#BCS

Описание: #Bioequivalence is a vital concern in drug development, even more, significant in the case of Narrow Therapeutic Index (NTI) drugs.
In the clinical development of New Chemical Entities (NCE), bioequivalence studies necessitate being performed when the formulation of the pharmaceutical dosage form has been changed.
In vivo, pharmacokinetic data can be used as surrogate parameters for in vivo solubility and permeability data.
The Biopharmaceutics Classification System (BCS) has emerged as a helpful tool in product development by alluding to the in vivo performance of the active substance.
The bio-relevance of the BCS properties and the in vitro release are best expressed through a correlation between in vitro and in vivo data.
Recently BCS has been implemented for waiving bioequivalence studies based on the solubility and gastrointestinal permeability of drug substances and can be strategically deployed to save time and resources during generic drug development.
The BCS has been adopted as a handy tool for in vivo drug design and development worldwide, particularly in regulatory standards.
A BCS-based biowaiver has become an important and cost-saving tool in the approval of generic drugs.

In vitro-in vivo correlation (IVIVC)
In vitro-in vivo correlation (IVIVC) technology allows formulation and manufacturing (CMC) professionals to understand how dissolution parameters affect in vivo drug performance. IVIVC can be performed at one of three levels—A, B, and C. Getting the most out of this tool requires knowing when and how to use which level of IVIVC.
Here are some questions (and answers) that I’ve gotten regarding best practices for this approach.
Q: Do you prefer using arithmetic mean or a geometric mean when running Level C correlation on mean data?
A: You can use arithmetic mean or geometric mean. The difference is not important if you don’t have any outliers. Arithmetic means are very sensitive to extreme values. If you want to be more stable, use the geometric mean and median.
You can also use all the raw data to establish the IVIVC. Then the linear regression will result in parameters (slope and intercept) close to those of arithmetic means, but variability will be associated with the estimates.
If you use arithmetic means, you have to consider that if you use all the raw data to perform IVIVC Level C, your IVIVC Level C will go through the arithmetic mean. Geometric means are closer to what you calculate in bioequivalence (BE) studies because you log transformation in these studies.
Q: When is a Level C IVIVC useful compared to a Level A IVIVC?
A: A Level C IVIVC can be very useful when you don’t have enough data to make a Level A, or you don’t know if it’s possible, and you don’t want to invest a lot of time. You can easily try with mean values for Cmax, AUC, and Tmax to see if you have a match with your dissolution data. If yes, and it matches the three parameters, you can consider investing the time to perform Level A IVIVC.
The second case is when, for example, you have a prodrug that has a limited plasma concentration compared to the active metabolite. In this case, the metabolite concentration levels will reflect the initial pre-systemic metabolism, but it will also reflect the current elimination for the plasma. Thus, performing Level A IVIVC would be misleading.
Lastly, sometimes you don’t have enough data. For example, you may lack intravenous (IV) or fast-release data as the unit impulse response (UIR) to perform deconvolution. In this case, you’re forced to make a Level C IVIVC. These are the three main cases in which a Level C IVIVC is indicated.
Q: Can I perform a Level C IVIVC with only one or two formulations?
A: No. But, you can use two formulations when performing Level A IVIVC. That’s because Level A uses all the plasma concentration data. By contract, Level C restricts the plasma concentration curve to one point, Cmax or the AUC. If you have only two profiles, or two formulations A and B, and you’ve restricted it to Cmax and AUC, and only to the mean values, of course, you will have a straight line between the two mean values. That is one of the drawbacks of Level C IVIVC. Thus, this approach is less powerful than Level A.

Q: Could Level C IVIVC be used as a surrogate of in vivo bioequivalence?
A: According to the guidelines, no. But, some authorities accept it when you can correlate all the bioavailability parameter values (Cmax and AUCs) with dissolution. That means you can Level C to predict the risk that the formulations are not bioequivalent. In this case, it can be used as an in vivo surrogate, and some authorities will accept it.