[NMusers] RE: Extrapolation to achieve actual half-life

[Kevin Feng]

3rd attempt to send the following message!

Dear Anuja,

Just to clarify a few things:
"parallel study for BE- failed on the lower side of Cl limits"

-Solid oral administration

-Test formulation (T) dissolution profile may be slower than the 
reference formulation (R)

-The PK observations is good enough to produce PK parameters such as 
Cmax, Tmax, t_1/2, AUClast, AUCinf from NCA

-You already have a few in vitro dissolution profiles for both T and R 
from different in vitro test methods e.g. USP apparatus, rotation speed, pH, 
volumes, media type etc.
"achieved final model and done with VPC,LLP "

-You use both T and R to build and validate the models.

-Or you build models from T and R separately

-It is a very good sign that the final model achieved with VPC etc.

With the above clarification, I would suggest to do steps below:
Model built and in vitro test method identification:

1.  Find the in vitro dissolution models e.g. hill or Weibull

2.  Add the in vitro model to your build pop-PK model - e.g. ref: Buchwald, 
2003 JPP

3.  Validate the models with both R and T plasma/blood concentration 
observation data

4.  Find the best validated in vitro test methods for simulation - e.g. 
comparing OFV or AIC etc.
Simulation:

1.  Used the validate models above. Note: if you use models built 
separately from T and R, it is very hard or impossible to do a 2X2 crossover 
simulation because you need to create same individuals every time for the 
crossover design

2.  Do the simulation with 2X2 crossover and make sure the sequence and 
period correct and well design. (TR & RT)

3.  Produce the PK parameters such as Cmax, Tmax, AUC

4.  Do the BE test and find CI limits using the testing formulation from 
the simulated data
Test formulation validation from test bounds

1.  Make sure you have enough washout at this step for all individuals in 
the simulation e.g. far more than 4~5 half life

2.  If you T is successful in the BE test from the above 2X2 crossover 
simulation, you may want to see how your T is lay within the test bounds

3.  Manually create a lower bound and upper bound in vitro profile

4.  Build this in vitro models from these test bounds

5.  Add this in vitro models for 2X2 crossover simulation and get the BE 
test result

6.  Make sure your T is lay within the test bounds in vitro.

7.  If you T is outside the test bounds in vitro, you may need to think 
about to have a new formulation strategy. At this step, you need to make sure 
you use the correct in vitro test methods with the above model building step 
e.g. with correct USP apparatus, rotation speed, pH, volumes, media type etc.
Sufficient wash-out period design

1.  Use the above validated models for 2X2 crossover simulation

2.  Manually create a few scenarios with different wish out period

3.  Do the BE test from all the above scenarios - better to do a plot 
together with (80,125) lines

4.  Do the ANOVA or linear mixed effect analysis to make sure no carry over 
effect.

5.  Find the best scenario and shortest wish out period with the successful 
BE test without carry over effect.

We have a tool available to automate all the above processes. If you happen to 
attend PAGE meeting this year, you can find us from Certara booth and we can do 
you a demo.
   Automatic framework for bioequivalence studies from In Vitro 
test to In Vivo study design

Best wishes,
Kevin Feng


From: owner-nmus...@globomaxnm.com 
[mailto:owner-nmus...@globomaxnm.com] On Behalf Of Anuja Dhas/Formulation/VKH
Sent: Wednesday, March 14, 2018 1:17 AM
To: nmusers@globomaxnm.com
Subject: [NMusers] Extrapolation to achieve actual half-life

Hello Everyone,
We have done one parallel study to prove Bioequivalence, which failed on the 
lower side of Cl limits. We want to do crossover study, but in previous study 
we failed to capture actual half life. The API is having a half life around 4-5 
days and we did a parallel study for 2 days.

By M, we want to extrapolate to get actual half-life. And we want to 
calculate the sufficient wash-out period so that the carry-over effect will be 
<5% of Cmax in period 2 of crossover study.

We have achieved final model and done with VPC,LLP, please guide me for 
simulation.



Thanks & Regards
Anuja
''Legally privileged confidential information and subject to "Disclaimer". 



NOTICE: The information contained in this electronic mail message is intended 
only for the personal and confidential 
use of the designated recipient(s) named above. This message may be an 
attorney-client communication, may be protected 
by the work product doctrine, and may be subject to a protective order. As 
such, this message is privileged and 
confidential. If the reader of this 

[NMusers] RE: Extrapolation to achieve actual half-life

[Kevin Feng]

Dear Anuja,

Just to clarify a few things:
"parallel study for BE- failed on the lower side of Cl limits"

-Solid oral administration

-Test formulation (T) dissolution profile may be slower than the 
reference formulation (R)

-The PK observations is good enough to produce PK parameters such as 
Cmax, Tmax, t_1/2, AUClast, AUCinf from NCA

-You already have a few in vitro dissolution profiles for both T and R 
from different in vitro test methods e.g. USP apparatus, rotation speed, pH, 
volumes, media type etc.
"achieved final model and done with VPC,LLP "

-You use both T and R to build and validate the models.

