How to Perform Level C IVIVC in Phoenix

In vitro in vivo correlation (IVIVC) is built on the premise that the in vitro dissolution characteristics of a drug can serve as a surrogate for a bioequivalence study. This type of analysis is attractive to sponsors because dissolution assays are cheaper and faster to perform than clinical testing. It also provides reassurance that a positive benefit/risk balance for patients is maintained throughout the life of a drug. IVIVC encompasses levels A, B, and C.

Level C correlation relates one dissolution time point (t50%, t90%, dissolution observed at 1h, etc.) to one mean pharmacokinetic parameter such as AUC (the area under the concentration-time curve), Tmax (the time after administration of a drug when the maximum plasma concentration is reached) or Cmax (peak concentration). Only a partial relationship between absorption and dissolution is established since it does not reflect the complete shape of plasma drug concentration time curve, which is the critical factor that defines the performance of a drug product.

Due to its limitations, the usefulness of a Level C correlation is restricted in predicting in vivo drug performance. In early formulation development, Level C correlations can help select pilot formulations. Waiver of an in vivo bioequivalence study (biowaiver) is generally not possible.

In contrast to level C, Multiple Level C correlations refer to the relationship between more than one pharmacokinetic parameter of interest (Cmax, AUC, or any other suitable parameters) and the amount of drug dissolved at several time points in the dissolution profile. Multiple Level C correlations are more powerful than a single level C as it could predict, for example, the two parameters of bioavailability rate (Cmax) and extent (AUC). In those conditions, it may be used to justify a biowaiver provided that the correlation has been established over the relevant dissolution point with all the bioavailability parameters of interest. A multiple Level C correlation should be based on at least three formulations and, if possible, on all the bioavailability parameters: AUC and Cmax.

The development of a level A correlation should also be possible when multiple Level C correlations are achieved for all relevant pharmacokinetic parameters describing rate and extent such that the effect on the in vivo performance of any change in dissolution can be assessed. However, this Level A correlation is not always possible even when a multiple level C exists, for example, when the drug of interest is a metabolite formed pre-systemically or during the elimination processes when administered as a prodrug. In this case, the multiple level C could be seen as the best possible achievable correlation.

In this webinar, Professor Jean-Michel Cardot explained how to perform Level C IVIVC using Phoenix. By watching this webinar, you will learn the following:

  • How to calculate pharmacokinetic parameters via the non-compartmental analysis (NCA) module
  • How to calculate dissolution parameters via the dissolution module
  • How to link the in vivo pharmacokinetic parameters and in vitro dissolution parameters via the linear relationship module
  • How to calculate dissolution limits