Application of IVIVCs in Formulation Development Douglas F Smith

Transcription

1 Application of IVIVCs in Formulation Development Douglas F Smith PQRI Workshop on Application of IVIVC in Formulation Development September 5-6, 2012 Bethesda, Maryland

2 In Vitro/In Vivo Correlations - Goals Establish a correlation between in vitro drug dissolution and in vivo drug absorption Develop a model that can accurately predict bioavailability characteristics for a drug product based on dissolution profile characteristics

3 Applications of IVIVC Understanding key formulation variable(s) Biowaivers for changes in drug product Lower strengths New strengths Changes in components and/or composition (within SUPAC guidelines) - Release rate controlling - Non-release rate controlling Changes in manufacturing site, process and/or equipment (within SUPAC guidelines) Setting dissolution specifications Justification of limits other than +/-10%

4 Development of IVIVC In vitro release (Dissolution at multiple ph and agitations) Administration to healthy volunteers (Crossover design) Design of MR Formulations IVIVC Deconvolution (Absorption)

5 Practical Application: In Vivo and In Vitro Data Required In Vivo Data Bioavailability Studies At least 2 test formulations with different release rates (3 or more recommended) Solution, immediate release, or IV reference (unit impulse response) Crossover studies in fasted subjects Parallel studies acceptable (common treatment across studies) In Vitro Data Dissolution Studies Test formulations should exhibit at least 10% difference in dissolution USP apparatus I 100 rpm) or II 50 rpm) preferred Adjust dissolution conditions to fit in vivo data/obtain proper discrimination If dissolution is faster or slower than in vivo absorption, adjust the time scale

6 Case Study 1 BCS Class III Drug Fraction absorbed approximately 80% Reformulation of a currently marketed modified release formulation IVIVC desired to support site change for manufacture of reformulated drug product

7 Plasma Concentrations Following Oral Administration 5 4 Formulation B (Fast Release) Formulation A (Slow Release) Formulation C (Medium Release) Market Product Reference IR Reference [Drug] (ng/ml) Time (Hours)

8 Dissolution and Absorption Profiles Water as Dissolution Medium Drug Dissolution Drug Absorption Cumulative Percent Label Claim Dissolved Slow Release Medium Release Fast Release Cumulative Relative Percent Absorbed Slow Release Medium Release Fast Release Time (Hours) Time (Hours)

9 IVIVC Model Water as Dissolution Medium Cumulative Percent Absorbed Slow Release Formulation Medium Release Formulation Fast Release Formulation Slow and Fast IVIVC R 2 = Cumulative Percent Dissolved

10 IVIVC Validation Internal Validation Predict plasma concentration-time profiles, C max and AUC values using in vitro dissolution data for the formulations that were used to develop the IVIVC Average absolute percent prediction error (%PE) of 10% or less for C max and AUC and no individual %PE of individual formulation more than 15% validates IVIVC External Validation Predict plasma concentration-time profiles, C max and AUC values using in vitro dissolution data for a formulation that was not used in the development of IVIVC %PE of 10% or less for C max and AUC validates IVIVC Proof of external validation provides greater confidence in IVIVC than internal validation

11 Level A IVIVC Validation Water as Dissolution Medium Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Slow Release Fast Release Average %PE 4.84 Average %PE 13.7 External Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Medium Release AUC units: ng-hr/ml, C max units: ng/ml

12 Dissolution and Absorption Profiles - Acetate Buffer as Dissolution Medium Drug Dissolution Drug Absorption Cumulative Percent Label Claim Dissolved Slow Release Medium Release Fast Release Cumulative Relative Percent Absorbed Slow Release Medium Release Fast Release Time (Hours) Time (Hours)

13 IVIVC Model Acetate Buffer as Dissolution Medium Cumulative Percent Absorbed Slow Release Formulation Medium Release Formulation Fast Release Formulation Slow and Fast IVIVC R 2 = Cumulative Percent Dissolved

