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EMA has updated the "Questions & Answers: Positions on specific questions addressed to the Pharmacokinetics Working Party" EMA/618604/2000 Rev. 3" (dated 26 January 2011, published 14 March 2011).
The interesting part is Section 11. "Clarification on the recommended statistical method for the analysis of a bioequivalence study" (pages 21-32). Example data sets of a full replicate and a partial replicate design as well as SAS code and results are given.
If you use Phoenix/WinNonlin consider:
3.3. Alternative computer programs
SAS (version 9.1, SAS Institute Inc, NC) was used in the previous computations. Results obtained by alternative, validated statistical programs are also acceptable except spreadsheets because outputs of spreadsheets are not suitable for secondary assessment.
I've already posted a project-file containing the two data sets at Pharsight's Extranet. Unless a coding matching EMA's results is available, you cannot use Phoenix/WinNonlin in evaluating replicate design studies for an application in the EU.
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
1070 Vienna, Austria
I have been brain storming with few scientists towards a peculiar situation. This compound in question (with moderate to high permeability and moderate pgp efflux ratio) is nearly 4 times more soluble in fed state (feSSIF) as compared to fasted state (FaSSIF) simulated intestinal fluid (max solubility~0.1 mg/mL in FeSSIF). However, the POPK data of this compound dosed (at same dose) in dogs is strikingly opposite to the solubility data. The exposure is almost 20-30% more (with average variance) in fasted state as compared to fed state at same dose.
Is it possible that at fed state the marginal advantage of solubility is getting nullified and the diffusion of compound (from delivery matrix) may become rate limiting or could there be other explanations. Appreciate, if PK scientific fraternity have views to explain this.
Vaibhav Sihorkar, Ph.D
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Marked increase in measured solubility in the feed state can indicate hydrotropic behavior, similar to amiodarone (Cordarone).
Regards, Frank Bales, Ph.D.
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