Bioequivalence and Characterization of Generic Drugs Xinyuan (Susie) - PowerPoint PPT Presentation

Bioequivalence and Characterization of Generic Drugs Xinyuan (Susie) Zhang DQMM/ORS/OGD/CDER/FDA November 18, 2016 CERSI workshop: Substitutability of Generic Drugs: Perceptions and Reality Disclaimer: The views expressed in this presentation are those of the speaker and not necessarily those of the Food and Drug Administration (FDA).

OGD General Procedures to Study Substitutability of Generic Drugs Root cause analysis In vitro performance Problem Formulation identification Conclusion and In vivo performance communication evaluation Absorption modeling for risk evaluation Conduct studies GDUFA research studies 2

Evaluate the impact of slow dissolution in a specific pH condition on BE (warfarin sodium tablets) 3

Warfarin Case Background Root cause analysis (OPQ, 2013-2014) Signals detection in Modeling and FAERS (OSE, 2013- simulation (OGD, 2014) 2014) In vivo BE study (VACR, 2015) 4

In Vitro Studies • Purpose – Identify an appropriate condition to stress the tablets • Stress Conditions – 40 °C/75% RH for 1, 3, 4 hours, 1, 2, 4, 7, and 14 days – additional 2, 4, and 7 days, respectively, at 25 °C/60% RH • In vitro performance test – Dissolution • Two-stage (pH 1.0 -> pH 7.5) • pH 4.5 • Water – Assay, Impurities, IPA – Crystallinity 5

Slightly Change in Color Top row: Coumadin Bottom row: Taro 40 ° C/75%RH 6

Assay was within spec under the stress condition for less than 7 days 7+7 4+7 2+7 14d 7d 7d 4d 2d 4h 3h 1h untreated 80 85 90 95 100 105 110 Taro Coumadin 7+7 and 14 days conditions failed the assay specification. 7 7

Isopropyl Alcohol (IPA) was not detected after the tablets were exposed in the stressed condition for more than 4 hours IPA warfarin sodium sample condition amount(%) content(%) weigh (mg/tablet) Untreated 5.15 103.06 8.63 Not 40 ° C, 75%RH 1 d 4.89 97.81 detectable Coumadin 40 ° C, 75%RH 1 d and Not shipping for one 5.02 100.33 detectable week Untreated 5.12 102.45 9.40 Not 40 ° C, 75%RH 1 d 4.93 98.65 detectable Taro 40 ° C, 75%RH 1 d and Not shipping for one 5.01 100.20 detectable 8 8 week

XRPD: Excipients vs Fresh Tablets Magnesium Stearate starch Lactose Taro fresh Coumadin fresh 9 9

Crystallinity transformed to amorphous form after treatment WFS powder Peak at 2-theta angle of approx 8 is warfarin Na crystal specific Taro treated Coumadin treated Taro untreated Coumadin untreated Taro fresh Coumadin fresh 10 10

Dissolution in Water at 30 min 11 11

Dissolution decreased in acidic conditions after being treated in stressed condition. 2-stage pH 4.5 120 120 100 100 Coumadin Coumadin untreated 80 80 % Dissolved untreated (C) % Dissolved (C) Taro untreated (A) Taro untreated (A) 60 60 Coumadin 1day (D) Coumadin 1day (D) 40 40 Taro 1day (B) Taro 1day (B) 20 20 0 0 0 50 100 150 200 0 20 40 60 80 Time (min) Time (min) 12 12

Hypotheses • The loss of isopropyl alcohol (IPA) will have impact on in vivo performance • The slower dissolution in acidic media will have impact on BA/BE Crystalline warfarin sodium is a clathrate with 8-8.5% isopropanol (IPA) 13

Mechanistic Oral Absorption Modeling and Simulation 14

Innovative Model for Future Product Development 15

PBPK modeling for oral dosage forms 16 Zhang X. et al. (2014) Clinical Pharmacology & Therapeutics

Simplified Absorption Process 17 Zhang X. et al. (2014) CPT

Inputs and Outputs Drug substance and product PK parameters Clearance, Vd information: • • Tissue/organ parameters • Dose and dose volume for physiologically based • Solubility vs. pH profiles distribution and • logP, pKa elimination models • Dissolution: MR: dissolution profiles; IR: particle size and density Fh, BA • • Diffusion coefficient • PK profiles • Permeability • Metabolic kinetics Metabolite Info Physiological parameters • GI transit time • GI geometry • Fa, Fg • GI fluid properties Parent and In vivo dissolution • • Enzymes/transporters distribution metabolite PK • Drug in each cmpt • Blood flow 18

General Practice Data PBPK/absorption Model BE collection model building validation simulation Zhang X. et al. (2011) The AAPS Journal 19 Babiskin A. et al. (2015) J Pharm Sci.

