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In vivo in vitro correlation - copy

This document discusses concepts related to in vivo-in vitro correlation (IVIVC) including definitions, approaches, applications, limitations, and uses of dissolution as a surrogate for bioavailability. It describes the Biopharmaceutics Classification System (BCS) which categorizes drugs based on solubility and permeability. The expectations for establishing IVIVC are discussed for different BCS classes. The document also covers topics such as quantitative IVIVC levels, dissolution methodologies for immediate and extended release products, acceptance criteria, and apparatus used for dissolution testing.

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CONTENTS Concepts BCS Classification IVIVC Approaches Applications Limitations Dissolution as serrogate to immediate release formulations Dissolution as serrogate to extended release formulations
Concepts and Introduction In Vivo In Vitro correlation is defined as the predictive mathematical model that describes the relationship between an in vitro property (such as rate and extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration) USP defines IVIVC as the establishment of a relationship between a biological property produced from a dosage form and a physiochemical property of the same dosage form.
Applications of IVIVC I. To ensure batch to batch consistency in the physiological performance of a drug product by use of such in vitro values II. To serve as a tool in the development of a new dosage form with desired in vivo performance III.To assist in validating or setting dissolution specifications i.e. the dissolutions specifications are based on the performance of product in vivo IV.It minimizes the number of bioequivalence studies performed during the initial approval process and during scaling up and post approval changes V. It assists in validating dissolution specifications VI. Biowaiver for minor formulation and process changes
Limitations of IVIVC I. The IVIVC is limited to a certain drug product. It can be used only on that particular formulation II. The IVIVC cannot be used on the products with different release mechanisms
Quantitative In Vitro In Vivo Correlation A. Correlation based on the plasma level data: Parameters used for correlating in vitro dissolution with plasma data In vitro dissolution parameters In vivo plasma drug parameters Time for specific amount of drug to dissolve AUC, Cmax Amount dissolved at a specific time point Fraction absorbed, absorption rate constant Ka Mean dissolution time Mean residence time, mean dissolution time, mean absorption time Parameter estimated after modelling the dissolution process Concentration at time t , amount absorbed at time t
B. Correlations based on the urinary excretion data: Parameters such as amount of drug excreted unchanged in the urine, cumulative amount of drug excreted as a function of time. C. Correlation based on the pharmacological response : an acute pharmacological effect such as LD50 in animals in related to any of the dissolution parameters. Statistical moments theory: can be used to determine the relationship such as mean dissolution time vs. mean residence time.
In Vivo In Vitro Correlation levels Level A : It shows relationship between fraction absorbed and fraction dissolved. No direct comparison is possible. It is considered as a predictive model for relationship between the entire in vitro and in vivo response. There exists a linear correlation 1:1. There is point to point relationship. It is highest level of correlation and most preferred to achieve. 0 5 10 15 20 25 1 2 3 4 Fractionabsorbed Fraction dissolved Level A Correlation
Level B: In this the mean in vitro dissolution time is compared with mean in vivo residence time or mean in vivo dissolution time. It is based on statistical moment analysis. It is not point to point correlation. It is least used for regulatory purposes. 0 10 20 30 1 2 3 4 MRT(invivo) MDT ( in vitro) Level B Correlation
Level C Correlation: It is single point correlation that is established in between one dissolution parameter like t 50% and one of the pharmacokinetic parameters like tmax, Cmax, AUC. It is helpful in early stages of formulation . 0 5 10 15 20 25 1 2 3 4 AUC MDT Level C Correlation
Multiple level C Correlation: It reflects the relationship between one or several pharmacokinetic parameters of interest and amount of drug dissolved at several time point of dissolution. It is similar to Level A correlation. Level D Correlation: It is not considered useful for regulatory purpose.
Class Solubility Permeability Absorption Pattern Examples 1 High High Well absorbed Diltiazem, Propanolol, Metoprolol 2 Low High Variable Nifedipine, Carbamazepin e, Naproxen 3. High Low Variable Insulin, Metformin, Cimetidine 4. Low Low Poorly absorbed Taxol, Chlorthiazide, Furosemide The Biopharmaceutics Classification System For Drugs
Drug properties that determine BCS classification Drug property influencing absorption Corresponding parameter Solubility: a drug with high solubility is the one whose largest dosage strength is soluble in 250 ml or less of water over a pH range of 1-8 Dose number: It is the mass of drug divided by an uptake volume of 250 ml and the drug solubility Dissolution rate: A drug product with rapid dissolution is the one when ≥85% of the labelled amount of drug substance dissolves within 30 minutes using USP apparatus 1 or 2 in more than 900 ml volume buffer solution. Dissolution number : It is the ratio of mean residence time to mean dissolution time Permeability : A drug with high permeability is the one having extent of absorption greater than 90% of the administered dose given that the drug is stable in GIT Absorption Number: it is ratio of MRT to absorption time.
