IVIVC

It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.

1. In vitro- in vivo correlations ( IVIVC) By SURYAKANT VERMA Assistant Professor, Department of Pharmaceutics, Dr. K. N. Modi Institute of Pharmaceutical Education & Research, Modinagar , U.P., India.

2. In vitro- in vivo correlations (IVIVC) Criteria for IVIVC Objective of IVIVC Levels of IVIVC BCS for Immediate - Release Drug Product and IVIVC Expectations. BCS for Extended - Release Drug Product and IVIVC Expectations. Applications of IVIVC.

3. In vitro- in vivo correlations (IVIVC): In IVIVC, "C" denotes "Correlation", which means "the degree of relationship between two variables". This term does not limit a relationship to only the linear type, but allows for non-linear relationships as well. It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”. The main objective of developing and evaluating IVIVC is to use dissolution test to serve as alternate for in vivo study in human beings.

4. In vitro- in vivo correlations (IVIVC): USP definition “The establishment of rational relationship b/w a biological property or a parameter derived from a biological property produced by a dosage form and physicochemical property of same dosage form” Conceptually, IVIVC describes a relationship between the in vitro dissolution / release versus the in vivo absorption. FDA definition “A predictive mathematical model describing relationship between in-vitro property of a dosage form and in-vivo response.”

5. In vitro- in vivo correlations (IVIVC): BASIC:- Simply a mathematical model describing the relationship b/w in vitro and in vivo properties of drug. In vitro –in vivo correlation can be achieved using Pharmacological correlation “Based on clinical observations” Semi quantitative correlation “Based on the drug blood levels or urinary excretion data” Quantitative correlation “Arising from absorption kinetics and calculation of in vivo dissolution rate and absorption rate constants”

6. In vitro- in vivo correlations (IVIVC): CRITERIA FOR IVIVC • Successful IVIVC can be developed when in-vitro dissolution is rate limiting step in absorption and appearance of drug in in- vivo circulation following oral or other routes of administration. •These studies are to be conducted during the early stages of drug product development in order to select the most effective formulation and to establish appropriate dosage regimen. •The release- controlling excipients in the formulations should either be identical or very similar.

7. In vitro- in vivo correlations (IVIVC): OBJECTIVE OF IVIVC •To reduce the number of human studies during the formulation development. •To serve as a surrogate for in vivo bioavailability •To support biowaivers . •To validates the use of dissolution methods and specification settings(This is because the IVIVC includes in vivo relevance to in vitro dissolution specifications). •To assist quality control for certain scale-up and post-approval changes (SUPAC). • Due to all above objective, such IVIVC leads to 1. Shortens the drug development period, 2. Economizes the resources and 3. Leads to improved product quality.

8. In vitro- in vivo correlations (IVIVC): Correlations of IVIVC: Correlations based on the plasma level data Correlations based on the urinary excretion data Correlations based on the pharmacologic response Levels of IVIVC : Level A: The highest category of correlation. It represents point to point correlation between in vitro dissolution and in vivo rate of absorption. The data treatment involves a two stage Deconvolution Method. Estimation of the in vivo absorption profile using Wagner-Nelson or Loo-Riegelman method Comparison of fraction of drug absorbed ( Fa ) and fraction of drug dissolved.

9. In vitro- in vivo correlations (IVIVC): Advantages: Serves as alternate for in vivo study, change in manufacturing Procedure or formula can be justified without the need of additional human studies. Providing process control and quality assurance Determining stable release characteristics of the product over time. Level B: The mean in vitro dissolution time is compare with mean in vivo residence time. It is not point to point correlation. Data can be used for quality control standards. A predictive model for relationship between summary parameters that characterize the in-vitro and in-vivo time course.

10. In vitro- in vivo correlations (IVIVC): •No point to point correlation • It compares 1. MDT vitro to MDT vivo, 2. MDT vitro to MRT, 3. In-vitro Dissolution Rate Constant. This is of limited interest and least useful for regulatory purposes because more than one kind of plasma curve produces similar MRT. Level C: Mathematical model of relationship between the amount of drug dissolved in-vitro at a particular time and a summary pharmacokinetic parameter that characterizes in-vivo time course. (e.g., Cmax , Tmax , T1/2 or AUC).

11. In vitro- in vivo correlations (IVIVC): It is single point correlation. e.g. t50%, Tmax , Cmax . This level is only useful as guide for formulation development or quality control. Level C correlations can be useful in the early stages of formulation development when pilot formulations are being selected. Lowest correlation level. Does not reflect a complete shape of plasma concentration time curve. MULTIPLE Level C: It relates one or more pharmacokinetic parameters to the percent drug dissolved at several time points of dissolution profile and thus may be more useful. If a multiple Level C correlation is possible, then a Level A correlation is also likely and is preferred.

12. Biopharmaceutical Classification System (BCS) for Immediate - Release Drug Product and In vitro- in vivo correlations (IVIVC) Expectations: CLASS SOLUBILITY PERMEABILITY IVIVC Expectations for Immediate- Release Drug Product Possibility of predicting IVIVC from dissolution data I High High IVIVC expected, if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlation. Yes II Low High IVIVC expected, if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high. Yes III High Low Absorption (permeability) is rate determining and limited or no IVIVC with dissolution. No IV Low Low Limited or no IVIVC is expected. No

13. Biopharmaceutical Classification System (BCS) for Extended - Release Drug Product and In vitro- in vivo correlations (IVIVC) Expectations: CLASS SOLUBILITY PERMEABILITY Level of IVIVC I High and site independent High and site independent IVIVC Level A expected II High and site independent Dependant on site and narrow absorption window IVIVC Level C expected III Low and site independent High and site independent IVIVC Level A expected IV Low and site independent Dependant on site and narrow absorption window Little or no IVIVC Va : Acidic Variable Variable Little or no IVIVC Vb : Basic Variable Variable IVIVC Level A expected

14. Applications of IVIVC: IVIVC IN DRUG DELIVERY Early stages of drug delivery technology development Formulation assessment Dissolution specifications FUTURE BIOWAIVERS : for minor formulation and process changes Ivivc parenteral drug delivery : causes of failure of parenteral IVIVC. Burst Release Potent Drugs & Chronic Therapy Limited volume of tissue fluids and Area of absorption at the site of administration, unlike following the oral route of administration. Therefore, it is very difficult to specify the in vitro dissolution conditions that reflect the observed differences in the in vivo plasma profiles corresponding to the in vitro release profiles.

15. Applications of IVIVC: NEW IVIVC APPLICATIONS IVIVC for transdermal estradiol systems (novel pharmaceuticals) Why IVIVC fail for immediate release dosage form Dissolution simulators Gronings model Sartorius dissolution simulator Sartorius membrane filter solubility simulator Sartorius membrane filter absorption simulator.