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`Slides for the August 8, 2012 Meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology
`
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`FDA Presentations for the August 8, 2012 Meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology
`
`FDA
`
`Topic 1: Uses and Limitations of In Vitro Dissolution Testing (PDF - 3.35MB)1
`
`Topic 2: Biosimilars – An Update (PDF - 5.49MB)2
`
`Page Last Updated: 08/16/2012
`Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
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`1. /7993/20170404154915/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM315763.pdf
`2. /7993/20170404154915/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM315764.pdf
`
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`3/2/2018
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`Page 1
`
`SHIRE EX. 2038
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`U.S. Food and Drug Administration
`Protecting and Promoting Public Health
`
`www.fda.gov
`
`Use and Limitations of In Vitro
`Dissolution Testing:
`Topic Introduction and Overview
`Lawrence X. Yu, Ph. D.
`Deputy Director for Science and Chemistry
`Office of Generic Drugs
`Food and Drug Administration
`
`Advisory Committee for Pharmaceutical Science
`and Clinical Pharmacology
`August 8, 2012
`
`Page 2
`
`

`

`U.S. Food and Drug Administration
`Protecting and Promoting Public Health
`
`www.fda.gov
`
`In Vitro Dissolution Testing: Objectives
`
` Assure batch to batch quality
`
` Guide development of new formulations
`
` Provide “process control” and quality
`assurance
`
` Ascertain the need for bioequivalence studies
`
` Different strengths
`
` Post-approval changes
`
` Multi-source products
`
`– – –
`
`2
`
`• • • •
`
`Page 3
`
`

`

`U.S. Food and Drug Administration
`Protecting and Promoting Public Health
`
`www.fda.gov
`
`Dissolution Testing: Issues
` Dissolution testing can be “non-discriminating”.
` Dissolution testing can be “over discriminating”.
` Products that dissolve about 70% in 45 minutes often
`have no medically relevant bioequivalence problems.
` Dissolution testing (especially only a single point
`criterion) is often not sufficient to assure product
`quality/ bioavailability.
` Demonstration of in vitro-in vivo correlation (IVIVC) is
`necessary.
` IVIVC’s are “Product Specific”.
`
`•
`•
`•
`
`•
`
`•
`
`•
`
`3
`
`Page 4
`
`

`

`U.S. Food and Drug Administration
`Protecting and Promoting Public Health
`
`www.fda.gov
`
`•
`
`•
`
`Desired Future State of
`In Vitro Dissolution Testing
` Sensitive enough to detect relevant product
`changes so as to ensure the quality and
`consistent performance of products
` Predictive of in vivo performance of drug
`products and thus reduce unnecessary human
`studies, accelerate drug development, and
`hasten evaluation of post-approval changes
`
`4
`
`Page 5
`
`

`

`U.S. Food and Drug Administration
`Protecting and Promoting Public Health
`
`www.fda.gov
`
`Cindy Buhse
`
`Arzu Selen
`
`Uses and Limitations of
`In Vitro Dissolution Testing
`Use and Limitations of In Vitro Dissolution Lawrence Yu
`Testing: Topic Introduction and Overview
`Dissolution Testing: Evolving Dissolution
`Apparatus
`Dissolution Testing: Evolving Dissolution
`Media for Predicting In Vivo Performance
`Oral Bioperformance & 21st Century
`Dissolution Testing
`Dissolution Testing and Quality-by-Design Lawrence Yu
`Followed by:
`Topic Wrap-up and Future Directions
`–
`Questions to the Committee/Committee Discussion
`–
`
`Gregory Amidon
`
`5
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`Page 6
`
`

`

`Oral Bioperformance
`&
`21st Century Dissolution Testing
`
`Gregory E. Amidon
`Research Professor of Pharmaceutical Sciences
`College of Pharmacy
`University of Michigan
`
`1
`
`Page 7
`
`

`

`“What is it that we can’t do today, but if we
`could, it would revolutionize our business?”
`Joel Barker
`Futurist
`
`Comprehensive computational tools and
`meaningful in vitro test methods that accurately
`reflect and predict oral bioperformance would
`revolutionize oral formulation development.
`
`2
`
`Page 8
`
`

`

`Topics
`•
`Where are we now?
`•
`What opportunities are there? There are many!
`•
`GI physiology
`•
`Fluid volume
`•
`Hydrodynamics
`•
`Buffer (bicarbonate)
`Advanced dissolution methods
`•
`Two phase systems (simulating dissolution and absorption)
`•
`Two compartment systems (simulating stomach and intestine)
`Computational Tools
`•
`Fluid Dynamics
`•
`Dissolution
`•
`Absorption Modeling
`
`•
`
`•
`
`3
`
`Page 9
`
`

