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).

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OGD General Procedures to Study Substitutability of Generic Drugs

In vivo performance evaluation Conclusion and communication GDUFA research studies

Absorption modeling for risk evaluation Conduct studies

Problem identification Root cause analysis

Formulation In vitro performance

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

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Warfarin Case Background

Root cause analysis (OPQ, 2013-2014) Modeling and simulation (OGD, 2014) In vivo BE study (VACR, 2015)

Signals detection in FAERS (OSE, 2013- 2014)

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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

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Slightly Change in Color

Top row: Coumadin Bottom row: Taro 40°C/75%RH

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Assay was within spec under the stress condition for less than 7 days

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80 85 90 95 100 105 110 untreated 1h 3h 4h 2d 4d 7d 7d 14d 2+7 4+7 7+7 Taro Coumadin

7+7 and 14 days conditions failed the assay specification.

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Isopropyl Alcohol (IPA) was not detected after the tablets were exposed in the stressed condition for more than 4 hours

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sample condition warfarin sodium weigh (mg/tablet) amount(%) IPA content(%) Coumadin Untreated 5.15 103.06 8.63 40°C, 75%RH 1 d 4.89 97.81 Not detectable 40°C, 75%RH 1 d and shipping for one week 5.02 100.33 Not detectable Taro Untreated 5.12 102.45 9.40 40°C, 75%RH 1 d 4.93 98.65 Not detectable 40°C, 75%RH 1 d and shipping for one week 5.01 100.20 Not detectable

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XRPD: Excipients vs Fresh Tablets

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starch Magnesium Stearate Lactose Taro fresh Coumadin fresh

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Crystallinity transformed to amorphous form after treatment

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Peak at 2-theta angle

• f approx 8 is warfarin Na

crystal specific

Coumadin treated Taro untreated Coumadin untreated Taro fresh Coumadin fresh Taro treated WFS powder

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Dissolution in Water at 30 min

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Dissolution decreased in acidic conditions after being treated in stressed condition.

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20 40 60 80 100 120 50 100 150 200 % Dissolved Time (min)

2-stage

Coumadin untreated (C) Taro untreated (A) Coumadin 1day (D) Taro 1day (B) 20 40 60 80 100 120 20 40 60 80 % Dissolved Time (min)

pH 4.5

Coumadin untreated (C) Taro untreated (A) Coumadin 1day (D) Taro 1day (B)

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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)

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Mechanistic Oral Absorption Modeling and Simulation

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Innovative Model for Future Product Development

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PBPK modeling for oral dosage forms

Zhang X. et al. (2014) Clinical Pharmacology & Therapeutics

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Simplified Absorption Process

Zhang X. et al. (2014) CPT

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Inputs and Outputs

Drug substance and product information:

• Dose and dose volume
• Solubility vs. pH profiles
• logP, pKa
• Dissolution: MR: dissolution profiles;

IR: particle size and density

• Diffusion coefficient
• Permeability
• Metabolic kinetics

Physiological parameters

• GI transit time
• GI geometry
• GI fluid properties
• Enzymes/transporters distribution
• Blood flow

PK parameters

• Clearance, Vd
• Tissue/organ parameters

for physiologically based distribution and elimination models

• Fa, Fg
• In vivo dissolution
• Drug in each cmpt
• Fh, BA
• PK profiles

Metabolite Info

Parent and metabolite PK

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General Practice

Data collection PBPK/absorption model building Model validation BE simulation

Zhang X. et al. (2011) The AAPS Journal Babiskin A. et al. (2015) J Pharm Sci.

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Warfarin Sodium Parameters

API Warfarin sodium pKa 5.28 Solubility vs. pH: Various solubility values were reported logP 2.6 Permeability High T1/2 (hr) Average 40 hrs, range 20-60 hrs

pH 4.5 pH 6.8 pH 7.5 aa 0.005 0.279 1.11 b 0.0001 0.279 1.11 c 1.11 1.11 1.11 d 0.0001 0.005 0.005 e 0.0001 0.01 0.01 f 0.0001 0.02 0.02

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Solubility profile does not impact PK significantly

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Particle size and density do not impact PK significantly

100 200 300 0.99 1 1.01 1.02 particle diameter (µm) Cmax ratio 100 200 300 0.99 1 1.01 1.02 particle diameter (µm) AUCt ratio 1 2 3 0.99 1 1.01 1.02 particle density (g/mL) Cmax ratio 1 2 3 0.99 1 1.01 1.02 particle density (g/mL) AUCt ratio

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Effect of Dose on PK (under single dose condition)

0.9 1 1.1 1.2 1.3 0.9 1 1.1 1.2 1.3 dose ratio PK ratio Cmax AUCt

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Warfarin dissolution profiles

40°C/75% RH One Day plus 25°C/60% RH for 7 Days

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Simulation based on the Z factor predicts BE

Cmax AUC0-72 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 Reference Test

σWR = 0.1 (0.955, 80%) (0.5, 30%) (0.5, 80%)

Mapping the Dissolution Space for BE

Based on the RSABE criteria, if the PE of Cmax 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.

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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

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Average BE Analysis (2016)

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

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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.

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Summary

• OGD conducts both internal and external

research activities to address the substitutability

• f generic drug products issues.
• Modeling and simulation plays a significant role

in the studies of substitutability of generic drug products.

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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