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Four Levels of In-Vitro-In-Vivo Correlation

1) There are four levels of in vitro-in vivo correlations (IVIVC) ranging from Level A to Level D. Level A correlation involves point-to-point correlation of dissolution and absorption profiles and is most useful for regulatory purposes. Level B uses statistical moments, while Level C correlates single dissolution timepoints to pharmacokinetic parameters. 2) The document discusses a case study developing a Level A IVIVC for a prolonged-release hydrocodone formulation. Dissolution and pharmacokinetic profiles from clinical studies were used to establish a direct correlation between % dissolved and % absorbed using linear and nonlinear time scaling. 3) The Level A IVIVC showed good predictability of less than 10%

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FOUR LEVELS OF IVIVC AND THEIR EFFECTIVE IMPLEMENTATION TO DEVELOP QUALITY DRUGS Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core Committee Cadila Pharmaceuticals Ltd. Former Senior Clinical Reviewer, TPD (Canadian FDA) Presented at the IVIVC & BABE SUMMIT 2015 Holiday Inn, Mumbai, Nov. 23, 2015 1
CONTENT GUIDELINES  LEVEL A  Correlation of the entire in vitro and in-vivo profiles pertaining to regulatory relevance  LEVEL B  The principles of statistical moment analysis  LEVEL C  One or more PK parameters correlated with amount of drug dissolved at several time point of dissolution profile  LEVEL D  Semi quantitative; rank order correlation  Case study  Conclusion 2
UNDERSTANDING CORRELATION  Correlation:  Strength of associative relationship between two variables  Broad class of statistical relationships involving dependence 3
4 Four sets of data with the same correlation of 0.816
DEFINITION OF IVIVC  IVIVC is the predictive, mathematical models relating an in-vitro property such as dissolution 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. –US FDA  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. – USP 5Valid in-vitro and in-vivo methods valid IVIVC
CLASSIFICATION SYSTEM (BCS) & IVIVC EXPECTATIONS Amidon et al. (1995), Pharm Res, 12, 413-420 6
SYSTEMIC DRUG ABSORPTION: CARBAMAZEPINE CR 15 N STABLE ISOTOPE STUDY Wilding et al. Br J Clin Pharmac (1991), 32, 573-579 7
CUMULATIVE IN-VIVO ABSORPTION OF CBZ FROM THE OROS SYSTEM IN INDIVIDUAL SUBJECTS COMPARED WITH CUMULATIVE IN VITRO RELEASE Wilding et al. Br J Clin Pharmac (1991), 32, 573-579 8
BCS Class PK Data IVIVR API – Physicochemi- cal Properties Scale factor Dosage Form Properties Biorelevent Dissolution Computer Modeling Using Convolution including Transporters, PK Models, and PK Parameters, API properties or Drug Release Data IVIVC 1 2 3 GENERALAPPROACH TO DEVELOP IVIVC Wang et al (2009) Diss Tech, 8, 6-12 9
IVIVC CORRELATION LEVELS 1. Level A: highest level; point to point relationship between in-vitro dissolution rate and in-vivo input rate of the drug from the dosage form 2. Level B: uses statistical moments; MDTvitro of the product is compared to either MRT or MDTvivo 3. Level C: one dissolution time point (t50%, t90%..) is compared to one mean PK parameter (AUC, tmax or Cmax) 4. Multiple Level C: relates one or several PK parameters (AUC, Cmax ..) to the amount of drug dissolved in-vitro at several time points 5. Level D: is a rank order and qualitative analysis. 10
LEVEL A: POINT TO POINT CORRELATION  % Drug absorbed calculated by means of model dependent techniques such as Wagner-Nelson or Loo-Riegelman or by model-independent deconvolution  These techniques utilize all of the dissolution and plasma level data  Purpose of Level A corr. is to define a direct relationship such that measurement of in-vitro dissolution rate is a surrogate for in-vivo performance  change in manufacturing site, method of manufacture, raw material supplies, minor formulation modification, product strength using the same formulation can be justified  excellent quality control procedure since it is predictive of the dosage form’s in-vivo performance  Of highest regulatory value 11 Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.
LEVEL B: UTILIZING STATISTICAL MOVEMENT  As mentioned above, it uses statistical moments; MDTvitro of the product is compared to either MRT or MDTvivo  Level B correlation uses entire in-vitro & in-vivo data, yet it is not a point-to-point corr., since number of different in-vivo curves will produce similar MRT values  A level B correlation does not uniquely reflect the actual in-vivo plasma level curves  Alone is not enough to justify SUPAC, biowaiver etc. 12 Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.
LEVEL C: ONE DISSOLUTION PT. TO ONE PK PARAMETER  Level C relates one dissolution time point (t50%, t90%, etc.) to one mean PK param. e.g., AUC, tmax or Cmax  This is a weak level of correlation as only partial relationship between absorption and dissolution  Does not reflect the complete shape plasma-conc. time curve, defining performance of a drug in-vivo  In the early stages of formulation development Level C correlations can be useful when pilot formulations are being selected  Biowaiver is generally not possible 13 Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.