Warfarin Sodium Parameters API Warfarin sodium pKa 5.28 Solubility vs. pH 4.5 pH 6.8 pH 7.5 pH: Various a a 0.005 0.279 1.11 solubility b 0.0001 0.279 1.11 c 1.11 1.11 1.11 values were d 0.0001 0.005 0.005 reported e 0.0001 0.01 0.01 f 0.0001 0.02 0.02 logP 2.6 Permeability High T1/2 (hr) Average 40 hrs, range 20-60 hrs 20

Solubility profile does not impact PK significantly 21

Particle size and density do not impact PK significantly 1.02 1.02 Cmax ratio AUCt ratio 1.01 1.01 1 1 0.99 0.99 0 100 200 300 0 100 200 300 particle diameter ( µ m) particle diameter ( µ m) 1.02 1.02 Cmax ratio AUCt ratio 1.01 1.01 1 1 0.99 0.99 0 1 2 3 0 1 2 3 particle density (g/mL) particle density (g/mL) 22

Effect of Dose on PK (under single dose condition) 1.3 Cmax AUCt 1.2 PK ratio 1.1 1 0.9 0.9 1 1.1 1.2 1.3 dose ratio 23

Warfarin dissolution profiles 40°C/75% RH One Day plus 25°C/60% RH for 7 Days 24

Simulation based on the Z factor predicts BE Cmax AUC0-72 Reference Test Pred. Pred. RLD untreated Test treated 1.0000 1.0181 RLD untreated RLD treated 0.9996 1.0181 RLD untreated Test untreated 0.9998 1.0081 RLD treated Test treated 1.0004 1.0000 Test untreated Test treated 1.0002 1.0100 RLD treated Test untreated 1.0002 0.9901 25

Mapping the Dissolution Space for BE (0.955, 80%) σ WR = 0.1 (0.5, 80%) (0.5, 30%) Based on the RSABE criteria, if the PE of C max was 0.955 and the passing rate was 80%, it required minimum 30% release at 30 min in pH 4.5 and 80% release at 30 min in pH 6.8.

BE study design • Four treatments – A: Taro 5 mg tablets stored at room temperature. – B: Taro 5 mg tablets 40 °C/75% RH for 1 day. – C: Coumadin 5 mg tablets stored at room temperature. – D: Coumadin 5 mg tablets 40 °C/75% RH for 1 day. • Four sequences – ABCD, BCDA, DCAB, DABC 27

Average BE Analysis (2016) AUC0-72 Cmax Geometric 90% Confidence Geometric 90% Confidence Mean Ratio Limits Mean Ratio Limits Primary Comparisons B vs. C 1.007 (0.957, 1.059) 0.998 (0.968, 1.030) C vs. D 1.009 (0.941, 1.082) 0.996 (0.965, 1.028) Secondary Comparisons A vs. C 0.990 (0.906, 1.082) 1.017 (0.979, 1.056) B vs. D 1.014 (0.974, 1.056) 1.014 (0.974, 1.056) A vs. B 0.979 (0.916, 1.048) 1.015 (0.990, 1.041) A vs. D 1.007 (0.909, 1.116) 1.014 (0.974, 1.056) A: Test 5 mg tablets stored at room temperature. B: Test 5 mg tablets 40°C/75% RH for 1 day. C: RLD 5 mg tablets stored at room temperature. 28 D: RLD 5 mg tablets 40°C/75% RH for 1 day.

Results • Solubility in low pH, particle size, and particle density did not have significant impact on bioavailability. • Dose (potency) impacted PK proportionally. • Dissolution rate at pH 6.8 was the most relevant condition to bioavailability. • An in vivo BE study confirmed the prediction. • M&S helped map the post-market risk assessment space where it’s infeasible to conduct in vivo studies for all scenarios. 29

Summary • OGD conducts both internal and external research activities to address the substitutability of generic drug products issues. • Modeling and simulation plays a significant role in the studies of substitutability of generic drug products. 30

Acknowledgements • Hong Wen, Ph.D. • Jianghong Fan, Ph.D. • Minori Kinjo, Ph.D. • Jill Brown, B.S., R.N. • Wanjie Sun, Ph.D. • Wenlei Jiang, Ph.D. • Myong-Jin Kim, Pharm.D. • Liang Zhao, Ph.D. • Robert Lionberger, Ph.D. • Purdue University: Prof. Tonglei Li, Ph.D. • VACR 31