IN-VITRO AND IN-VIVO CORRELATIONS.pptx

M.PHARM PPTs KL UNIVERSITY

1. IN-VITRO AND IN-VIVO CORRELATIONS PRESENTED BY SHAMSELFALAH A. H 2101580003 M.PHARM 1 ST YEAR DEPT.OF PHARMACEUTICS KLU

2. CONTENT INTRODUCTION DEFINITIONS LEVELS OF CORRELATION IVIVC AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEM IN-VITRO DISSOLUTION IN-VIVO ABSORPTION FACTORS AFFECTING IVIVC APPLICATIONS OF IVIVC AND DRUG DELIVERY CONCLUSION REFERENCES

3. INTRODUCTION Rapid drug development necessities the research to find out link between the dissolution testing and the bioavailability, which result as concept of in-vitro and in-vivo correlations. In recent years, the concept and application of the in-vitro-in-vivo correlation for pharmaceutical dosage form have been a main focus of attention of pharmaceutical industry, academia and regulatory sectors. Development and optimization of formulation is an integral part of manufacturing and marketing of any therapeutic agent which is indeed a time consuming and costly process. The rational development of a delivery system is sensible and expensive procedure. In this regard, use of in-vitro data to predict in-vivo bio-performance can be considered as the rational development of controlled-release formulations.

4. Definitions F rom biopharmaceutical standpoint, correlation could be referred to as the r e lationship between appropriate in-vitro release characteristics and in-vivo bioavailability parameters. A ccording USP IVIVC is 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. T ypically, the parameter derived from the biological property is AUC or Cmax, while the physicochemical property is the in-vitro dissolution FDA defined the IVIVC as predictive mathematical model describing the relation between an in-vitro property of a dosage form and a relevant in-vivo response.

5. Levels of correlation From definition, five correlation levels of IVIVC have been defined in IVIVC FDA guidance. Level A Correlation Level B Correlation Level C Correlation Multiple-level C Correlation Level D Correlation

6. Level A correlation T his correlation represents a point-to-point r e lationship between in-vitro dissolution and in-vivo dissolution (input/absorption rate) and is consider as the highest category of correlation. L evel A IVIVC is also viewed as a predictive model for the relationship between the entire in vitro release time course and entire in vivo response time course. I n general, correlation are linear at this level. A lthough a concern of acceptable non-linear correlation has been addressed, no formal guidance on the non-linear IVIVC has been established. L evel A correlation is the most informative and very useful from a regulatory perspective.

7. Level B correlation Level B IVIVC uses the principle of statistical moment analysis. In this level of correlation, the mean in-vitro dissolution time (MDT vitro ) is compared to either mean in-vitro residence time(MRT) or the mean in-vitro dissolution time (MDT vivo ). Even though it utilizes all of the in-vitro and in-vivo data but it is not considered as point-to-point correlation, because a number of different in-vivo curves that will be produce similar mean residence time values A level B correlation does not uniquely reflect the actual in-vivo plasma level curves. Therefore, one can not rely upon a level B correlation alone to justify formulation modification, manufacturing site change, excipient source change, etc. It is not useful for quality control purposes but useful for regulatory purpose.

8. Level C correlation A level C IVIVC establishes a single point relationship between a dissolution parameter (e.g., t50% or dissolved in 4 hrs) and a pharmacokinetics parameter (e.g., AUC or C max). A level C correlation dose not reflect the complete shape of the plasma concentration-time curve, which is the critical factor that defines the performance of Extended Release (ER) products. T herefore this the weakest level of correlation as partial relationship between absorption and dissolution is established. D ue to it is obvious limitations, the usefulness of a level C correlation is limited in predicting in-vivo drug performance. L evel C correlation can be useful in early formulation development, including selecting the appropriate excipients, to optimize manufacturing processes, for quality control purpose and to characterize the release pattern for newly formulated immediate-release and modified-release product.

9. Multiple level C correlation M ultiple level C correlation reflects the relationship between one or several pharmacokinetic parameters of interest and amount of drug dissolved at several time points of the dissolution profile. 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. I f such a multiple level C correlation is achievable, then the development of a level A correlation is also likely . M ultiple point level C correlation may be used to justify a biowaivers, provided that the correlation has been established over the entire dissolution profile with one or more pharmacokinetic parameters of interest.