14 Level A IVIVC Validation Acetate Buffer as Dissolution Medium Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Slow Release Fast Release Average %PE 4.69 Average %PE 5.93 External Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Medium Release AUC units: ng-hr/ml, C max units: ng/ml

15 Dissolution of Target Formulation Acetate Buffer as Dissolution Medium 100 Cumulative Percent Label Claim Dissolved Medium Release Formulation Target Release Formulation Candidate Target Release Formulation Time (Hours)

16 Plasma Concentrations Following Oral Tablet Administration 5 4 Observed Levels for Target Formulation Observed Levels for Market Product Reference [Drug] (ng/ml) Time (Hours)

17 Level A IVIVC Validation Acetate Buffer as Dissolution Medium Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Slow Release Fast Release Average %PE 4.69 Average %PE 5.93 External Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Medium Release Target Release AUC units: ng-hr/ml, C max units: ng/ml

18 Setting of Dissolution Specifications Dissolution at Release Dissolution at Release (%) and After 3 Months (%) Time (Hr) Mean -10% +10% -3 SD +3 SD Mean - 3SD +3 SD Simulated Bioavailability Parameters Parameter Mean -10% +10% -3 SD +3 SD Mean - 3SD +3 SD AUC % Diff from Mean % Diff Low to High Cmax % Diff from Mean % Diff Low to High

19 Case Study 2 BCS Class II Drug Highly variable pharmacokinetics AUC and Cmax dependent upon input rate Reformulation of generic formulation to IR reference drug products at three dose levels Controlled release required to achieve bioequivalence to reference drug product IVIVC desired to support change in tablet coating and change in site of manufacture

20 Mean Plasma Concentration-Time Profiles Following Administration of Low Dose Reformulation Candidates 1400 [MPA] (pg/ml) % Polymer 4.5% Polymer 5.25% Polymer 6.25% Polymer 6.5% Polymer 7.0% Polymer 0% Polymer Reference Time (Hours)

21 Dissolution of Low Dose Reformulation Candidates by QC Release Method (USP Monograph) 100 Cumulative Percent Label Claim Dissolved % Polymer 5.25% Polymer 6.25% Polymer 6.5% Polymer 7.0% Polymer 8.0% Polymer Time (Minutes)

22 % Polymer Prediction Model to Achieve Bioequivalence for Low Dose Formulations 2.5 % Polymer vs C max Ratio R 2 = C max and AUC Geometric Mean Ratios Maximum GMR for C max % Polymer vs AUC Ratio R 2 = % Polymer = 6.40 Minimum GMR for AUC % Polymer = % Polymer

23 Mean Dissolution and Absorption Profiles of Drug From Low Dose Formulation Candidates Dissolution Absorption Cumulative Percent Label Claim Dissolved % Polymer 5.25% Polymer 4.5% Polymer 6.25% Polymer 6.5% Polymer 7% Polymer Cumulative Relative Percent Absorbed % Polymer 5.25% Polymer 4.5% Polymer 6.25% Polymer 6.5% Polymer 7% Polymer Time (Hours) Time (Hours)

24 Absorption Versus Dissolution Relationship for Drug From Low Dose Reformulation Candidates % Polymer 5.25% Polymer 6.25%% Polymer 6.5% Polymer 7% Polymer 8% Polymer IVIVC Model R 2 = Absorption Dissolution

25 Internal and External Predictability Measures of the Level A IVIVC for Drug from Low Dose Formulation Candidates Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE 8.0% Polymer 7.0% Polymer 4.5% Polymer 5.25% Polymer 6.25% Polymer 6.5% Polymer Average % PE 4.06 Average % PE 5.36 External Predictability AUC units: pg-hr/ml, C max units: pg/ml

26 Dissolution Specifications For Low Dose Formuation Dissolution IVIVC Based Absence of IVIVC Time (Hr) Mean Lower Upper Lower Upper NLT 73 NLT 72 Parameter Simulated Bioavailability Parameters AUC % Diff from Mean -- 12% 10% 14% 11% % Diff Lower to Upper -- 20% 22% Cmax % Diff from Mean -- 8% 12% 9% 13% % Diff Lower to Upper -- 18% 20%