`

`USP Compendial Tests for Oral Bioperformance
`•
`1950: Disintegration Test
`•
`1970: Dissolution Apparatus 1 (rotating basket)
`•
`1980: Dissolution Apparatus 2 (paddle)
`• …….
`• …….
`
`600
`
`USP Dissolution Test (paddle)
`USP Dissolution Test (basket)
`
`.------_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_:;-
`USP Disintegration Test
`
`----
`
`0..
`V)
`::, 500
`
`C ·-""'C
`G.I
`~ 400
`!!
`
`! 300
`
`-----Jf-
`
`.... ¾ -
`
`----:---3'1f-----3!E--~~
`
`
`
`=-------l----
`
`l-
`
`Cl -+--
`1930
`
`Year
`
`I.ISP Disintegration
`
`ll P Ois:s;olu iion
`-
`------.--------,
`19 0
`
`000
`
`4
`
`Page 10
`
`

`

`Dissolution Testing is what links the dosage form
`to the proven efficacy (eg: typically the clinical
`lot used in the Phase 3 pivotal efficacy study)!
`
`…..
`Dissolution testing is what links every lot of the
`dosage form from every manufacturer to the
`labeling (proven efficacy and safety)! This can
`be 100s or 1000s of lots separated by years or
`decades as well as continents from the pivotal
`efficacy lot.
`
`5
`
`Page 11
`
`

`

`Some areas of success (1970-2012)
`•
`Dissolution Testing as an “analytical” measure of:
`•
`Product consistency
`•
`Product quality
`•
`Manufacturing process control
`IVIVC, IVIVR, IVIVE
`BCS
`Intestinal media simulation
`•
`FaSSIF
`•
`FeSSIF
`Physiologically relevant solubility
`Improved understanding of GI environment
`Application of computational tools
`
`•
`•
`•
`
`•
`•
`•
`
`6
`
`Page 12
`
`

`

`Some weaknesses (1970-2012)
`•
`IVIVC, IVIVR, IVIVE
`•
`Application of oral physiology understanding to drug and
`drug product testing
`•
`Dissolution Testing as in vivo simulation
`•
`Application of advanced computational tools
`•
`Application of comprehensive physicochemical
`principles to oral absorption
`
`7
`
`Page 13
`
`

`

`8
`
`The price of “less than ideal” in vitro methods is:
`•
`
`Over-discriminatory in vitro test methods
`•
`Result is wasted resources and delays in the development of new
`products to meet unmet medical needs
`
` Chasing down unimportant problems
`
` Conducting unnecessary clinical or animal testing
` Spending unnecessary development and analytical resources
`•
`•
`Slowing development of innovative dosage forms for difficult
`to deliver drugs
` Under-discriminatory in vitro test methods
`• Result in a lack of meaningful product quality control
`• Difficulty comparing innovator and generic products
`• Product failure (eg: efficacy and/or safety) in patients!
`
`•
`
`••
`
`Page 14
`
`

`

`A better dissolution test!
`
`Rube Goldberg
`
`More Accurate Oral Bioperformance Prediction would help:
`•
`Formulation finding/screening (early development)
`•
`Define meaningful in vitro performance requirements such as
`disintegration, dissolution, supersaturation extent and time,
`functional excipient impact (solubilizer, precipitation inhibitor) etc.
`Optimize dosage form delivery rate
`Enhance material and process understanding ( Quality by Design)
`Facilitate meaningful in vitro testing of varying in vivo conditions
`
`•
`•
`•
`
`9
`
`Page 15
`
`

`

`Topics
`•
`Where are we now?
`•
`What opportunities are there (there are many)?
`•
`GI physiology
`•
`Fluid volume
`•
`Hydrodynamics
`•
`Buffer (bicarbonate)
`Advanced dissolution methods
`•
`Two phase systems (simulating dissolution and absorption)
`•
`Two compartment systems (simulating stomach and intestine)
`BCS Advances
`Computational Tools
`•
`Fluid Dynamics
`•
`Dissolution
`•
`Absorption Modeling
`
`•
`•
`
`•
`
`10
`
`Page 16
`
`

