Application Strategy of PBPK for Generic Drugs and Its Current Challenges

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1 BUILD A PHARMACEUTICAL COMPANY Application Strategy of PBPK for Generic Drugs and Its Current Challenges Bo Liu June 18,

2 PuraCap Global Presence PuraCap Laboratories LLC, Kentucky PuraCap Pharmaceutical LLC. New Jersey EPIC New York PuraCap Caribe LLC., Peurto Rico HumanwellHealthcare Group Humanwell PuraCap Pharma, Wuhan,China Yichang Humanwell Pharma, Yichang,China We have 5 facilities which are US FDA inspected and ALL products are excellent quality for US/ EU markets

3 R&D ---Reaching Global Resource New Jersey Kentucky Puerto Rico Well Equipped R&D Labs & Research Institute New York 4 research centers globally to support our R&D projects Page 3 Wuhan, China Wuhan, China 3

4 Generic Drugs for US & EU Market Over 140 Generic Drugs in our portfolio Currently Own market FDA Approved ANDAs for US Filed another ANDAs & NDA under FDA review Other pipeline products includes NDA ANDAs & 4

5 Difference between Generic and New Drug Too many New uncertainties Drug Project Initiate Preclinical Phase Ⅰto Ⅲ Project Approve Post Launch Product Enhancement PBPK Project Initiate Product Development Exhibit Batches Absorption Generic Drug unknown 5 Pivotal BE/ Clinical Trial Product Approve Post Approve Change

6 Preparation for Applying PBPK in Generic Drug Development In vivo PBPK In vitro 6

7 Preparation for Applying PBPK in Generic Drug Development In vivo PBPK In vitro 7

8 Preparation for Applying PBPK in Generic Drug Development 8

9 PBPK Application Strategy RLD Formulation screen Prior BE study Post BE study 9

10 RLD and Formulation Screen Stage 10

11 Application of Virtual Bioequivalence- Safe Space Design Building The optimum values of the α and β Weibull parameters were estimated on the basis of the virtual trials ensuring BE (Cmax and AUC within % of the Target formulation) 11

12 Prior BE stage 12

13 Dissolution% In vitro Dissolution Profiles (USP 2) 100 Ibuprofen Salt Time (h) Ibuprofen Free Acid Ibuprofen Mechanistic In vitro Modelling USP 2 Paddle 75RPM 5 mm Phosphate buffer ph 6.7 Microclimate ph Model Particle radius estimated (PE) Lumped scalar (salts) (PE) DR(t) NS h D eff eff ( t) 4 a( t) a( t) h ( t) (S ( t) C ( t) ) eff surface bulk 13

14 Time course in hypothetical Effect Compartment was simulated. PD Endpoint Dental Pain Relief Score PBPK Virtual BE studies (fasted) crossover design IBU salt vs free form Mechanistic understanding and modelling Scientifically-based criteria for demonstrating therapeutic equivalence 14

15 Post BE stage 15

16 Post BE stage No commercial software is used in this case. Drug C BCS 2 drug Dose: 400 mg Acid Soft Capsule USP method In house method 16

17 Post BE stage PBPK simulation Item Ratio Geometric mean Confidence interval Prediction based on USP method (N=40) Prediction based on in house method (N=40) Observed value (N=33) Cmax (%) AUC (%) Cmax (%) AUC (%) Cmax (%) AUC (%) AUC ratio C max ratio 17

18 The effect of BE on the DDI 18

19 Plasma Concentration of KTZ ( mg/ml) Ketoconazole Time ( h ) Liu, B. et al. 2016, Biopharmaceutics & Drug Disposition 19 Volume 38 Issue

20 Plasma Concentration of KTZ (µg/ml) Ketoconazole A. KTZ 100 mg A. KTZ 100 mg B. KTZ 200 mg B. KTZ 200 mg C. KTZ 400 mg C. KTZ 400 mg Time (h) 20 Time (h)

21 Plasma Concentration of MDZ (µg/ml) Ketoconazole & Midazolam Time (h) 21 Time (h)

22 Pre. AUC ratio/ Obs. AUC ratio Pre. C max ratio/ Obs. C max ratio Ketoconazole & Midazolam A B C 0 A B C 22

23 Plasma Concentration of MDZ (ng/ml) Ketoconazole & Midazolam Time (h) [Relative to MDZ Administration] 23 Time (h) [Relative to MDZ Administration]

24 AUC ( ng/ml.h) AUC ( ng/ml.h) Ketoconazole & Midazolam A B C D E 0 A B C D E Observed Simcyp Default Simcyp Optimized 24 Observed Simcyp Default Simcyp Optimized

25 Desired State (ANDA) Paul Seo, 2015 Gpha Fall Techinical Conference 25

26 Final Goal for ANDA And by 26

27 Challenge and Opportunity 1. Knowledge preparation: in vitro, in vivo and in silico. 2. Develop effective bio-relevant dissolution method rather than use the USP method (In house method) 3. Pay the attention to the input data (Data Quality) 4. Using PBPK model to define the Clinical Relevant in vitro Acceptance Criteria, 5. Consider to use PBPK/PD simulation 6. Bridging the clinical trial and in vitro studies 7. The strategy recommended here can effectively accelerate ANDA development and ensure the BE success rate. 27

28 BUILD A PHARMACEUTICAL COMPANY 28