27 Dissolution Specifications For Low Dose Formuation Dissolution FDA Proposed Wyeth Proposed Time (Hr) Mean Lower Upper Lower Upper NLT 80 NLT 73 Parameter Simulated Bioavailability Parameters AUC % Diff from Mean -- 10% 10% 12% 8% % Diff Lower to Upper -- 18% 18% Cmax % Diff from Mean -- 6% 14% 3% 19% % Diff Lower to Upper -- 17% 19%

28 Controlled Release Formulation IR or MR? PK and PD profile is that of an IR drug product Clinical safety and efficacy profile is that of an IR drug product Product does not meet requirements of MR dosage formulation No reduction in dosing frequency No reduction in plasma concentration fluctuations No modified release characteristics exhibited in plasma concentration-time profile Are changes to formulation subject to SUPAC-IR guidance or SUPAC-MR guidance?

29 % Polymer Prediction Model to Achieve Bioequivalence for Medium Dose Formulations 2.0 C max Ratios BA Study 1.8 AUC Ratios BA Study C max Ratios BE Study AUC Ratios BE Study C max and AUC Geometric Mean Ratios Maximum GMR for C max % Polymer = Minimum GMR for AUC % Polymer = % Polymer

30 % Polymer Prediction Model to Achieve Bioequivalence for High Dose Formulations 1.8 C max and AUC Geometric Mean Ratios % Polymer = 2.89 % Polymer = 3.95 C max Ratios BA Study AUC Ratios BA Study C max Ratios BE Study AUC Ratios BE Study Maximum GMR for C max Minimum GMR for AUC % Polymer

31 Case Study 3 BCS Class I Drug Development of MR dosage for an existing IR market product Initial IVIVC developed with data from slow, medium and fast release formulations Small scale batches Lowest strength to be marketed IVIVC desired to support change in process parameters and change in site of manufacture

32 In vitro release and in vivo absorption profiles from 75 mg Formulations Dissolution Absorption Cumulative Percent Label Claim Dissolved Slow Release Medium Release Fast Release Dissolution Conditions: - USP I (baskets) rpm - 0.9L Water - 37 o C Cumulative Percent Absorbed Slow Release Medium Release Fast Release Time (Hours) Time (Hours)

33 In Vitro / In Vivo Relationship for 75mg Capsules 100 Slow Release Medium Release Fast Release Linear Regression R 2 = Cumulative Percent Absorbed Cumulative Percent Dissolved

34 Internal and External Predictability Measures of the Level A IVIVC Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE Slow Release Medium Release Fast Release Average % PE 4.74 Average % PE 12.5 External Predictability 2x75mg x150mg AUC units: mcg-hr/ml, C max units: mcg/ml

35 Demonstration of in vitro release independence of dissolution test conditions Dissolution tests for 75mg and 150mg formulations USP I (baskets) and USP II (paddles) at 50, 75 and 100 rpm Dissolution media of water, SGF (without enzymes) and SIF (without enzymes All dissolution profiles similar to reference profile (USP I, 100 rpm, water) - f 2 > 65 Dissolution tests for 225mg formulations USP I (baskets) at 100 rpm Dissolution media of water, SGF (without enzymes), buffers at ph 4.5, 6.8 and 7.4 All dissolution profiles similar to reference profile (USP I, 100 rpm, water) - f 2 > 78

36 In Vitro / In Vivo Relationship for 75mg and 150mg Formulations Study 1 75 mg US Mfg Study 1 75 mg PR Mfg Study mg PR Mfg Study 2 75 mg US Mfg Study mg PR Mfg IVIVC Model R 2 = Cumulative Percent Absorbed Cumulative Percent Dissolved

