RE: Extrapolation to achieve actual half-life

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