`

`What have we learned about human physiology that
`might related to dissolution testing?
`
`Intestinal Contents
`Bicarbonate (mEq L-1)
`Bile salts (mM)
`Lipids (mg/mL)
`Phospholipids (mM)
`Pepsin (mg/mL)
`Lipase
`Potassium (mM)
`Sodium (mM)
`Chloride (mM)
`Calcium (mM)
`Buffer capacity (mmol L-1 pH-1)
`Osmolality (mOsm kg-1)
`Surface tension (mN m-1)
`Viscosity
`Volume
`Shear
`pH
`
`(
`(
`(
`
`11
`
`Key considerations include:
`Fluid volume
`Intestinal surface area
`Buffer (bicarbonate)
`pH (average, range)
`Ionic strength
`Surfactants (bile acids)
`Carbonic anhydrase
`Hydrodynamics
`Residence time
`Stomach emptying rate
`•….
`
`••••••••••
`
`Page 17
`
`

`

`Physiology: What volume of liquid is the dosage form exposed to?
`
`•
`
`~ 100 mL
`
`Average aqueous volume in the fasted small intestine is ~100 ml (Refs: multiple)
`Total volume in the small intestine
`86, 81, 112±27, 109 ± 36, 165±22, 105±72
`
`Fasted
`
`Mean
`
`Fed
`
`Range
`
`Mean
`
`Range
`
`34-46, 37-130, 45-319
`47, 381, 590±73, 54±41
`18-78, 343-491, 20-156
`
`• Evidence of liquid pockets Schiller et al. Aliment Pharmacol .Ther. 22:971-979 (2005).
`Fasted
`Fed
`
`Number of liquid
`pockets
`
`Volume of liquid
`pocket (mL)
`
`Mean
`Individual
`(approx.)
`Median
`
`4
`
`6
`
`2, 3, 4, 5, 8
`
`2, 5, 6, 7, 11
`
`12
`
`4
`
`Ref: D.M. Mudie, G.L. Amidon, and G.E. Amidon. Physiological Parameters for Oral
`Delivery and In Vitro Testing. Mol Pharmaceutics. 7:1388-1405 (2010).
`
`12
`
`Page 18
`
`

`

`Physiology is complex
`
`Jejunum
`
`So - compendia! dissolution testing in 900
`ml with a paddle (or rotating basket)
`doesn 't really capture it.
`
`13
`
`Page 19
`
`

`

`Some physiological dissolution “systems”
`
`•
`Artificial Dynamic GI System, TIM-1 (TNO)
`•
`Stress test apparatus
`•
`Dissolution/Permeation system (uses Caco-2 cells)
`•
`Two-compartment apparatus:
`•
`Artificial Stomach and Duodenum (ASD)
`•
`FloVitro Technology (Rohm and Haas)
`•
`Two-phase dissolution apparatus
`• Simultaneous dissolution and partitioning in single
`compartment containing two phases (water:organic)
`
`Duodenum Companment
`
`Stomach Compartmtn1
`
`1-octanol
`
`water
`
`. . .
`
`. . .
`
`14
`
`Page 20
`
`

`

`In-vivo Intestinal Fluid Flow Rates
`
`'.
`---n
`"
`
`~
`
`I ,
`
`• -+-
`
`"'
`
`Ill
`
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`
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`
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`
`•
`
`0
`
`..0,.2
`
`-(J1
`
`-0.6
`
`0 1 8
`
`VJ
`(l)
`~ ro
`3:
`0 -LL
`
`~
`
`4
`
`r
`_Kif
`lI .l
`.... 1111
`~ ~, ·~ - ,
`, ....
`7 (IJ611 t>:
`,t
`
`'
`
`, , II
`
`I Iii
`
`~
`
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`
`V '
`
`(cid:127) Volu11111eer
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`
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`k l
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`i
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`~ .............
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`
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`
`,.
`
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`
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`
`(cid:127) Volunte,er 2
`Time (s)
`
`(cid:127) Volunteer 3,
`
`Gutzeit A, Patak MA, Weymarn Cv, Graf N, Doert A, Willemse E, Binkert CA, Froehlich JM 2010. Feasibility of Small
`Bowel Flow Rate Measurement With MRI. Journal of Magnetic Resonance Imaging 32:345-351.
`
`15
`
`Page 21
`
`

