Introduction and Definition
Development of a drug and optimisation of a formulation are very tedious, time taking and expensive process, and during these processes in vitro-in vivo correlations (I VIVC) play an important role. Optimisation of a formulation includes alteration in formulation, composition, equipment, batch sizes, and manufacturing processes. If any such types of one or more alterations are made to the formulation, the new formulation demands carrying out bioequivalence studies to prove its similarity with the previous formulation and thus increases the cost of optimisation process.
As a result of these alterations, the market cost of the new formulation increases. These problems can be resolved by developing in vitro tests that reflect bioavailability data. IVIVC is the technique which can be used to develop new pharmaceuticals so that the number of human studies during the development of formulation can be reduced. So IVIVC acts as a surrogate for in vivo bioavailability and supports bio waivers.
United State Pharmacopoeia (USP) defined IVIVC as “the establishment of a rational relationship between a biological property or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form”.
Food and Drug Administration (FDA) defined IVIVC as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”.
The in vitro studies are performed to analyse the rate or extent of drug dissolution or release, while the in vivo studies help to study the plasma drug concentration or amount of drug absorbed. IVIVC is performed to obtain drug dissolution results from two or more products so that the similarity or dissimilarity of expected plasma drug concentration profiles can be determined. It is important to know how to establish similarity or dissimilarity of in vivo response, i.e., plasma drug, concentration profiles before deducing a relationship between the results obtained from in vitro and in vivo studies. The method used to establish similarity or dissimilarity of plasma drug concentration profiles is called bioequivalence testing. There are well-defined guidelines and standards for establishing bioequivalence between drug profiles and products.
Purpose of IVIVC
The purposes or objectives of IVIVC can be given as:
- To Reduce Regulatory Burden: Under some specific circumstances, IVIVC serves as a substitute for additional in vivo experiments.
- In Optimisation of Formulation: The optimisation of formulations includes alterations in composition, manufacturing process, equipment, and batch sizes. Therefore, an exhaustive study of bioequivalence (BE)/bioavailability (BA) is necessary to prove the validity of a new formulation that is bioequivalent with the target formulation.
- To Justify the Product’s Therapeutic Quality: IVIVC technique is used to prove the therapeutic efficiency of the formulation.
- To Scale-up Post-Approval Changes (Time and Cost Saving during Product Development): Validated IVIVC process is used as approval tool for biowaivers during the filings of a Level 3 (or Type II in Europe) variation, either during scale-up or post-approval, and also for line extensions (e.g., different dosage strengths).
- Used as Surrogate for in vivo Bioequivalence and Support Biowaivers (Time and Cost Saving): The main aim of an IVIVC process is to utilise in vitro dissolution profiles as a surrogate for in vivo bioequivalence studies and to support biowaivers.
Levels of IVIVC
As per the FDA guidelines, there are four levels of IVIVC, which include levels A,B,C, and multiple C. The correlation level concept is based on the ability of the correlation to reflect the entire plasma drug level-time profile which is the result of administration of the given dosage form.
Level A Correlation
The level A correlation of IVIVC has regulatory relevance and correlates the entire in vitro and in vivo profiles. It is the highest category of correlation and represents a point-to-point relationship between in vitro dissolution rate and in vivo input rate of the drug from dosage form.
It is important to achieve level A correlation because it allows biowaiver for changes in manufacturing site, raw material suppliers, and minor changes in formulation. Level A correlation defines a direct relationship between in vivo data such as the measurement of in vitro dissolution rate is required to determine the biopharmaceutical rate of the dosage form.
Level B Correlation
The level B correlation of IVIVC relies on the principles of statistical moment analysis. This level includes comparison of in vitro dissolution time (MDT vitro) of the product to either in vivo residence time (MRT) or in vivo dissolution time (MDT vivo). Level B correlation is not so useful for regulatory purposes because it does not reflect the actual in vivo plasma level curves, and also in vitro data from such a correlation cannot be used to justify the extremes of quality control standards.
Level C Correlation
The level C correlation relates one dissolution time point (t50% , t90% , etc.) to one mean pharmacokinetic parameter (AUC, tmax, or Cmax ). It is the weakest level of correlation as partial relationship between absorption and dissolution is established because it does not represent the complete shape of plasma drug concentration-time curve (the critical factor that defines the performance of a drug product). Therefore, the usefulness of level C correlation is restricted during the prediction of in vivo drug performance.
In the initial phase of formulation development, level C correlations can be useful when pilot formulations are being selected while waiver of an in vivo bioequivalence study (biowaiver) is generally not possible.
Multiple Level C Correlations
Mutliple level represents the relationship between one or more desirable pharmacokinetic parameters (Cmax, AUC, etc.) and concentration of drug dissolved at different time points of dissolution profile. If the correlation has been established over the entire dissolution profile with one or more pharmacokinetic parameters of interest, the multiple level C correlation can be used to justify biowaivers.
It is important that a multiple level C correlation should be based on minimum three dissolution time points including the early, middle, and late stages of the dissolution profile. Also the development of a level A correlation occurs, when multiple level C correlation is achieved at each time point at the same parameter so that the effect on in vivo performance of any change in dissolution can be evaluated.
Level D Correlation
The level D correlation is a semi-quantitative (qualitative analysis) and rank order correlation. It is not a formal correlation and is not useful for regulatory purpose, but can be used during the development or processing of a formulation.
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