37 Internal Predictability Measures of the Level A IVIVC Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE 2x75mg Study 2 1x150mg Study 2 2x75mg Study 1 1x150mg Study 1 2x75mg Study Average % PE 4.16 Average % PE 7.61 AUC units: mcg-hr/ml, C max units: mcg/ml

38 Case Study 4 BCS Class III Drug Fraction absorbed approximately 80% Development of MR dosage for which no IR market product Multiple strengths developed to achieve same in vitro dissolution release profile 50mg 70% HPMC 75mg 57% HPMC 100mg 50% HPMC 200mg 30% HPMC IVIVC desired to support development of other strengths

39 MR Tablet Dissolution Profiles in 0.9% NaCl 100 Cumulative Percent Label Claim Dissolved mg 100 mg 200 mg Time (Hours)

40 50 mg MR Tablet Dissolution Profiles in Alternate Media 100 Cumulative Percent Label Claim Dissolved % NaCl - Reference Media Water, f 2 = N HCl (ph 1.0), f 2 = N HCl / 0.2M Phosphate (Two-Stage), f 2 = M Acetate (ph 4.5), f 2 = M Phosphate (ph 6.8), f 2 = Time (Hours)

41 200 mg MR Tablet Dissolution Profiles in Alternate Media 100 Cumulative Percent Label Claim Dissolved % NaCl - Reference Media Water, f 2 = N HCl (ph 1.0), f 2 = N HCl / 0.2M Phosphate (Two-Stage), f 2 = M Acetate (ph 4.5), f 2 = M Phosphate (ph 6.8), f 2 = Time (Hours)

42 MR Tablets Absorption Profiles 100 Cumulative Percent Label Claim Absorbed mg 100 mg 200 mg Time (Hours)

43 In Vitro / In Vivo Relationship for MR Tablets Cumulative Percent Absorbed mg 100 mg 200 mg Linear Regression R 2 = Cumulative Percent Dissolved

44 Validation of Level A IVIVC for MR Tablets Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE 2x50 mg x100 mg x200 mg Average % PE 8.88 Average % PE 2.05 External Predictability 2x75 mg AUC units: mcg-hr/ml, C max units: mcg/ml

45 Approaches to a Level A IVIVC Traditional Approach Non-traditional Approach % absorbed Vs % dissolved mg absorbed Vs mg dissolved One strength Multiple strengths Multiple formulations with different levels of rate-controlling parameter Multiple formulations with different levels of rate-controlling parameter Differences among formulations in both % and mg released profiles Differences among formulations only in mg released profiles Point to point relationship between in vitro dissolution (%) and in vivo dissolution (%) Point to point relationship between in vitro dissolution (mg) and in vivo dissolution (mg)

46 FDA Guidance on Development, Evaluation and Application of IVIVCs Traditional Approach Level A Correlation is.... comparison of fraction of drug absorbed to the fraction of drug dissolved release rates, as measured by percent dissolved, for each formulation studied, should differ adequately (e.g., 10%) most commonly seen processes Non-traditional Approach Alternative approaches to developing Level A IVIVCs are possible Whatever the method used to establish a Level A IVIVC, the model should predict the entire in vivo time course from the in vitro data. In this context, the model refers to the relationship between in vitro dissolution of an ER dosage form and an in vivo response such as plasma drug concentration or amount of drug absorbed Release rate: Amount of drug released per unit time as defined by in vitro or in vivo testing

47 MR Tablet Dissolution Profiles (Cumulative % Dissolved in 0.9% NaCl) 100 Cumulative Percent Label Claim Dissolved mg 100 mg 200 mg Time (Hours)

48 MR Tablet Dissolution Profiles (Cumulative mg Dissolved in 0.9% NaCl) mg (70% HPMC) 100 mg (50% HPMC) 200 mg (30% HPMC) Cumulative mg Label Claim Dissolved Time (Hours)

49 MR Tablets Absorption Profiles (Cumulative % Absorbed) 100 Cumulative Percent Label Claim Absorbed mg 100 mg 200 mg Time (Hours)