`

`Hydrodynamics of dissolution apparatus: USP
`Apparatus 2 - Velocity & Shear Profiles
`
`•
`
`•
`
`Highest velocities occur at the tip of
`the paddle (~20 cm/sec)
`The lowest velocities are directly
`beneath the centerline of the
`impeller and around the shaft of the
`impeller.
`
`y-plane, 50 rpm
`
`meters/s
`
`-01
`2 .00
`1 ~Oe'-01
`1 8@8-01
`1 _7 0e .01
`1 60
`-01
`1,50
`"I
`-01
`,
`,I
`1 ,3 0a •01
`1.20 ... 0 ·
`1 10!!<-Qt
`1 .0 0.0-0 '1
`9 .000 -02'
`sno,. .~
`7 ,DOai-02
`-02 '
`-0::Z
`
`•
`•
`
`The Reynold’s numbers (Re) vary depending on
`the rotational speed and location(Re ~ 104).
`The shear rates throughout the vessel are
`heterogeneous.
`Maximum shear rates: 92s-1 at 50 RPM
`Average shear rates: ~ 20s-1 at 50 RPM
`
`50 RPM
`
`92
`
`20
`
`4
`
`0.2
`
`(a)
`
`(I
`
`Ref: Bai G, Wang Y, Armenante PM 2011. Velocity Profiles and Shear Strain Rate Variability in the
`USP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds. International Journal of
`Pharmaceutics 403:1-14.
`
`16
`
`Page 22
`
`

`

`Flow Through Cell
`• May allow for testing at more physiologically relevant Reynolds
`number (5 – 300) and flow rates (0.1 – 0.6 cm/sec).
`
`Pressure outlet- - - - ----
`
`
`
`Tablet-------------------- _
`
`Dlsso lut lon
`lesl section
`
`Di ffu ser or
`pttcked
`b ed
`section
`
`0 5 mm bead
`check-valve ,
`red ruby bead
`
`Velocity Profiles in a 12mm Cell
`-,u:,,
`
`(cid:143) 4- m L.Jmi111
`B m L.Jmi111
`o 16,mll..Jm i'n
`
`..
`E'
`E ,s.o
`.._..
`
`000000
`
`0 00
`
`00
`
`00
`
`A~A6666A
`
`A 6
`
`-6 ,
`1C!lll,
`a: - 2 .0
`
`0
`
`O
`.
`,66 ,i!,. . .
`0
`088~ 0
`0
`·£,.
`(cid:143) 9~
`
`.
`
`1.0
`0.8
`0.6
`0.4
`0.2
`0.0
`Norma llised r,ad uus r(no units)
`
`Ref: Schematic of a flow through cell: Kakhi (2009). Mathematical Modeling of the Fluid Dynamics in the Flow
`Through Cell. International Journal of Pharmaceutics. Vol 376, pg 25.
`
`17
`
`Page 23
`
`(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)(cid:143)
`

`

`Impact of Fluid Shear on Particle Dissolution (happ):
`High Performance Computational Analysis
`
`1)3.0
`
`IM
`...
`E
`10.0
`!
`~ 10,0
`"
`
`IM
`
`0,0
`M
`
`t b~ ~r,111
`I ~IPJ-100"1
`... - lr1nlllri1, 10~m
`--1
`lin,l I
`
`II
`
`I
`
`!,;;~ 1."0S'r ,,
`
`/
`
`lq•H16~,
`t•0.9t!8
`
`120 -e
`::S. 100 --Cl)
`.s::. -... 60
`..J 401-
`
`80
`
`Cl)
`(I)
`C
`.:,,:
`.l:
`
`(I)
`>,
`C!I
`
`C
`0
`vi :::,
`== C
`
`2012
`
`....
`------... --1--.. -(cid:173)
`...
`... ...
`•• •
`-· ...
`
`10.0
`
`lO,O JO.O
`
`io.o
`
`!0.0 6),0
`
`luliDs ~11)
`Parric~ Sar&ce
`
`o "
`0
`
`20
`
`r
`80
`60
`40
`Radius (µm)
`
`100
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`S=0s-1
`
`s = 0.1 s-1
`
`s= 1 s-1
`
`S= 10s-1
`
`s = 100s -1
`
`S =SO0s -1
`
`Ref: (1) JJSheng, etal. JPharmSci. 97:4815-4829 (2008).
`(2) Wang, Brasseur, Penn State University (unpublished)
`
`Hintz, Johnson (1989)
`
`'""····
`
`Predicted based on
`human intestinal shear
`rates
`
`18
`
`Page 24
`
`

`

`Importance of physical chemistry and
`physiologic buffer (bicarbonate)
`•
`Drug Properties:
`•
`Solubility
`•
`pKa
`•
`Diffusion coefficient
`•
`Particle size
`Physiological Properties:
`•
`pH
`•
`Buffer species and concentration
`•
`Fluid hydrodynamics
`•
`Intestinal motility
`•
`Bulk concentration
`•
`Volume and temperature etc.
`
`•
`
`19
`
`Page 25
`
`

