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Level C IVIVC: What Is It, and When Do You Use It?

In vitro in vivo correlation (IVIVC) links in vitro drug data to in vivo performance. Regarding in vivo performance, IVIVC can predict either the in vivo plasma time-concentration curve or in vivo pharmacokinetic (PK) parameters like Cmax and AUC. In this blog, I will discuss Level C IVIVC, and when you should use this approach.

IVIVC is a statistical tool that employs in vitro data. It can be used to waive regulatory requirements to show evidence of in vivo bioavailability (BA) or bioequivalence (BE). The aim of IVIVC is to reduce the in vivo bioequivalence study burden. Thus, IVIVC can be a surrogate of in vivo bioequivalence. If we have satisfactory in vitro data, we can use them as a surrogate of in vivo data. In vivo bioequivalence is demonstrated using two main PK parameters—Cmax and AUC.

IVIVC levels

IVIVC can be performed at one of three levels—A, B, and C. For the Level A, (see graph on the left) we link a drug’s observed in vitro dissolution with its observed in vivo absorption. Thus, for all the observed time points, you plot the amount of drug that is absorbed in vivo and dissolved in vitro. While you can perform this regression with data from a single drug formulation, it’s better—and recommended by regulatory authorities—to use at least two or three formulations.

Level C IVIVC involves determining the relationship between in vivo PK parameters and in vitro dissolution data. The right side graph below depicts, as an example, the percent of drug dissolved in vitro at the time X vs the Cmax in vivo. Each data point on the curve represents a formulation.

Deciding which level of IVIVC to perform

From the regulatory viewpoint, Level A IVIVC is more powerful than the Level C because you’re using all information from the plasma concentration curves. If you have a Level C IVIVC which can correlate Cmax to some in vitro dissolution parameters, and at the same time, the area under the plasma concentration curve (AUC) to some in vitro dissolution parameters, you can predict all the PK parameters related to BA/BE. In some cases, Level C IVIVC can serve as a surrogate of in vivo studies because it supports predicting drug bioavailability.

Although Level A IVIVC is the most powerful type of IVIVC, you can’t always perform it. This occurs in two common scenarios. The first is when you use metabolite data. According to bioequivalence guidelines, you have always to measure the amount of parent drug. But, sometimes metabolites are formed pre-systematically, which complicates measuring the parent compound’s concentration in the blood. Also, metabolites can be formed during the elimination process. Then, the resulting absorption curve does not represent drug input because it includes both parent drug input and the formation of the metabolite during the elimination process.

The second case when making a Level A IVIVC isn’t possible occurs when you cannot perform deconvolution in the absence of a unit impulse response (UIR: intravenous drug plasma concentration-time data, for example) or when the drug’s PK is best described by a two-compartment model rather than a one-compartment model (thus, the Wagner-Nelson deconvolution approach is not appropriate).

Benefits and limitations of Level C IVIVC

In both cases, the Level C IVIVC can be a good alternative. While a Level C IVIVC cannot predict the full in vivo plasma concentration-time profile of a drug, it can predict the main PK parameters (Cmax, AUC) which can help you to establish BA/BE.

Level C IVIVC requires that you use only test formulations that have similar release mechanisms and technology. Thus, you can’t use a competitor’s formulation as the reference to establish a Level C IVIVC and then try to extrapolate the results to your own test formulations.

Interested in learning how to perform Level C IVIVC in Phoenix? Please watch the webinar I presented on this topic.

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By: Jean-Michel Cardot

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