T & R in a single

population:

- Allows determination of corresponding centiles, e.g.,

10th, 50th, 90th

- In vitro data can be scrutinised for differences in

performance at corresponding flow rates

- If in vitro differences exist at clinically relevant flow rate

consider additional PK data

- Consider clinical circumstances, e.g., 10th centile

important for acute treatment

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Limitations

Do not provide information on regional pulmonary deposition

Usmani O et al, Am J Resp Crit Care Med 2005

• 12 asthmatic subjects

• 3-way crossover study μcg dose of 3 monodisperse salbutamol aerosols

• 30 μcg dose of 3 monodisperse salbutamol aerosols: 1.5, 3, 6 μm MMAD

• Fast and slow inhalation

• Assessed lung deposition with scintigraphy, and change in FEV1

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Regional Drug Deposition


1.5 μm 3 μm 6 μm

56.3% 51.0% 46.0% Total Lung Deposition

(% delivered dose)

31.6% 33.8% 35.1% Central/intermediate Zone

Deposition

(% delivered dose)

Lung deposition, slow inhalation (30 L/min)

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• With fast inhalation (67 L/min) C+I deposition pattern reversed

• → greatest C+I deposition with 1.5 μm aerosol, least with 6 μm

• → greatest FEV1 increase with 1.5 μm aerosol, least with 6 μm

• Strongly supportive of importance of central airways deposition for β-2

agonists

Munnik et al, JAMPDD 2009

• Cumulative-dose, crossover study

• 80 μcg dose of 3 monodisperse salbutamol aerosols (4,5,6 μm MMAD)

• Greatest bronchodilatation with 6 μm formulation

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Goldin et al, J Allergy Clin Immunol 1999;104:S258-67

• 31 asthmatic subjects

• Double-blind, randomised, parallel group study

• 4 weeks treatment with:

- 200 μcg beclometasone-HFA (MMAD 0.8-1.2 μm), or

- 200 μcg beclometasone-CFC (MMAD 3.5-4.0 μm)

• Baseline and post-treatment high resolution CT

• Less air trapping with BDP-HFA

• Implications for small airways disease / exacerbation rates?

Baseline lung attenuation

(Hounsfield units)

Post-treatment lung

attenuation

(Hounsfield units)

Change

(Hounsfield units)

BDP-CFC -695 -692 3

BDP-HFA -674 -635 39

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• Are Usmani’s & Goldin’s data relevant to commercial

polydisperse formulations designed to be similar to one another?

• Further data on effects of differential regional deposition

v.desirable

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Conclusions

• OIP guideline primarily advocates PK as adjunct to PD data

• Likely to change with experience, although new PD models being evaluated

• Lack of information on regional deposition is primary limitation of PK -?relevance to generic / reference context

• PK studies in conjunction with scintigraphy an attractive regulatory package

• Consider pilot studies

• Attention to various PK idiosyncrasies key to successful submission

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