`

`Bicarbonate Buffer Physiological
`Relevance
`• Bicarbonate is secreted by the pancreas and
`epithelial cells throughout the GI lumen.
`
`GI Lumen
`
`࡯ࡻ૛ ൅ࡴ૛ࡻ՞ ࡴ૛࡯ࡻ૜ ՞ࡴ൅ ൅ࡴ࡯ࡻ૜െ
`࡯࡭ ࡵࡵ ርۛሮࡴ૛࡯ࡻ૜՞ࡴ൅൅ࡴ࡯ࡻ ૜െ
`࡯ࡻ૛ ൅ࡴ૛ࡻ
`
`Blood
`
`Ref: Sly WS, Hu PY 1995.
`Human Carbonic Anhydrases
`and Carbonic Anhydrase
`Deficiencies. Annu Rev
`Biochem 64:375 - 401
`
`20
`
`Page 26
`
`

`

`Dissolution (37oC) of Ibuprofen in bicarbonate
`buffer compared to phosphate buffer (rotating disk)
`i
`
`0 .4
`
`Dissolution in 50 mM phosphate
`buffer @ pH=7.2 (USP test)
`is 0.7 mg/cm2/min
`
`N
`
`'"i:o 0-25
`
`0.35 -C ·-E 0.3
`""
`E u
`E -QJ 0_2
`
`"'""
`ra a:
`C 0.15
`Q
`;;
`
`::, -0
`II) .~
`Q
`
`0.1
`
`Phosphate buffer pH=6.5
`
`0.05
`
`Bicarbonate buffer, pH=6.5
`
`0
`
`0
`
`10
`
`20
`
`40
`30
`Buffer Concentration (mM)
`
`so
`
`60
`
`70
`
`21
`
`Page 27
`
`

`

`Topics
`•
`Where are we now?
`•
`What opportunities are there (there are many)?
`•
`GI physiology
`•
`Fluid volume
`•
`Hydrodynamics
`•
`Buffer (bicarbonate)
`Advanced dissolution methods
`•
`Two phase systems (simulating dissolution and absorption)
`•
`Two compartment systems (simulating stomach and intestine)
`BCS Advances
`Computational Tools
`•
`Fluid Dynamics
`•
`Dissolution
`•
`Absorption Modeling
`
`•
`•
`
`•
`
`22
`
`Page 28
`
`

`

`Combining dissolution and
`absorption (two phase model)
`•
`•
`•
`
`0
`0
`0
`
`1-octanol
`
`water
`
`•
`
`•
`
`•
`
`Ten + systems described in literature
`Being used in industry
`Overcome difficulties in maintaining
`sink conditions for poorly-soluble
`drugs (BCS 2, 4), super-saturable
`systems, and controlled-release
`Circumvent analytical difficulties
`associated with lipid-based capsule
`formulations
`Simultaneously study impact of
`formulation changes (e.g.
`surfactants) on dissolution and
`absorption processes!
`Can potentially be scaled to more
`accurately reflect in vivo conditions!
`
`23
`
`Page 29
`
`

`

`Two-phase IVIVR: Nifedipine GITS tablets
`
`•
`BCS IIc
`•
`Sol. FaSSIF = 0.024mg/ml
` Log P = 2 - 4
`•
`
`-i::,
`
`.. u
`
`,....._
`~ ·!;.., 100
`:'A 80
`0
`i:.:
`u
`'Jl
`0
`Q
`......
`0
`c::
`0
`·.:i
`u
`~
`µ..
`
`60
`
`40
`
`20
`
`0
`
`Single-phase
`
`•
`
`10m g
`
`••
`•
`• •
`
`r = 0.9469
`'
`y ,: 1.1888..'{ + 12.93
`
`•
`•
`
`100
`
`80
`
`60 -
`
`40
`
`20
`
`••
`
`60mg
`
`• • • •
`
`,· = 0.9725
`
`Y = l.2484X • 6.42
`
`0
`
`20
`
`40
`
`40
`20
`0
`80 100
`60
`Fraction of Do se Absorbed (~Ii,)
`[Wagn er-Nel son Method]
`
`60
`
`80 100
`
`Two-phase
`
`31.1mg
`
`-~
`100
`~
`V.
`~ Ii) ......
`"' d
`8
`r< .,
`c
`C
`
`80
`
`60
`
`40
`
`20
`
`0
`
`§
`";J u
`I:!
`"""
`
`0
`
`20
`
`40
`
`100
`
`80
`
`60
`
`40
`
`2U
`
`60 mv,
`
`Y-
`
`1.119lX + O.M
`
`0
`
`40 uO 80
`80 100
`0
`20
`60
`~-m, .:li, ,n ,1f D m,e Absorbed ("!.)
`(Wagner-NcL,;o n Me thod]
`
`10
`
`~
`,L.
`100
`
`~
`~
`
`l
`"' ~ .,,
`0
`......
`0
`d
`' g
`~ tL
`
`80
`
`6
`
`40
`
`zo
`
`0
`
`30mg
`
`Y = J.0256X · 9.n
`
`100
`
`80
`
`60
`
`40
`
`20
`
`60 me
`
`,.- =0.,-.Jl o
`
`\" - 1. 1-l()~X-!lm
`
`0
`
`20
`
`40
`
`0 +-'-
`80 100
`60
`0
`Pmc tio n o f Dose Ab so rbt>d (" '•)
`lllc,:-onvnl11rinn (f)eM on.: )l
`
`...... --
`20
`
`----
`4()
`60
`
`-
`
`80
`
`1 01)
`
`24
`
`Page 30
`
`

