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IVIVC Toolkit™ for WinNonlin®— Frequently Asked Questions

Q Must one have to absolutely have IV data to be able to do IVIVC using the toolkit?

A

Because the IVIVC Toolkit currently supports the two-stage process (deconvolution, then modeling) there must be some kind of reference.  One can use IV-bolus, IV-infusion, or oral data as a reference.

Q What do you mean by "reference"?

A

The reference formulation is the one that is used to establish the pharmacokinetic behavior of the compound.  The deconvolution process uses the reference to determine the systemic input (absorption) rate necessary to explain the observed in vivo data.

Q Are there limitations on what can be used as the reference?

A

An IV bolus, IV infusion, or quickly absorbed oral formulation (solution, suspension, IR Tablet/Capsule) should work well.  They key feature is that the reference absorption rate is not dissolution limited.

Q What is the "strip ka" option?

A

When fitting a polyexponential function to the reference using the IVIVC Wizard (one of the tools in the Toolkit) there is an option to "strip ka".  Selecting this options enforces an assumption that absorption of the reference is a first order process.  The benefit is that the fitted function describes the compound pharmacokinetics as if the formulation were an IV bolus.  If the assumption is valid, doing this can remove a source of bias in the deconvolution results.

Q How many formulations are needed to perform a correlation?

A

The IVIVC Wizard needs to have at least one formulation (with dissolution and PK data) to build a correlation.  Depending on the intended use of the correlation, one probably needs a minimum of two or three formulations with different release rates.  Refer to the FDA Guidance for requirements for regulatory submission of an IVIVC.

Q Can the IVIVC Wizard build non-linear correlations?

A

Yes, the IVIVC Wizard provides a very easy method for writing an arbitrary custom model in the WinNonlin modeling language.  In this fashion, one can deal with unique combinations of factors such as absorption windows, time dependent dissolution rate, localized gut first pass, and saturated absorption.  Remember, however, that use of deconvolution implies linear (first order) pharmacokinetics (though not necessarily absorption).

Q What deconvolution options are available in the IVIVC Toolkit?
A

Wagner-Nelson, Loo-Riegelman, and Numerical Deconvolution tools are available in the IVIVC Toolkit.  The IVIVC Wizard uses the Numerical Deconvolution (Deconvolution through Convolution) routine because of its generality and stability.

Q Does the FDA have access to the IVIVC Toolkit?

A

The FDA has access to WinNonlin and The IVIVC Toolkit for WinNonlin through a CRADA with Pharsight.