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 re=
ference formulation (R)
- The PK observations is good enough to produce PK parameters such a=
s Cmax, Tmax, t_1/2, AUClast, AUCinf from NCA
- You already have a few in vitro dissolution profiles for both T an=
d 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: Buchw=
ald, 2003 JPP
3. Validate the models with both R and T plasma/blood concentration ob=
4. Find the best validated in vitro test methods for simulation - e.g.=
comparing OFV or AIC etc.
1. Used the validate models above. Note: if you use models built separ=
ately from T and R, it is very hard or impossible to do a 2X2 crossover sim=
ulation because you need to create same individuals every time for the cros=
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 fro=
m 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 B=
E 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 s=
ure 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 t=
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 t=
ogether 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 succes=
sful 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 w=
e can do you a demo.
Automatic framework for bioequivalence studies from In Vitro=
test to In Vivo study design
From: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ma=
ilto:owner-nmusers_at_globomaxnm.com] On Behalf Of Anuja Dhas/Formulation/VKH
Sent: Wednesday, March 14, 2018 1:17 AM
Subject: [NMusers] Extrapolation to achieve actual half-life
We have done one parallel study to prove Bioequivalence, which failed on th=
e lower side of Cl limits. We want to do crossover study, but in previous s=
tudy we failed to capture actual half life. The API is having a half life a=
round 4-5 days and we did a parallel study for 2 days.
By M&S, we want to extrapolate to get actual half-life. And we want to calc=
ulate 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 sim=
Thanks & Regards
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Received on Fri Mar 16 2018 - 12:02:21 EDT