IVIVC Methods and Applications in MR Product Development

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1 IVIVC Methods and Applications in MR Product Development H. Rettig LLC

2 Purpose of IVIVC and BCS Reduction of regulatory burden: IVIVC in lieu of additional in vivo experiments, leading to Time/Cost savings during product development Scale-up, post approval changes Biowaiver Enhanced significance of in vitro testing Justification for therapeutic product quality therapeutically meaningful release specifications (Less testing in humans)

3 Outline Definitions (IVIVC, BCS) Mathematical Procedure Applications

4 In Vitro-In Vivo Correlation (IVIVC) Working Definition: A predictive mathematical treatment describing the relationship between an in vitro property of a dosage form (usually the rate or extent of drug release) and a relevant in vivo response (e.g. plasma drug concentrations or amount of drug absorbed).

5 Categories of In Vitro-In Vivo Correlations Level A Level B Level C functional relationship between in vitro dissolution and the in vivo input rate, correlation of profiles, linear or non-linear relationship correlation based on statistical moment analysis (in vitro dissolution time is correlated with mean residence time) single point relationship between one dissolution parameter, (e.g. T50%, % dissolved in 4h) and one pharmacokinetic parameter (e.g. AUC, C max ) (Level D: multiple point relationship)

6 Biopharmaceutics Classification System Class Solubility Permeability IVIVC Expectations 1 High High IVIVC posible if dissolution rate (DR) is slower than gastric emptying rate. Otherwise limited or no IVIVC. 2 Low High IVIVC expected if in vitro DR is similar to in vivo DR. 3 High Low Absorption (permeability) is rate determining, therefore limited IVIVC with DR to be expected. 4 Low Low Limited or no IVIVC expected.

7 BCS Criteria highly soluble drugs: therapeutic dose is soluble in 250 ml (ph 1 7.5) highly permeable drugs: extent of absorption: > 90% P > 2 x eff, ph6.5: 10-4 cm/sec in human jejunum P > 1 x app: 10-5 cm/sec in Caco-2 cells (rapidly dissolving: no less than 85% within 30 min, USP II / 50 rpm /ph ; always considered similar if 85% released in less than 15 min)

8 The IVIVC methodology is described in Guidances (as opposed to Guidelines) and addresses which product change can be filed with an IVIVC the quality of the raw data which are needed for the generation of an IVIVC how the IVIVC model can/should be developed the acceptable prediction error when applying the IVIVC (validation criteria)

9 Drug or Product Requirements for an IVIVC Does a correlation make medical or scientific sense? Caution, if narrow therapeutic range Linear pharmacokinetics Preferably BCS I or II

10 Data Requirements In vitro data data from batches tested in vivo compendial method (justify other method) aqueous medium, n 12 (!), CV < 10% profiles of test products of the same type curve (difference factor f1, similarity factor f2)

11 Data Requirements In vivo data data from study in humans, n 6, fasted cross-over design formulations with different release rates reference formulation (solution, i.v. bolus) same moiety as measured in vitro (biobatch)

12 Starting point: In Vitro and In Vivo Data In vitro dissolution profile Plasma concentrations % rele ase d Cp (ng/ml) Time (h) Time (h)

13 Level A Correlation It is not possible to directly correlate an in vitro dissolution curve with an in vivo plasma concentration profile. Therefore, Two-step procedure: 1. Retrospective calculation of in vivo dissolution from in vivo response (plasma concentrations) 2. Quantitative correlation between in vitro and in vivo release profiles

14 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-independant based on Theory of Linear System Analysis (Convolution / Deconvolution)

15 First step: Calculation of in vivo release profiles from plasma concentrations of an oral solution and different formulations 100 Plasma concentrations: Oral solution and three formulations 100 In vivo release profiles Cp (ng/ml) % released Time (h) Time (h)

16 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 100 In vitro vs. in vivo release IVIVC Model: Regression line: Y = 0.97X % released 50 Vivo (%) Time (h) Vitro (%)

17 Evaluation of Predictability of IVIVC Estimation of the magnitude of the error in predicting the bioavailability from in vitro dissolution data Different approaches are acceptable: Internal predictability (with the formulations used for the development of IVIVC) External predictability (with the formulations not used for the development of IVIVC)

18 Metrics to Evaluate Predictability of IVIVC Percent prediction error (%PE): For C max : {[C max(obs) C max(pred) ]/ C max(obs) }*100 For AUC: {[AUC (obs) AUC (pred) ]/AUC (obs) }*100 Acceptance Criteria: 15% for absolute prediction error (%PE) of each formulation 10% for mean absolute prediction error (%PE)

19 Limitation of the Predictability Metrics Metrics used to evaluate the predictability is described simply as the prediction error (%PE) for C max and AUC, i.e. predicted plasma profiles are reduced to only two PK parameters C max predicted with the IVIVC model represents the maximum of the mean plasma profile - but is compared with the mean C max observed calculated as the average of individual profiles (at different T max!) T max is not included in predictability metrics

20 Weakness of the Predictability Metrics C max predicted ~ C max observed, but T max different 600 Mean plasma profiles Predicted with IVIVC Cp (ng/ml) Observed in vivo Time (h)

21 Main Applications of the IVIVC in Product Development Evidence for biorelevant and/or discriminating dissolution method Basis for biorelevant in vitro release specifications Justification for a biowaiver - Wider than standard (±10%) in vitro release specifications - Level 3 or Type II modification of the registered product - Line extensions (intermediate or lower strength)

22 Benefit from an IVIVC for the Registration of New Products Modified release products: justification of release specifications Justification for discriminating in vitro test method Modifications made during Scale-up (basis for biowaiver) Line extensions (e.g. intermediate strength) (Anticipation of later product changes)

23 Registration of Changes for Existing Products where a Robust IVIVC can Substitute a Bioequivalence Study Level 3 Changes (U.S.) [SUPAC] Type II Variations (European Union) (Line extensions (bracketing principle)) Exceptions exist, e.g. narrow therapeutic range drugs, nonlinear pharmacokinetics, etc.

