In-Vitro-In-Vivo Correlation (IVIVC): A Tool In drug Development

1. In-Vitro-In-Vivo Correlation (IVIVC): A Tool In drug Development Mr. Somnath Sakore Cadila Pharmaceuticals Ltd

2. Outline Definition of IVIVC Purpose of IVIVC Levels of IVIVC In vitro data In vivo data IVIVC models IVIVC development Predictability IVIVC in drug development of extended release products Issues Factors to be consider for correlation development Conclusion

3. Definition of IVIVC United State Pharmacopoeia (USP) definition of IVIVC 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 of IVIVC An In-vitro in-vivo correlation (IVIVC) has been defined by the Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”. e.g., amount of drug absorbed, thus allowing an evaluation of the QC specifications, change in process, site, formulation and application for a biowaiver etc.

4. PURPOSE OF IVIVC Reduction of regulatory burden: IVIVC can be used as substitute for additional in vivo experiments, under certain conditions. Optimization of formulation : The optimization of formulations may require changes in the composition, manufacturing process, equipment, and batch sizes. In order to prove the validity of a new formulation, which is bioequivalent with a target formulation, a considerable amount of efforts is required to study bioequivalence (BE) /bioavailability (BA).

5. PURPOSE OF IVIVC IVIVC as surrogate for in vivo bioequivalence and to support biowaivers (Time and cost saving) The main purpose of an IVIVC model to utilize in vitro dissolution profiles as a surrogate for in vivo bioequivalence and to support biowaivers. Scale up post approval changes (Time and cost saving during product development): validated IVIVC is also serves as justification for a biowaivers in filings of a Level 3 (or Type II in Europe) variation, either during scale-up or post approval, as well as for line extensions (e.g., different dosage strengths) Less testing in Human

6. Levels of IVIVC Level B Level A Level C Level A Level A – point-point; first deconvolution to get in vivo %drug absorbed, then compare with %dissolved Level B – Statistical moments; MRT or MDT in vivo vs. MDT in vitro Level C – single point; PK parameter vs. %dissolved Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv.

7. FACTORS TO BE CONSIDER IN DEVELOPING A CORRELATION 1. Biopharmaceutics Classification System (BCS) BCS guidelines are provided by USFDA, WHO, and EMEA Class I: HIGH solubility / High permeability, Class II: LOW solubility / High permeability, Class III: HIGH solubility / LOW permeability Class IV: LOW solubility / LOW permeability BCS Criteria • highly soluble drugs: therapeutic dose is soluble in 250 mL (pH 1 – 7.5) • highly permeable drugs: extent of absorption: > 90% •(rapidly dissolving: no less than 85% within 30 min, USP II / 50 rpm /pH 1 - 6.8 ; always considered similar if 85% released in less than 15 min)

8. Biopharmaceutics Classification System

9. Generation of In-Vitro Release Profile • USP apparatus 1 (basket, 100 rpm) or 2 (paddle, 50&75 rpm) • Aqueous dissolution medium, 900 ml • pH 1-1.5, 4-4.5, 6-6.5 & 7-7.5 at 370C • A surfactant may be required (For low solubility drugs) • In-vitro food effect • Rotating dialysis cell method • Effects of oils, enzymes and pH

10. 2. In vitro dissolution: • Compendial method (justify other method) • The dissolution profiles of at least 12 individual dosage units • from each lot should be determined • aqueous medium, n ≥ 12 (!), CV < 10% • difference factor f1, similarity factor f2

11. f1 values up to 15 (0-15) f2 values greater than 50 (50-100) n : number of time points, Rt : dissolution value of the reference batch at time t, Tt is the dissolution value of the test batch at time t Comparison between dissolution profiles could be achieved using a difference factor (f1) and a similarity factor (f2)

12. 3. In vivo absorption (Bioavailability studies) • Number of subjects : 6 to 36. • Crossover studies are preferred • formulations with different release rates • same moiety as measured in vitro • Washout period of at least five half-lives. • BA assessed from Plasma or urine data • AUC, Cmax, Tmax • In vivo absorption- Wagner-Nelson, Loo-Riegelman, and numerical convolution methods.

13. Generation of In-Vivo Release Profile • Compartmental Models • Wagner-Nelson • Loo-Riegelman • Linear Systems Models • Deconvolution • Convolution • Mathematically they all yield the same result

14. First step: Calculation of in vivo release profiles from plasma concentrations of an oral solution and different formulations

15. Second step: Comparison of calculated in vivo release with in vitro release data for the same formulations and establishment of a quantitative correlation model using a linear or non-linear regression

16. IVIVC MODELS

17. IVIVCDEVELOPMENT

18. IVIVC in the product development process for extended-release products J.Emami, J Pharm Pharmaceut Sci (www.cspscanada.org) 9(2):169-189, 2006

19. IVIVC Model Predictability (Validation) For Cmax: For AUC: • Acceptance criteria: According to FDA guidance • ≤15% for absolute prediction error (%P.E.) of each formulation. • ≤ 10% for mean absolute prediction error (%P.E.)

20. IVIVC Bench Issues (Practical issues) • Reliable and biorelevant dissolution method and apparatus suitability • Qualification and calibration of equipment, sink conditions • Ability to discriminate non-BE lots • Apparatus and media for continuous IVIVC (minimum 3 lots) and tuning with GI conditions • Accurate deconvolution of the plasma concentration-time profile • e.g., %absorbed in-vivo may be reflective of processes other than release; absorption rate limitation is common for CR products • Dissolution Specifications • Based on biological findings rather than pharmacopeial or mechanistic

21. IVIVC Modeling Issues • Intra- and Inter-subject variation • High variations can distort the mean data and in turn the deconvolution • Enterohepatic recycling or second peak • Reproducibility of reference profiles • Modeling • Smoothness of input and response functions • Jumps in input rate functions, e.g., delayed release or gastric emptying • Statistical properties of the models

22. Conclusions The pharmaceutical industry has been striving to find a ways to saving precious resources in relevance to the budgets and increasing cost of drug development. IVIVC is a tool applied in various areas and stages of drug development to find a place in the regulatory bodies around the world. Biorelevant and reliable dissolution profiles can predict the in-vivo absorption of drugs from CR formulations. Batches with similar dissolution will be BE and dissimilar dissolution will be non-BE Several methods exist for estimating in-vivo absorption Level A (point-to-point) or B (mean dissolution times) correlation can be obtained for BCS class 1 or 2 drugs At least 3 lots (desirable, fast and slow) must be established with IVIVC and proper reference.

23. IVIVC is useful in SUPAC and biowaivers can save substantial costs and time when registering product changes Both practical and modeling issues must be addressed need to develop methodologies and standards for non-oral delivery systems, to develop more meaningful dissolution and permeation methods.   Conclusions

24. THANKS…!!!