invitro invivo correlation (IVIC)
Pharmaceutical development of a dosage form will be easier if a system is developed that exactly mimics the conditions of human body. Unfortunately, till date, such a system does not exist. Dissolution serves the purpose to some extent for the prediction of various pharmacokinetic parameters. Bioavailability is the rate and extent of absorption of drug whereas dissolution is the rate and extent of drug that goes into solution. The rate constant that is calculated in dissolution indicates the rate of absorption of drug and the extent of dissolution indicates the amount of drug absorbed. A good correlation of invitro values with invivo values has several advantages. Bioavailability studies during formulation development can be minimized. It gives support to the bioequivalence studies that are required during development of generic drug product. Establishing strong IVIC also helps in approval of scale up and post approval changes (my previous blog). Any small changes like batch size, equipment, site change that may affect the bioavailability can be justified by strong IVIC. Regulatory guidance was given by FDA on IVIC. Five correlation levels have been given by FDA1.
Level A correlation1: It is the highest degree of correlation. All the parameters calculated invitro exactly matches with invivo. The percentage of drug released exactly matches with the invivo drug absorbed calculated from methods like Wagner Nelson method or Loo-Reilgman method. Raw material changes, manufacturing site or any other small changes in formulation can be justified.
Level B correlation1: It is not exact correlation of the points and depends on principles of statistical moment analysis. Mean dissolution time, mean residence time calculated from invitro and invivo data are considered. This correlation cannot justify manufacturing site change, formulation modification.
Level C correlation1: It is the weakest correlation. At a single point of time, the amount of drug dissolved is compared with invivo parameter. Either the values of t 50%, t 90% are compared with AUC or cmax, tmax. This type of correlation is generally useful during early stages of formulation development.
Multiple - level C correlation1: As the name indicates, AUC
or cmax is compared with amount of drug dissolved at several time points of
dissolution. The time points represent
early, middle and late stages of dissolution.
If the correlation is more at different points, it suggests that level A
correlation can also be achieved.
Level D correlation1: It is the qualitative analysis and not useful for regulatory purposes but used during formulation.