24 Specification Setting for Modified Release Products (EMEA) Three points (20-30%, around 50%, more than 80%) Specifications must be met during shelf-life of product No IVIVC: Justify that side-batches are bioequivalent difference upper / lower limit: up to 20% IVIVC established: Predicted profiles from upper and lower release limits are in 20% range of AUC

25 Application / Request for a Biowaiver Phase Preclin. I II III IV (marketed) New Active Compound Classification according to BCS: Solubility in the ph range Assessment of permeability If dissolution rate determining for absorption: Initial development of IVIVC from first in vivo data (Inclusion of rapid formulation in study for use as weighting function) IVIVC study with final formulation Justification for discriminating dissolution method IVIVC as base for biorelevant release specification setting IVIVC as justification for biowaiver if formulation has to undergo Type II modification IVIVC as justification for a biowaiver 1. of additional strengths or line extensions 2. of Type II modifications Already Registered Compound If additional extended release form from registered normal product (or IVIVC exists already for normal formulation) Dissolution profiles in ph range Development of IVIVC from in vivo data from at least two ER formulations (as well as IR formulation or solution) If imitator product (generic): IVIVC study with 2 formulations as well as reference product and solution (weighting function) Justification for discriminating dissolution method IVIVC as base for biorelevant release specification setting IVIVC as justification for biowaiver if formulation has to undergo Type II modification IVIVC as justification for a biowaiver 1. of additional strengths or line extensions 2. of Type II modifications

26 Example: In vitro Release of ER Tablets 100 Product A ER Tablets 500mg Mean in vitro release profiles (n=12) 80 % Released "fast" standard "slow " Time (h)

27 Example: In Vivo Data ER and IR 1000 Product A ER Tablets 500mg Mean plasma concentration profiles (n=15) Cp (ng/ml) immediate release "fast" "standard" "slow " Time (h)

28 Calculated in vivo Release 120 Product A ER Tablets 500mg In vivo release profiles 100 % Released "fast" "standard" "slow " Time (h)

29 IVIVC / Nonlinear Regression 100 Product A ER Tablets 500mg IVIVC Model % Released in vivo (Y) "fast" "standard" "slow " curvelinear regression % Released in vitro (X)

30 Calculated Bioequivalent Side Batches 100 Product A ER 500 mg Side Batches In vitro release profiles 80 % Released upper limit "standard" low er limit Time (h) 16 24

31 Predicted in vivo Profiles 1000 Product A ER 500 mg Side Batches Mean plasma concentration profiles Cp (ng/ml) upper limit predicted "standard" observed low er limit predicted Time (h)

32 Validation Ratios for Side Batches Relative Bioavailability PK-parameters Predicted UL Predicted LL Observed Standard UL/LL UL/Standard LL/Standard Cmax AUC(0-24h)

33 The Regulatory Framework for the IVIVC (FDA) Scale up and Post Approval Changes-Immediate Release (SUPAC-IR), November, 1995 Scale up and Post Approval Changes-Modified Release (SUPAC-MR), June, 1996 FDA Guidance for Industry: Dissolution Testing of Immediate Release Solid Dosage Forms, August, 1997 FDA Guidance for Industry: Development, Evaluation and Application of In vitro-in vivo Correlations for Extended Release Solid Oral Dosage Forms, September, 1997 FDA Guidance for Industry: Biowaiver for IR Oral Forms Based on BCS, August, 2000 FDA Guidance for Industry: BA and BE Studies for Orally Administered Drug Products, October 2000

34 Regulatory Framework for the IVIVC (EMEA) Note for Guidance on Modified Release Dosage Forms: A. Oral Dosage Forms, B: Transdermal Dosage Forms, Section I (Quality) (CPMP/QWP/604/96), July 1999 Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/ QWP/ 1401/98), July, 2001 Variations to Marketing Authorizations (EC 1084/ June )

35 Summary IVIVCs cannot be generated for all drugs or formulations. But if the criteria are met, they are accepted by the authorities in USA and EU, Japan will probably also accept them as part of the ICH IVIVC is a credible tool to select the discriminating in vitro test conditions and to set therapeutically meaningful in vitro release specifications Applied correctly, the IVIVC can save substantial costs and time when registering product changes (biowaiver!)

36 Summary (cont d) Essential data (needed for a later IVIVC) ought to be generated in the regular development path of a compound. Following the BCS is helpful in this regard Deconvolution/Convolution mathematics are more widely applicable for an IVIVC than methods based on PK models It is advantageous to discuss the plan for filing an IVIVC - supported product change with the health authorities

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