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IN VITRO - IN VIVO CORRELATION

The document discusses in vitro - in vivo correlation (IVIVC), which establishes the relationship between the drug's dissolution characteristics in vitro and its pharmacokinetic responses in vivo. IVIVC is essential for pharmaceutical development as it aids in predicting bioavailability and assists in quality control and regulatory compliance through various correlation levels (A, B, C, etc.). The document also outlines the prerequisites for establishing IVIVC, including biopharmaceutics classification and bioavailability studies.

Health & Medicine◦
IN VITRO - IN VIVO CORRELATION BY NADIKATLAANUSHA M.Pharm
CONTENTS • In-vivo studies • Pharmacokinetic parameters • Correlation levels  Level A correlation  Level B correlation  Level C correlation  Multiple-level c correlation  Level D correlation • Biopharmaceutics classification system (BCS) • Procedure for in-vitro in-vivo correlation • Evaluation of predictability of ivivc ANUSHA NADIKATLA
 United State Pharmacopoeia (USP) 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) definition IVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed. IN VITRO - IN VIVO CORRELATION ANUSHA NADIKATLA
• In vitro - in vivo correlation refers to the establishment of rational relationship between a biological response produced by a dosage form and a physicochemical characteristics. • In recent years, the concept and application of the in vitro-in vivo correlation (IVIVC) for pharmaceutical dosage forms have been a main focus of attention of pharmaceutical industry, academia, and regulatory sectors. • The main objective of an IVIVC is to serve as a surrogate for in vivo bioavailability and to support biowaivers. • IVIVCs could also be employed to establish dissolution specifications and to support and/or validate the use of dissolution methods. ANUSHA NADIKATLA
IVIVC could also be employed to establish dissolution specifications and to support and/or validate the use of : • Dissolution methods • Quality control procedures • Tablet or Capsule disintegration • Instrumental methods of analysis • Dissolution Rate Test • The rate of drug absorption • Dissolution Profile Parameters • In Vivo Performance • Proper In-Vitro Dissolution Rate • Correlate the data with the bioavailability Important Purpose: 1. Providing necessary process control 2. Determing stability of dosage form ANUSHA NADIKATLA
• In-Vivo Studies In-vivo studies deals with the evolution of bioavailability and bio equivalence of pharmaceutical dosage forms using parameters like AUC, Cmax etc.. PARAMETERS 1. Drug concentration in plasma at each sampling time 2. Apparent rate constant for elimination 3. Biological half life 4. Urinary excretion rate and amount excreted in urine at infinity ANUSHA NADIKATLA
PHARMACOKINETIC PARAMETERS 1. Mean Residence Time(MRT) 2. Mean Absorption Time(MAT) 3.Cmax/AUC 4.The Peak Occupancy Time(POT) 5.Multiple Dosing 6.Co-efficient of variation ANUSHA NADIKATLA
 Correlation is a measure of relationship between two mathematical variables or measured data values, which includes the Pearson correlation coefficient as a special case. CORRELATION LEVELS • Five correlation levels have been defined in the IVIVC FDA guidance. • The concept of correlation level is based upon the ability of the correlation to reflect the complete plasma drug level-time profile which will result from administration of the given dosage form. ANUSHA NADIKATLA
Level A Correlation • This level of correlation 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 the dosage form. • Generally, percent of drug absorbed may be calculated by means of model dependent techniques such as Wagner-Nelson procedure or Loo-Riegelman method or by model-independent numerical deconvolution. • These techniques represent a major advance over the single-point approach in that these methodologies utilize all of the dissolution and plasma level data available to develop the correlations ANUSHA NADIKATLA
It is a point –point relationship between in-vitro data and in-vivo input rate of drug from dosage form ADVANTAGES: 1. This is the highest category of relation which act as a meaningful quality control procedure predictive of invivo performance of formulation. 2. The invitro curve at stimulated dissolution conditions can serve as surrogate for invivo performance of formulations. ANUSHA NADIKATLA
ANUSHA NADIKATLA Mean absorption time is plotted against mean dissolution time for atleast 3 different preparations. A level B IVIVC utilizes the principles of statistical moment analysis. In this level of correlation, the mean in vitro dissolution time (MDTvitro) of the product is compared to either mean in vivo residence time (MRT) or the mean in vivo dissolution time (MDTvivo). Level B Correlation MAT=MRT-MRToral
LIMITATIONS 1. It utilizes all data but is non unique as diferent shaped absorption/dissolution curve could result in same moment value. 2. This correlation alone fails to justify formluations,modification ,manufacturing ,site change ,excipient source change etc. 3. It does not justify the extremes of qualtiy control standards. ANUSHA NADIKATLA
Level C Correlation • In this level of correlation, one dissolution time point (t50%, t90%, etc.) is compared to one mean pharmacokinetic parameter such as AUC, tmax or Cmax • This is the weakest level of correlation as partial relationship between absorption and dissolution is established. • Level C correlations can be useful in the early stages of formulation development when pilot formulations are being selected. • Selected parameters are correlated for 3 or more preparations Eg: Time for 50% dissolution vs AUC,Cmax or Tmax ANUSHA NADIKATLA
MULTIPLE-LEVEL C CORRELATION • A multiple level C correlation relates one or several pharmacokinetic parameters of interest (Cmax, AUC, or any other suitable parameters) to the amount of drug dissolved at several time points of the dissolution profile. • A multiple level C correlation be used to justify a biowaiver. • A multiple Level C correlation should be based on at least three dissolution time points covering the early, middle, and late stages of the dissolution profile. ANUSHA NADIKATLA