`

`100
`
`90
`
`80
`
`70
`
`60
`
`Two phase physiologic dissolution model
`Pm= 5 x 10-4 cm/sec, particle radius = 50 µm
`BCS Class II
`Sol=100µg/mL Dose
`= 25 mg
`(Dose number = 1)
`A/V = 2.3
`Vw = 100 mL
`
`
`
`50%
`
`40
`
`30
`
`20
`
`10
`
`......
`··············
`··········
`... , ...
`···--····~·······
`.......... •······
`..... •·
`······•··
`'~
`... .. .-. ........... _..
`·• ..
`··• .
`. ,, ....
`.
`/
`---~
`---:...::...__""'_
`--,-.. ._.._ ·• ..
`..
`~
`~
`'--..:::!:!:.:.:,
`-==.....,-------........ -------
`~------------------
`
`0
`200
`150
`100
`0
`50
`250
`300
`time, min
`
`% in buffer - two phase
`% in 1-octanol
`% dissolved - two phase
`% in buffer (% dissolved) - single phase
`% saturation in buffer - two phase
`% saturation in buffer - single phase
`
`350
`
`25
`
`Page 31
`
`

`

`Two phase physiologic dissolution model
`Pm= 2 x 10-4 cm/sec, particle radius = 50 µm
`BCS Class II
`Sol=100µg/mL Dose
`= 25 mg
`(Dose number = 1)
`A/V = 2.3
`Vw = 100 mL
`
`80
`
`70
`
`60
`
`100
`
`90
`
`..... ···
`it
`j
`.
`.
`.
`
`50
`
`40
`
`30
`
`20
`
`10
`
`%
`
`% in buffer - two phase
`·········· ...
`% in 1-octanol
`······ ····· ····•····
`.. ..
`% dissolved - two phase
`·• .
`................ ··•·--······················································
`% in buffer (% dissolved) - single phase
`...........
`·· ...
`
`...............
`% saturation in buffer - two phase
`.
`.... --..... -.......
`••'
`....
`. ... •··
`% saturation in buffer - single phase
`-- ~,..:~~............
`•· ..
`..
`..
`-.....
`-................. ·• .. .
`...
`..... ,
`~,
`, ... ~........ ·········
`...... -~ ..... :::_·::··:::::.::.::c:::..1,111,
`250
`300
`350
`
`0
`0
`
`50
`
`100
`
`150
`200
`time, min
`
`26
`
`Page 32
`
`

`

`Two phase physiologic dissolution model
`Pm= 1 x 10-4 cm/sec, particle radius = 50 µm
`BCS Class II
`Sol=100µg/mL Dose
`= 25 mg
`(Dose number = 1)
`A/V = 2.3
`Vw = 100 mL
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`%
`
`% in buffer - two phase
`% in 1-octanol
`% dissolved - two phase
`% in buffer (% dissolved) - single phase
`% saturation in buffer - two phase
`% saturation in buffer - single phase
`
`27
`
`....
`..
`. •·
`.··
`:! ...
`.
`. .
`. .
`.
`
`······ ..........
`. ...
`···•····
`
`···········-·········
`
`·
`
`···················
`
`·
`
`·············
`
`• • •
`
`, •••••••••••••••
`
`······•• . . .. .. .. .. ·· .. ·· . ..
`·· ..
`--~ ...........
`... ""'-.. --..
`.
`·· ...
`..,,······
`... _____________
`~.....
`··• ..
`--...........
`,...
`..
`. ...
`,........
`.... .... .... ......
`......... _
`
`0
`0
`
`50
`
`100
`
`150
`200
`time, min
`
`250
`
`300
`
`350
`
`Page 33
`
`

