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A seminar on Factor affecting IVIVC Guided by: Presented by: Dr.Manish.P.Patel Patel Jignesh.P Head of Department M.pharm-1sem Department of pharmaceutics M.pharm, Nootan Pharmacy college Visnagar. 1/37
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.
Conceptually , IVIVC describes a relationship between the in vitro dissolution / release versus the in vivo absorption.
FDA had defined IVIVC as “A predictive mathematical model describing relationship between in-vitro property of a dosage form and in-vivo response.”
In-vitro properties are rate or extent of drug released under a given set of conditions. In-vivo properties are plasma drug conc. expressed in terms of Cmax, AUC.
Theoretically worthwhile, but Clinical approach is a poor tool for accurate measurement of bioavailability.
Determination of drug level at the site of administration.
Urinary excretion analysis of drug is meaningful for establishing IVIVC but complicated pharmacokinetic considerations.
Thus it is generally assumed that blood (serum/plasma) level measurements give a better assessment of bioavailability and bioequivalence.
7/37 To explore the relationship To assist quality control for certain SUPAC. Research tool for Formulation Screening To support biowaivers for bioequivalence testing Development of drug delivery systems. To set the dissolution specifications As a surrogate of in vivo bioavailability To reduce the number of human studies IMPORTANCE OF IVIVC
Pharmacological correlations based on clinical observations.
Semi quantitative correlations based on the drug blood levels or urinary excretion data.
Quantitative correlations arising from absorption kinetics and calculation of in vivo dissolution rate and absorption rate constants.
Factors affecting development of a predictable IVIVC 9/37 DISSOLUTION METHOD PYSICOCHEMICAL METHOD COMPOSITION COMPLEXITY
Mean Residence Time: MRT = AUMC / AUC where, AUMC = Area under first moment Curve (Concentration*time Vs time) AUC = Area under zero moment curve (Concentration Vs time) Mean Absorption Time: MAT = MRT oral – MRT i.v. Mean In-vivo Dissolution Time: MDT solid = MRT solid – MRT solution Percent Prediction Error: % PE = [(Observed value – Predicted value) / Observed value] x 100 FEW DEFINITIONS 10/37
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, T 1/2 or AUC).
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.
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.
15/37 C max , T max , K a , Time to have 10, 50, 90% absorbed, AUC Disintegration time, Time to have 10, 50, 90% Dissolved, Dissolution rate, Dissolution efficiency C Statistical Moment: MRT, MAT Statistical Moment: MDT B Input (absorption) curves Dissolution curve A In vivo In vitro Level
Pearson product moment correlation coefficient , quantify strength of relationship between x & y. r (-1 to +1)
Rank order correlation : (Spearman rank correlation, r s ) Values of the two variables are ranked in ascending or descending order. Rank order correlations are qualitative and are not considered useful for regulatory purposes.
16/37 No Linear Relationship 0 Perfect Negative -1 Perfect Positive +1 Linear relationship Correlation (r) between variables
17/37 Correlation Methods SIMPLE POINT TYPE COMPARISON OF PROFILES DIRECT DIFFERENTIAL EQUATION- BASED IVIVC
The principles of IVIVC model development have been successfully applied to oral dosage forms.
However, the rules for developing and validating IVIVC models for novel and non-oral dosage forms/delivery systems (micro spheres, implants, liposomes, etc) are still unclear today.
For orally administered drugs, IVIVC is expected for highly permeable drugs or drugs under dissolution rate-limiting conditions, which is supported by BCS.
For extended-release formulations following oral administration, modified BCS containing the three classes (high aqueous solubility, low aqueous solubility, and variable solubility) is proposed.
21/37 Limited or no IVIVC expected. Low Low IV Absorption/Permeability is rate determining and limited or no correlation with dissolution rate. Low High III IVIVC is expected if in-vitro dissolution rate is similar to in-vivo dissolution rate, unless dose is very high. High Low II IVIVC: if dissolution rate is slower than gastric emptying rate. Otherwise limited or no correlation required High High I IVIVC EXPECTATION PERMEABILITY SOLUBILITY CLASS
 For a new formulation the relevant exposure parameters are predicted using its in vitro dissolution profile and the IVIVC model and are compared to the observed parameters.
 For Cmax and AUC, the % PE for the external validation formulation should not exceed 10%. A prediction error of 10% to 20% indicates inconclusive predictability and illustrates the need for further study using additional data sets.
 For drugs with narrow therapeutic index , external validation is required despite acceptable internal validation, whereas internal validation is usually sufficient with non-narrow therapeutic index drugs.
28/37 IVIVC – PARENTERAL DRUG DELIVERY DISSOLUTION SPECIFICATIONS FORMULATION ASSESSMENT EARLY STAGES OF DRUG DELIVERY TECHNOLOGY DEVELOPMENT FUTURE BIOWAIVERS APPLICATIONS OF IVIVC IN DRUG DELIVERY Potent Drugs & Chronic Therapy Limited volume Burst Release