10. Level D correlation It is a rank order and semi quantitative correlation and it is not considered useful for regulatory purpose. IVIVC AND BIOPHARMACEUTICAL CLASSIFICATION SYSTEMS The BCS is defined in the FDA guidelines as’’ the scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability’’. When combined with the dissolution of drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from immediate release (IR) solid oral dosage forms such as dissolution, solubility and intestinal permeability which are defined as follow. Solubility : A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less than 250 ml aqueous media over the pH range 1-7.5.

11. P ermeability: A drug substance is considered highly permeable if the extent of drug absorption is 90% or greater than 90% of an administrated dose based on mass balance determination or in comparison to an intravenous reference dose. D issolution: A drug product is considered rapidly dissolving when no less than 85% of labelled amount of the drug substance dissolves within the 30 minutes using USP dissolution apparatus I at 100 rpm or USP dissolution apparatus II at 50 rpm in 900 ml in 0.1 IN HCL or SGF USP without enzymes/ Ph 6.5 buffers or SIF USP without enzymes BCS is a fundamental guideline for determing the conditions under which in-vitro or in-vivo correlations are expected. D issolution number T he absorption number : is the ratio of the mean residence time to the absorption time . T he dissolution number: is a ratio of mean resid e nce time to mean dissolution time. T he dose number: is the mass divided by uptake volume of 250 ml and the drugs solubility.

12. Characteristics of Drugs of Various BCS classes C lass I drugs: exhibit a high absorption number and a high dissolution number. T he rate limiting step is drug dissolution and if dissolution is very rapid then gastric emptying rate becomes the rate determining step. B ioav ai lability and dissolution is very rapid. S o bioavailability and bioequivalence studies are unnecessary for such product . IVIVC can not be expected. T hese compounds are highly suitable for design the SR and CR formulations. C lass II drugs: have a high absorption number but low dissolution number. I n-vivo drug dissolution is then a rate limiting step for absorption except at a very high dose number. T he drug exhibited variable bioavailability and need the enhancement in dissolution for increasing the bioavailability. T hese compounds are suitable for design the SR and CR formulations. IVIVC is usually accepted for class II drugs.

13. C lass III drugs: permeability is rate limiting step for drug absorption. T hese drugs exhibit a high variation in the rate and extent of drug absorption. S ince the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors. T hese drugs are problematic for controlled release development. T hese drugs showed the low bioavailability and need enhancement in permeability. C lass IV drugs: exhibit poor and variable bioavailability. S everal factors such as dissolution rate, permeability and gastric emptying from the rate limiting steps for the drug absorption. T hese are unsuitable for controlled release. C lass V drugs: are those ones that don’t come under the purview of BCS classification but includes the drug whose absorption is limited owing to their poor solubility in the GI G astric instability C omplication in GI lumen H igh first pass metabolisms etc

14. Table 1: BCS and Expected IVIVC for Immediate Release Drug Products class solubility permeability IVIVC Expectation for IR product Permeability of predicating IVIVC from dissolution data Class I HIGH HIGH IVIVC expected, if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlation yes Class II Low HiGH IVIVC expected, if dissolution rate, dose is very high yes Class III HIGH LOW Absorption (permeability) is rate determining and limited or no IVIVC with dissolution no Class IV LOW LOW Limited or no IVIVC is expected no

15. Table 1: BCS for Expected IVIVC for Immediate Release Drug Products Table 2: BCS for Extended Release Drug Products class solubility permeability IVIVC I A High and site independent High and site independent Level A expected I B High and site independent Rate is similar to in-vivo dissolution Dependent on site and narrow absorption window Level C expected II a Low and site independent High and site independent Level A expected II b Low and site independent Dependent on site and narrow absorption window Little or no IVIVC V a Acidic variable Variable Little or no IVIVC V b Basic Variable Variable IVIVC level A expected