`

`Two phase physiologic dissolution model
`Pm=1x10-4 cm/sec, particle radius = 5 µm
`
`BCS Class II
`Sol=100µg/mL Dose
`= 25 mg
`(Dose number = 1)
`A/V = 2.3
`Vw = 100 mL
`
`% in buffer - two phase
`% in 1-octanol
`% dissolved - two phase
`% in buffer (% dissolved) - single phase
`% saturation in buffer - two phase
`% saturation in buffer - single phase
`
`28
`
`41••·······••111••·········••111••············ ··::,.:• ••
`
`.. •·
`·· .
`.. •·
`..
`..
`.
`..
`•·.
`...
`..
`..
`.
`..
`..
`...
`•.
`...
`· ..
`....
`·· .
`. •··
`... •·
`·· ..
`. .
`....
`.. ..
`.. • ...
`·· . ·• . ·· ..
`. •··
`.. • ...
`···• ...
`...
`..
`..
`...
`...
`
`. •··
`.•·
`.•·
`...
`. •·
`...
`
`~
`
`-------, ..... ..... ....
`
`......
`
`........................................................ ~ ..................................
`.
`
`···• ......... .
`
`.. ·• .. . . .. . .. ..
`...... .... .... .... ..... ..... .... .....
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`%
`
`0
`0
`
`20
`
`40
`
`60
`
`80
`100
`time, min
`
`120
`
`140
`
`160
`
`Page 34
`
`

`

`Stomach and intestine: Two-compartment
`dissolution apparatus
`
`•
`
`•
`•
`
`Several publications in
`literature describing
`Artificial Stomach-
`Duodenum (ASD)
`Used in pharmaceutical
`industry
`Used to compare ASD
`performance with in vivo
`bioavailability values
`
`Relative bioavailability estimation
`of carbamazepine crystal forms
`
`Duodenum Compartment
`
`Stomach Compartment
`
`1500~~~/~
`
`1250
`
`~
`~ 1000
`:l.
`c5
`Cl)
`<(
`
`750
`
`AUC
`
`,~
`
`rm~III
`
`>-------;_>-r------<
`
`r = 0.99
`
`2
`
`4
`
`8
`6
`In Vivo, µg h/ml
`
`10
`
`1:
`
`1.4
`
`1.3
`
`1.2
`
`1.1
`
`E r 1.0
`ci 0.9
`CJ)
`-,:
`
`0.8
`
`0.7
`
`0.6
`
`Cmax
`
`For
`
`~
`
`hydrate
`
`1
`
`2
`
`4
`3
`In Vivo, µg mr'
`
`r= o.93
`
`5
`
`SRCarino, DCSperry, MHawley. JPharmSci 95:116-125 (2006).
`
`29
`
`Page 35
`
`

`

`Impact of stomach pH on Oral Absorption of
`Anticancer Agents
`
`Table3 Effect of acid-reducing agents on the oral absorption of targeted anticancer agents
`
`Drug(dose)
`
`Acid-reducing agent
`
`Dasatinib (50 mg)
`
`Famotidine (40 mg) 10 hours prior to dasatinib
`Famotidine (40 mg) 2 hours after dasatinib
`
`Dasatinib (50 mg)
`
`Maalox 30 ml 2 hours prior to dasatini b
`Maalox 30 ml coad ministered with dasatini b
`
`Dasatinib (100 mg) Omepra20le (40 mg) daily for 5 days and on day 5 with
`dasatinib
`
`Erlotinib (150 mg)
`
`Omepraz ole (40 mg) daily for 7 days
`
`Erlotinib (150 mg)
`
`Ran it idine 300 mg daily for 5 days and erlot inib 150 mg
`single dose 2 hours after ranitidine dose on third day
`
`Erlotinib (150 mg)
`
`Gefitinib (250mg)
`
`Ran it idine 150 mg b.i.d. for 5 days and erl otini b 150 mg
`single dose 2 hours before and 10 hours after ranitidine
`on third day
`
`Two oral doses of 450mg ranitidine (13 hours and 1
`hour before 250 mg of gefitinib) follcmed by sodium
`bi carbonate to maintain gastric pH above 5 for 8 hours
`
`I ma tin ib ( 400 mg)
`
`Omeprazole (40 mg) daily for 5 days and on day 5 with
`imatinib
`
`I ma tin ib ( 400 mg)
`
`Maalox Max (20 ml) 15 minutes before imati nib
`
`Lapatin ib (1,250 mg) Esomeprazole (40 mg) daily for 7 days at bedtime
`
`Nilotinib (400mg)
`
`Esomeprazole (40 mg) daily for6 days and on day6 with
`nilotinib
`
`Mean change
`
`AUC
`
`J.61%
`H
`
`H
`J.55%
`
`J.43%
`
`J.46%
`J.58%8
`
`J.33%
`
`cmax
`
`J.63%
`H
`
`1'26%
`J.58%
`
`J.42%
`
`J.61%
`J.69%8
`
`Subjects
`
`Comments
`
`Healthy subjects
`
`AUCo-12
`
`Healthy subjects
`
`AUCo-12
`
`Healthy subjects
`
`AUCint
`
`Healthy subjects
`
`Primary
`metabolite 8
`
`J.54%
`
`Healthy subjects
`
`j,, 15%
`
`j,, 17%
`
`Healthy subjects
`
`J.44%
`
`J.70%
`
`Healthy subjects
`
`Healthy subjects
`
`H
`
`J.26%
`
`J.34%
`
`H
`
`NA
`
`Healthy subjects
`
`Cancer patients
`
`J.27%
`
`Healthy subjects
`
`Rabeprazole (20mg) q.d.
`Axitinib (5 mg)
`AUC, area under the curve, c,,..,,,<' peak plasma concentration; NA, not applicable.
`•Primary metabolite data.
`Ref: N.R. Budha, A. Frymoyer, G.S. Smelick, J.Y. Jin, M.R. Yago, M.J. Dresser, S.N. Holden, L.Z. Benet, and J.A.
`Ware. Clinical Pharmacology & Therapeutics (2012).
`
`j,, 15%
`
`J.40%
`
`Cancer patients
`
`30
`
`Page 36
`
`