MULTIPLE LEVEL C  Relationship between Cmax, AUC, or any PK parameters and amount of drug dissolved at several time points of dissolution profile  It may be used to justify a biowaivers provided that the correlation has been established over the entire dissolution profile with one or more PK parameters  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  Level A is sometimes likely when multiple level C is achieved at each time point at the same parameter  thus effect on the in-vivo performance of any change in dissolution can be assessed 14 Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.
LEVEL D: RANK ORDER & QUALITATIVE  It is not a formal correlation but it is a semi quantitative (qualitative analysis) and rank order correlation  Not considered useful for regulatory purpose but can be serves as an aid in the development of a formulation or processing procedure 15 Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.
 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 Level A Level B Level ALevel C Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv. 16
OVERALL IVIVC DEVELOPMENT FOR MR FORMULATIONS For Market Retig et al. Diss Tech, Feb. 2008, 6-8 17
CASE STUDY TO DEVELOP A LEVEL A CORRELATION 18
THE PRODUCT  A new type of prolonged release Hydrocodone formulation based on Egalet® technology  Three tablet GMP batches (A to C) developed, all containing 20mg of Hydrocodone as tartrate salt.  They differed solely by the mass of the final tablet, corresponding to different diameters and lengths of the tablet (6, 7.5 or 9 mm, respectively) and adjusted by an increase of excipients’ mass  An IR tablet of 10 mg of Hydrocodone in combination with 325 mg of Paracetamol was also included in the clinical study as a reference and in order to perform deconvolution 19 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
DISSOLUTION STUDIES  Pharmacopoeial media: phosphate buffer pH 6.8; USP Apparatus 2 paddle method (Vankel VK7025 coupled to a Varian Cary 50 UV-visible spectrophotometer); dissolution vol: 1,000 mL; paddle speed: 50 rpm: temp.: 37 °C. 20 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
IN-VIVO BIOAVAILABILITY STUDIES  4-arm, single dose, randomized cross-over study comparing three test tablets to the reference  Plasma samples (0 - 42 hr) were measured by a validated HPLC- MS method  Cmax, Tmax & AUC were calculated, bioequivalence parameters under consideration were Cmax and AUC  Tmax was not analyzed as prolonged release formulation is involved  Absorption kinetics were calculated using a deconvolution technique using the IR reference tablet as response function  Deconvolution allows isolating the input (« absorption ») function as a function of the observed concentration for the studied tablet and for the IR reference tablet  This input function reflected the in-vivo release observed after administration of the PR test tablets  Simulations of the curves from the theoretic input were performed using convolution 21 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
IN-VIVO BIOAVAILABILITY STUDIES 22 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
IN-VIVO RELEASE & ABSORPTION OF 3 TABLETS 23 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
IVIVC  The clinical study was designed to support a level A correlation  In a linear correlation, the in-vitro dissolution and in-vivo input curves may be directly super-imposable or may be made to be super-imposable by the use of a scaling factor  e.g., if the dissolution is faster than the in vivo input rate then the two curves are not super-imposable  in this case a time scaling may be applied on the in vitro data for each %absorbed, the corresponding time in-vitro using a Levy’s plot  Model predictability was estimated internally by comparison of prediction errors on Cmax & AUC derived from mean observed and predicted in vivo data obtained by convolution  Regulatory guidelines state prediction errors for Cmax and AUC should not exceed 10 % as a mean and none greater than 15% 24
DISSOLUTION VS. IN-VIVO ABSORPTION 25 TIME SCALING: LEVY’S PLOT Hemmingsen PH et al. (2011). Pharmaceutics,3:73-87
IVIVC OF ALL FORMULATIONS USING A COMMON NON-LINEAR TIME SCALE 26 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
PREDICTABILITY BASED ON AUC AND CMAX 27 Based on IVIVC & in vitro data, input kinetics were back calculated and then, based on this input function, a convolution was performed to simulate the in vivo plasma concentration curve The predictability was good and in accordance with the FDA recommendation (5) with a mean error of −0.32% and −6.63% on Cmax and AUCinf, respectively, no case being greater than +10% Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
CALCULATION OF DISSOLUTION LIMITS One application of IVIVC is to predict bioavailability and to set dissolution limits. The residual error from ANOVA for Cmax and AUC and modelized absorption to a multi zero order absorption and a few more steps dissolution limits for bioequivalence. 28
IN-VIVO PREDICTION OF FORMULATION B TO ENSURE BIOEQUIVALENCE Based on the dissolution limits and on the modelization of the absorption, the in-vivo curves were simulated in three conditions corresponding to the modelized absorption 29 Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87
CONCLUSIONS  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  Level A (point-to-point) is most useful for regulatory purposes; multiple level C is also acceptable for regulatory purposes  At least 3 lots (desirable, fast and slow) must be established with IVIVC and proper reference  Time scaling and modeling of in-vitro & in-vivo parameters must be accurate and validated  Predictability should be high  IVIVC is useful in  QbD, SUPAC and biowaivers… 30
Thank You Very Much Acknowledge: Raji Nair 31