xinyuan (susie) zhang dqmm/ors/ogd/cder/fda november 18, 2016 · bioequivalence and...
TRANSCRIPT
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+77+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 of 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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0
20
40
60
80
100
120
0 50 100 150 200
% D
isso
lved
Time (min)
2-stage
Coumadinuntreated (C)
Taro untreated (A)
Coumadin 1day (D)
Taro 1day (B)
0
20
40
60
80
100
120
0 20 40 60 80
% D
isso
lved
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 7.5aa 0.005 0.279 1.11b 0.0001 0.279 1.11c 1.11 1.11 1.11d 0.0001 0.005 0.005e 0.0001 0.01 0.01f 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
0 100 200 3000.99
1
1.01
1.02
particle diameter (µm)
Cm
ax r
atio
0 100 200 3000.99
1
1.01
1.02
particle diameter (µm)
AU
Ct r
atio
0 1 2 30.99
1
1.01
1.02
particle density (g/mL)
Cm
ax r
atio
0 1 2 30.99
1
1.01
1.02
particle density (g/mL)
AU
Ct r
atio
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Effect of Dose on PK (under single dose condition)
0.9 1 1.1 1.2 1.30.9
1
1.1
1.2
1.3
dose ratio
PK r
atio
CmaxAUCt
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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 AUC0-72Pred. Pred.
RLD untreated Test treated 1.0000 1.0181RLD untreated RLD treated 0.9996 1.0181RLD untreated Test untreated 0.9998 1.0081RLD treated Test treated 1.0004 1.0000Test untreated Test treated 1.0002 1.0100RLD 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 of 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