`

`Advantages & disadvantages of two-
`compartment systems
`
`Advantages
`•
`Sequentially exposes drug to gastric followed by intestinal
`media
`• Differing media properties in stomach and intestine (e.g. pH,
`lipid & bile salt concentrations) can affect dissolution
`•
`Captures in vivo gastric-emptying rates and flow rates
`• Can vary to simulate effect on dissolution
`•
`Potential to integrate peristaltic motion
`Disadvantages
`• Does not contain separate phase/chamber for absorption
`• Assumes dissolved drug proportional to drug in plasma
`
`31
`
`Page 37
`
`

`

`Topics
`•
`Where are we now?
`•
`What opportunities are there (there are many)?
`•
`GI physiology
`•
`Fluid volume
`•
`Hydrodynamics
`•
`Buffer (bicarbonate)
`Advanced dissolution methods
`•
`Two phase systems (simulating dissolution and absorption)
`•
`Two compartment systems (simulating stomach and intestine)
`Computational Tools
`•
`Fluid Dynamics
`•
`Dissolution
`•
`Absorption Modeling
`
`•
`
`•
`
`-------~ -===-------------------
`--~ ~~
`a ε
`particle path
`
`32
`
`Page 38
`
`

`

`Exciting research is going on….
`Motility and Absorption in the Small Intestine
`Quantification of Small Bowel Water/Physiology
`Coupling Biorelevant Dissolution Testing with PBPK Modeling
`Modeling Hydrodynamics in the Intestine
`Bicarbonate Buffer and Surface pH
`In Vitro Dynamic Lipolysis Model
`Precipitation Kinetics of Poorly Soluble Drugs under Supersaturated State and Precipitation
`Inhibitors
`Rotating Disk as a Dissolution Tool
`Artificial Stomach Duodenum (2 compartment dissolution)
`Miniscale Dissolution-membrane Partitioning System
`Two Phase Dissolution System
`Two Compartment Caco2 model /Mini-scale Dissolution
`In vivo and computational biopharmaceutical aspects of precipitation and intestinal permeability
`Dynamic Dissolution (TIM-1)
`Methods for Estimation of Biorelevant Drug Solubility
`Combining Experimental and Computational Approaches for Predicting Oral Bioperformance
`
`33
`
`Page 39
`
`

`

`•
`
`Future Direction and Research Needs
`•
`Enhanced Understanding In Vivo environment (human, animal)
`Hydrodynamics
`•
`Volume
`•
`Gastric Emptying
`•
`Fluid content, buffer
`•
`Development of Relevant In Vitro Methodologies
`Likely not one-size-fits-all
`•
`•
`Address/simulate dissolution and absorption kinetics
`•
`Precipitation assessment / inhibition
`•
`Modified / Delayed Release optimization
`•
`Development of Advanced Computational Tools (In Vitro & In
`Vivo)
`Hydrodynamics
`•
`Dissolution
`•
`Absorption
`•
`Metabolism
`•
`Application of physicochemical principles to dissolution
`
`•
`•
`•
`
`34
`
`Page 40
`
`