-Or you build models from T and R separately

-It is a very good sign that the final model achieved with VPC etc.

With the above clarification, I would suggest to do steps below:
Model built and in vitro test method identification:

1.  Find the in vitro dissolution models e.g. hill or Weibull

2.  Add the in vitro model to your build pop-PK model - e.g. ref: Buchwald, 
2003 JPP

3.  Validate the models with both R and T plasma/blood concentration 
observation data

4.  Find the best validated in vitro test methods for simulation - e.g. 
comparing OFV or AIC etc.
Simulation:

1.  Used the validate models above. Note: if you use models built 
separately from T and R, it is very hard or impossible to do a 2X2 crossover 
simulation because you need to create same individuals every time for the 
crossover design

2.  Do the simulation with 2X2 crossover and make sure the sequence and 
period correct and well design. (TR & RT)

3.  Produce the PK parameters such as Cmax, Tmax, AUC

4.  Do the BE test and find CI limits using the testing formulation from 
the simulated data
Test formulation validation from test bounds

1.  Make sure you have enough washout at this step for all individuals in 
the simulation e.g. far more than 4~5 half life

2.  If you T is successful in the BE test from the above 2X2 crossover 
simulation, you may want to see how your T is lay within the test bounds

3.  Manually create a lower bound and upper bound in vitro profile

4.  Build this in vitro models from these test bounds

5.  Add this in vitro models for 2X2 crossover simulation and get the BE 
test result

6.  Make sure your T is lay within the test bounds in vitro.

7.  If you T is outside the test bounds in vitro, you may need to think 
about to have a new formulation strategy. At this step, you need to make sure 
you use the correct in vitro test methods with the above model building step 
e.g. with correct USP apparatus, rotation speed, pH, volumes, media type etc.
Sufficient wash-out period design

1.  Use the above validated models for 2X2 crossover simulation

2.  Manually create a few scenarios with different wish out period

3.  Do the BE test from all the above scenarios - better to do a plot 
together with (80,125) lines

4.  Do the ANOVA or linear mixed effect analysis to make sure no carry over 
effect e.g. formulation: sequence etc.

5.  Find the best scenario and shortest wish out period with the successful 
BE test without carry over effect.

We have a tool available to automate all the above processes. If you happen to 
attend PAGE meeting this year, you can find us from Certara booth and we can do 
you a demo.
   Automatic framework for bioequivalence studies from In Vitro 
test to In Vivo study design

Best wishes,
Kevin Feng


From: owner-nmus...@globomaxnm.com 
[mailto:owner-nmus...@globomaxnm.com] On Behalf Of Anuja Dhas/Formulation/VKH
Sent: Wednesday, March 14, 2018 1:17 AM
To: nmusers@globomaxnm.com
Subject: [NMusers] Extrapolation to achieve actual half-life

Hello Everyone,
We have done one parallel study to prove Bioequivalence, which failed on the 
lower side of Cl limits. We want to do crossover study, but in previous study 
we failed to capture actual half life. The API is having a half life around 4-5 
days and we did a parallel study for 2 days.

By M, we want to extrapolate to get actual half-life. And we want to 
calculate the sufficient wash-out period so that the carry-over effect will be 
<5% of Cmax in period 2 of crossover study.

We have achieved final model and done with VPC,LLP, please guide me for 
simulation.



Thanks & Regards
Anuja
''Legally privileged confidential information and subject to "Disclaimer". 



NOTICE: The information contained in this electronic mail message is intended 
only for the personal and confidential 
use of the designated recipient(s) named above. This message may be an 
attorney-client communication, may be protected 
by the work product doctrine, and may be subject to a protective order. As 
such, this message is privileged and 
confidential. If the reader of this message is not the 

[NMusers] RE: Extrapolation to achieve actual half-life

[Kevin Feng]

Dear Anuja,

Just to clarify a few things:
"parallel study for BE- failed on the lower side of Cl limits"

-Solid oral administration

-Test formulation (T) dissolution profile may be slower than the 
reference formulation (R)

-The PK observations is good enough to produce PK parameters such as 
Cmax, Tmax, t_1/2, AUClast, AUCinf from NCA

-You already have a few in vitro dissolution profiles for both T and R 
from different in vitro test methods e.g. USP apparatus, rotation speed, pH, 
volumes, media type etc.
"achieved final model and done with VPC,LLP "

-You use both T and R to build and validate the models.

-Or you build models from T and R separately

-It is a very good sign that the final model achieved with VPC etc.