50 MR Tablet Absorption Profiles (Cumulative mg Absorbed) mg (70% HPMC) 100 mg (50% HPMC) 200 mg (30% HPMC) Cumulative mg Label Claim Absorbed Time (Hours)

51 In Vitro / In Vivo Relationship for MR Tablets mg 100 mg 200 mg Linear Regression R 2 = Cumulative mg Absorbed Cumulative mg Dissolved

52 Validation of Level A IVIVC for MR Tablets Internal Predictability Formula Obs AUC Pred AUC %PE Obs C max Pred C max %PE 2x50 mg x100 mg x200 mg Average % PE 8.19 Average % PE 2.35 External Predictability 2x75 mg AUC units: mcg-hr/ml, C max units: mcg/ml

53 INTERNAL AND EXTERNAL PREDICTABILITY MEASURES OF LEVEL A IVIVC FOR 200 mg MR TABLETS Batch 15% HPMC Roller Compact MFG Site A 30% HPMC Roller Compact MFG Site A Batch 30% HPMC Wet Granulation MFG Site B Observed AUC Predicted AUC Intern al Predictability Absolute % PE Observed Cmax Predicted Cmax Absolute % PE Observed AUC Average % PE 2.57 Averag e % PE 3.51 Predicted AUC External Predictability Absolute % PE Observed Cmax Predicted Cmax Absolute % PE AUC units: ng hr/ml; Cmax units: ng/ml

54 Evaluation of Dissolution Specifications Time Point Statistical Limits 95% Chance of Passing L1 Statistical Limits 99% Chance of Passing L1 Limits Based on IVIVC 2 hours NMT 33% NMT 34% 17 37% 4 hours 33 50% 32 51% 32 52% 8 hours 50 73% 50 75% 52 72% 12 hours 63 95% 63 95% 69 89% 24 hours NLT 83% NLT 82% NLT 87%

55 Case Study 5 BCS Class I Drug Development of IVIVC for Marketed MR Product Change in process Multiple strengths manufactured and exhibit same in vitro dissolution release profile Retrospective analysis of data available from 7 BA studies Drug has significant first-pass metabolism Data from intubation study indicated increase in systemic availability in distal GI Correlation model developed using dissolution data directly as input First derivative of Weibull Function

56 Model Parameters of Dissolution Data

57 Model of Fraction of Drug Absorbed

58 Validation of the Model

59 Validation of the Model

60 Dissolution of Drug

61 Conclusions-Benefits of IVIVC Provides framework for formulation development Promotes prioritization of formulation efforts toward compounds with bioavailability problems and improves communication across disciplines Places development of biorelevant dissolution method formally into development process Defines manufacturing parameters at an early stage in the development process and facilitates early transfer of formulation to manufacturing site Reduces the risk of requiring Phase III to market BE studies

62 IVIVCs Lessons Learned FDA guidance is just that, not a regulation or requirement, but it is in the best interest of sponsor to evaluate feasibility Terminology in the guidance indicates sponsors are allowed some flexibility in developing IVIVCs Collaboration among various functional groups a necessity (formulations, analytical, clinical, regulatory, biopharmaceutics) Timing Developing IVIVCs is not a science, it is an art.

63 Acknowledgements Pharmaceutical Sciences Robin Enever Technical Services Stephen White Mike Dey John Pendregast Richard DeNeale Biopharmaceutics Sridhar Duvvuri Clinical Phil Mayer William McKeand Formulations Alice Nichols Ron Warner Steven Troy John Michelucci Deborah Sherman Regulatory David Korman John Clark James Murphy Shaleish Singh Simon Golec Chris Diorio Beth Kendsersky Ian Armstrong Chris Le Analytical Services Andy Beath Lusan Yao Patricia Mann Brian Spencer Marijo Weinzierl Quality Operations Joe DeVito David Sheats Deborah Parker Consultants Lewis Leeson Scott Stevens William Barr William Jock Mario Gonzalez