BCS for immediate release drug products and IVIVC expectations. Class Solubility Permeability IVIVC Expectations Possibility of predicting IVIVC from dissolution data 1 High High IVIVC expected Yes 2 Low High IVIVC expected Yes 3 High Low IVIVC not expected No 4 Low Low IVIVC not expected No
BCS for extended release drug products and IVIVC expectations Class Solubility Permeability IVIVC Expectations 1a High and site independent High and site independent IVIVC Level A expected 1b High and site independent Dependent on site and narrow absorption window IVIVC Level C expected 2a Low and site independent High and site independent IVIVC Level A expected 2b Low and site independent Dependent on site and narrow absorption window IVIVC not expected Va Variable Variable IVIVC not expected Vb Variable Variable IVIVC Level A expected
BCS based Biowaiver to in vivo studies In biowaivers the in vivo bioavailability and bioequivalence studies need not to be conducted for drug products under following circumstances: 1. Rapid and similar dissolution 2. High solubility 3. High permeability 4. Wide therapeutic window 5. Excipients used in dosage form are same as those present in approved drug product.
Dissolution As per IVIVC perspective dissolution is proposed to be a serrogate of drug bioavailability. Generally following types of apparatus are being used for conducting the dissolution studies. 1. Rotating basket apparatus 2. Rotating paddle type apparatus 3. Reciprocating cylinder apparatus 4. Flow through cell apparatus 5. Paddle over disc apparatus 6. Cylinder apparatus 7. Reciprocating disc apparatus  The conditions such as the stirring speed, choice of apparatus, pH of medium, and temperature of medium are important for conducting dissolution profile.  Dissolution medium used are: water, simulated gastric fluid (pH1.2), intestinal fluid (pH 6.8, 7.4)buffers with pH range of 4.5 to 7.5  Water and simulated gastric fluids are used for class 1 drugs  The normal test duration for immediate release is 15 to 60 minutes with a single time point.
Compendial dissolution apparatus types and their applications Apparatus Name Drug formulation tested Apparatus 1 Rotating basket apparatus Conventional tablets, chewable tablets, CR Formulations Apparatus 2 Rotating paddle FDT, Chewable tablets, capsules, CR Formulations Apparatus 3 Reciprocating cylinder CR Formulations, chewable tablets Apparatus 4 Flow through cell Implants, poorly soluble drugs, powders Apparatus 5 Paddle over disc Transdermal formulations Apparatus 6 cylinder Transdermal formulations Apparatus 7 Reciprocating disc CR Formulations
Dissolution acceptance criteria Q is considered as the acceptance criteria for dissolution which is defined as percentage of drug content dissolved in a given time period. Method of comparison of dissolution profile: Dissolution can be determined by calculating difference factor f1 and similarity factor f2 F1=∑(Rt-Tt)*100/∑Rt F2= 50log [(1+1/n∑(Rt-Tt)(Rt-Tt)]-0.5*100 where n= number of dissolution time points Rt = dissolution value of reference product Tt= dissolution value of test drug Comparison of dissolution profile: Difference factor f1 Similarity factor f2 Inference 0 100 Dissolution profiles are identical ≤15 >50 Similarity or equivalence of two profiles
The evaluation of dissolution profiles is based on following conditions: •Minimum 3 dissolution points are measured •Number of drug products tested for dissolution is 12 •Not more than one mean value of more than 85% dissolved for each product •S.D should not be more than 10%
Dissolution methology for immediate release products based on BCS BCS Class Dissolution methodology 1 Single point if NLT 85% Q in 15 minutes Multiple point if Q is less than in 15 minutes 2 Multiple point 3 Same as class 1 4 Same as class 2
Stage Number of dosage units tested Acceptance criteria S1 6 No dosage unit is less than Q+5% S2 6 Average of the twelve dosage units (S1+S2) > Q% and no dosage unit is less than Q-15% S3 12 Average of 24 dosage units (S1+S2+S3)> Q% and not more than 2 dosage units are less than Q-15% and no dosage unit is less than Q- 25% Dissolution Acceptance Criteria
Dissolution acceptance criteria for extended release Level Number tested Acceptance criteria S1 6 No individual value exceeds 10% dissolved S2 6 Average of the twelve dosage units (S1+S2) is not more than 10% dissolved and no individual unit is greater than 25%dissolved S3 12 Average of 24 dosage units (S1+S2+S3) ) is not more than 10% dissolved and no individual unit is greater than 25%dissolved
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