Level D correlation • Level D correlation is a rank order and qualitative analysis and is not considered useful for regulatory purposes. It is not a formal correlation but serves as an aid in the development of a formulation or processing procedure. • Methodology for developing the Correlation: • Develop formulation with different release rate such as slow,medium,fast or a single rate if dissolution is independent. • Invivo conc. Of plasma BA studies i.e., Wagnernelson method. • The intensity factor = time for 50% absorption/ time for 50% dissolution • Transform T to the corresponding invitro time point applying the equation T= invivo time/intensity factor. • Stereochemistry and First pass effect are the factors for developing correlation ANUSHA NADIKATLA
IMPORTANT CONSIDERATIONS IN DEVELOPING A CORRELATION • When the dissolution is not influenced by factors such as pH, surfactants, osmotic pressure, mixing intensity, enzyme, ionic strength, a set of dissolution data obtained from one formulation is correlated with a deconvoluted plasma concentration-time data set . • If one or more of the formulations (highest or lowest release rate formulations) may not illustrate the same relationship between in vitro performance and in vivo profiles compared with the other formulations, the correlation is still valid within the range of release rates covered by the remaining formulations ANUSHA NADIKATLA
BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) Class Solubility Permeability Absorption rate control IVIVC expectations for Immediate release product I High High Gastric emptying IVIVC expected, if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlations II Low High Dissolution IVIVC expected, if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high. III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution. IV Low Low Case by case Limited ANUSHA NADIKATLA
• The (BCS) is a drug development tool that allows estimation of the contribution of three fundamental factors including dissolution, solubility and intestinal permeability, which govern the rate and extent of drug absorption from solid oral dosage forms. • BCS is also a fundamental guideline for determining the conditions under which IVIVCs are expected. • It is also used as a tool for developing the in-vitro dissolution specification ANUSHA NADIKATLA
BIOAVAILABILITY STUDIES FOR DEVELOPMENT OF IVIVC • A bioavailability study should be performed to characterize the plasma concentration versus time profile for each of the formulation. • Bioavailability studies for IVIVC development should be performed with sufficient number of subjects to characterize adequately the performance of the drug product under study ANUSHA NADIKATLA
PROCEDURE FOR IN-VITRO IN-VIVO CORRELATION In-Vivo 1.Administer the drug as an oral solution 2.Administer the drug in 3 formulation 3.Apply numericall de conversions In-Vitro: Dissolution testing of product to asses release rates under various conditions. Plasma Level Data: It is established both for a batch of material. 1. Predictive Mathematical Model 2. Quality control tool. 3. Series of Dosage forms. Drug or Product Requirements for an IVIVC: • Caution, if narrow therapeutic range • Linear pharmacokinetics • Preferably BCS I or II ANUSHA NADIKATLA
Mathematical Techniques :Assessment of in vivo drug release or absorption from plasma profiles MODEL-DEPENDANT: based on the mass balance among the pharmacokinetic Compartments (e.g. Wagner-Nelson, Loo-Riegelman) MODEL-INDEPENDENT: based on Theory of Linear System Analysis (Convolution / Deconvolution) APPLICATIONS: • Batch to Batch consistency. • Development of new dosage form. • Assisting validity. • Biowaiver for minor formulations and process changes. ANUSHA NADIKATLA
EVALUATION OF PREDICTABILITY OF IVIVC • An IVIVC should be evaluated to demonstrate that predictability of in vivo performance of a drug product from its in vitro dissolution characteristics is maintained over a range of in vitro dissolution release rates and manufacturing changes. • Depending on the intended application of an IVIVC and the therapeutic index of the drug, evaluation of prediction error internally and/or externally may be appropriate. • External predictability evaluation is not necessary unless the drug is a narrow therapeutic index, or only two release rates were used to develop the IVIVC, or, if the internal predictability criteria are not met i.e. prediction error internally is inconclusive. ANUSHA NADIKATLA
INTERNAL PREDICTABILITY • All IVIVCs should be studied regarding internal predictability. One recommended approach involves the use of the IVIVC model to predict each formulation’s plasma concentration profile (or Cmax and/or AUC for a multiple Level C IVIVC) from each respective formulation’s dissolution data. EXTERNAL PREDICTABILITY • Most important when using an IVIVC as a surrogate for bioequivalence is confidence that the IVIVC can predict in vivo performance of subsequent lots of the drug product. • Therefore, it may be important to establish the external predictability of the IVIVC. This involves using the IVIVC to predict the in vivo performance for a formulation with known bioavailability that was not used in developing the IVIVC model. ANUSHA NADIKATLA
REFERENCES 1.BIOPHARMACEUTICS AND PHARMACOKINETICS (D.M.BRAHMANKAR, SUNIL B.JAISWAL). 2.PRINCIPLE AND APPLICATIONS OF BIOPHARMACEUTICS AND PHARMACOKINETICS (Dr.H.P.TIPNIS, Dr.AMRITA BAJAJ). 3. In VIVO HYDRAULIC CONDUCTIVITY OF MUSCLE (El Rasheid Zakaria, Joanne Lofthouse, and Michael F Flessner). 4. BIOPHARMACEUTICS AND PHARMACOKINETICS (Venkateshwarlu). 5 Chen, J.C., M.H. Chiu, R.L. Nie, G.A. Cordell, and S.X. Qius. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep, 22(3): 386-99 2005 ANUSHA NADIKATLA
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