16. IN-VITRO DISSOLUTION Drug absorption from a solid dosage form following oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilisation of the drug under physiological conditions and the permeability across the gastrointestinal tract. H owever, from the IVIVC standpoint, dissolution serves as a surrogate for drug bioavailability. D issolution Apparatus: Sr . No. Type of apparatus applications 1 Rotating Basket tablets 2 Rotating paddle Tablet, capsule, suspension, modified drug 3 Reciprocating cylinder Extended release products 4 Flow cell Drug products contains low water solubility 5 Paddle over disk Transdermal products 6 Cylinder over disk Transdermal products 7 Reciprocating disk Transdermal products

17. In-vivo absorption T he FDA requires in-vivo bioavailability studies to conducted for a new Drug Application (NDA). B ioavailability studies are normally performed in young healthy male ad ul t volunteers under some restrictive conditions such as fasting, non-smoking, and no intake of other medications. T he drug is usually given in a crossover fashion with a washout period of at least five half-lives. T he bioavailability study can be assessed via plasma or urine data. S everal approaches can be employed for determing the in-vivo absorption. W anger – Nelson, LooRiegelman and numerical deconvolution are such methods. W agner Nelson and looRiegeman are both model dependents in which the former is used for a one-compartment model and the latter is for multi-compartment system.

18. FACTORS AFFECTING IVIVC Before developing IVIVC some properties of the drug should be taken in to consideration, these properties are: S tereochemistry: due to the stereochemistry, one enantiomer may have more af f inity towards receptor than other. T his results in difference in pharmacokinetics and pharmacodynamics behaviour of two enantiomers of same drug. I n such condition dissolution data of the remate will not be useful for development of IVIVC. F irst pass affect: first pass effect decreases the systemic a availability of parent drug. T herfore the amount of drug reaching to systemic circulation will not match with amount of drug release in GIT. H ence use of plasma concentration data of parent drug will not be appropriate to ca lc ulate in-vitro drug release. I n such condition the the dissolution data of such drug will not be useful for the development of IVIVC. F ood effect: presence of food make may alter dissolution behaviour of drug and hence it becomes and important factor that should be considered in IVIVC development. P resence of food in stomach alters, pH, ionic, enzymes level, gastric emptying time, strength etc.

19. APPLICATIONS OF IVIVC IN DRUG DELIVERY IVIVC - Parenteral Drug Delivery IVIVC can developed and applied to parenteral dosage forms, such as controlled-release particulate systems, implants, liposomes, niosomes etc. That are either injected or implanted. T he current release research is focusing on shorting the time span of in-vitro release experiment with aim of providing quick reliable methods for assessing release. H owever there are relatively fewer successes in the development of IVIVC for such dosage forms, which could be due to several reasons like: B urst release P otent Drugs and Chronic Therapy

20. F ormulation Assessment: In-vitro Dissolution D issolution Specification E arly Stage of Drug Delivery Technology Development C ocept of Maping I n-vitro dissolution testing is important for: P roviding process control and quality assurance D eterming stable release characteristics of product over time F acilitating certain regulatory determinations O ral drug delivery is the major application of IVIVC .

21. CONCLUTION IVIVC is the link between in-vitro and in-vivo performance of the drug product. I t has wide application in drug delivery at various stages of development to setting dissolution specifications. T he most critical application of IVIVC with respect to cost savings due to the avoidance of expensive clinical trials. IVIVC includes in-vivo relevance to in-vitro dissolution specifications and can serve as surrogate for in-vivo bioavailability and to support biowaivers. I t can also assist in quality control for certain scale-up and post-approval changes. T herfore the activity in the area of IVIVC for oral extended release dosage forms has increased. T he FDA guidance on IVIVC provides general methods and guidelines for establishment of IVIVC .

22. References United States Pharmacopoeia . In-vivo Evaluations of Dosage Forms, Mack Publishing Co., Easton, PA., 2004. Kalaskar SG, Yadav AV , Patil VB. Invitro –In vivo correlation a ground discussion. Indian J. pharm. Educ . Res ., 2007; 41(4), 306.328. Devane J. and Butler J. The impact of in vitro-in vivo relationships on product development. Pharm . Tech. 1997;21(9) : 146.159.

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