With the above clarification, I would suggest to do steps below:
Model built and in vitro test method identification:

1.  Find the in vitro dissolution models e.g. hill or Weibull

2.  Add the in vitro model to your build pop-PK model - e.g. ref: Buchwald, 
2003 JPP

3.  Validate the models with both R and T plasma/blood concentration 
observation data

4.  Find the best validated in vitro test methods for simulation - e.g. 
comparing OFV or AIC etc.
Simulation:

1.  Used the validate models above. Note: if you use models built 
separately from T and R, it is very hard or impossible to do a 2X2 crossover 
simulation because you need to create same individuals every time for the 
crossover design

2.  Do the simulation with 2X2 crossover and make sure the sequence and 
period correct and well design. (TR & RT)

3.  Produce the PK parameters such as Cmax, Tmax, AUC

4.  Do the BE test and find CI limits using the testing formulation from 
the simulated data
Test formulation validation from test bounds

1.  Make sure you have enough washout at this step for all individuals in 
the simulation e.g. far more than 4~5 half life

2.  If you T is successful in the BE test from the above 2X2 crossover 
simulation, you may want to see how your T is lay within the test bounds

3.  Manually create a lower bound and upper bound in vitro profile

4.  Build this in vitro models from these test bounds

5.  Add this in vitro models for 2X2 crossover simulation and get the BE 
test result

6.  Make sure your T is lay within the test bounds in vitro.

7.  If you T is outside the test bounds in vitro, you may need to think 
about to have a new formulation strategy. At this step, you need to make sure 
you use the correct in vitro test methods with the above model building step 
e.g. with correct USP apparatus, rotation speed, pH, volumes, media type etc.
Sufficient wash-out period design

1.  Use the above validated models for 2X2 crossover simulation

2.  Manually create a few scenarios with different wish out period

3.  Do the BE test from all the above scenarios - better to do a plot 
together with (80,125) lines

4.  Do the ANOVA or linear mixed effect analysis to make sure no carry over 
effect e.g. formulation: sequence etc.

5.  Find the best scenario and shortest wish out period with the successful 
BE test without carry over effect.

We have a tool available to automate all the above processes. If you happen to 
attend PAGE meeting this year, you can find us from Certara booth and we can do 
you a demo.
   Automatic framework for bioequivalence studies from In Vitro 
test to In Vivo study design

Best wishes,
Kevin Feng


From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On 
Behalf Of Anuja Dhas/Formulation/VKH
Sent: Wednesday, March 14, 2018 1:17 AM
To: nmusers@globomaxnm.com
Subject: [NMusers] Extrapolation to achieve actual half-life

Hello Everyone,
We have done one parallel study to prove Bioequivalence, which failed on the 
lower side of Cl limits. We want to do crossover study, but in previous study 
we failed to capture actual half life. The API is having a half life around 4-5 
days and we did a parallel study for 2 days.

By M, we want to extrapolate to get actual half-life. And we want to 
calculate the sufficient wash-out period so that the carry-over effect will be 
<5% of Cmax in period 2 of crossover study.

We have achieved final model and done with VPC,LLP, please guide me for 
simulation.



Thanks & Regards
Anuja
''Legally privileged confidential information and subject to "Disclaimer". 



NOTICE: The information contained in this electronic mail message is intended 
only for the personal and confidential 
use of the designated recipient(s) named above. This message may be an 
attorney-client communication, may be protected 
by the work product doctrine, and may be subject to a protective order. As 
such, this message is privileged and 
confidential. If the reader of this message is not the intended recipient or an 
agent responsible for delivering it to 

[NMusers] RE: Extrapolation to achieve actual half-life

[Elin Svensson]

Dear Anuja,

We did some work looking at study design for drug-drug interaction studies with 
drugs having a long half-life, comparing parallel and cross-over designs, see 
this article:
https://www.ncbi.nlm.nih.gov/pubmed/26463060
Much of the reasoning could be applied for bio-equivalence too, so I hope you 
find it helpful.

Good luck!
Elin

From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On 
Behalf Of Anuja Dhas/Formulation/VKH
Sent: den 14 mars 2018 06:17
To: nmusers@globomaxnm.com
Subject: [NMusers] Extrapolation to achieve actual half-life

Hello Everyone,
We have done one parallel study to prove Bioequivalence, which failed on the 
lower side of Cl limits. We want to do crossover study, but in previous study 
we failed to capture actual half life. The API is having a half life around 4-5 
days and we did a parallel study for 2 days.

By M, we want to extrapolate to get actual half-life. And we want to 
calculate the sufficient wash-out period so that the carry-over effect will be 
<5% of Cmax in period 2 of crossover study.

We have achieved final model and done with VPC,LLP, please guide me for 
simulation.



Thanks & Regards
Anuja
''Legally privileged confidential information and subject to "Disclaimer".