the new science of oral bioequivalence: in vivo predictive...

The New Science of (Oral)

Bioequivalence:

In Vivo Predictive Dissolution (IPD)

Gordon L. Amidon

Charles Walgreen Jr. Professor of

Pharmacy

College of Pharmacy

University of Michigan

Ann Arbor, MI

FDA-PQRI May 16, 2014

Delivery Quality Product to

Patient

We are the Easter Bunny!

Product Quality

• Product Performance in vivo – Clinical

• What is our Measure of Performance?

• In Vivo Release of Drug

• Science of In Vivo Release

• In Vivo Variables

Oral Products

• The ‘Simplest’ Case

• In Vivo Release: Simple <-> Complex

• ‘One Size fits All’ <-> In Vivo BE

• Science has evolved since 1960’s

The Science of BE is at the

Absorption Site

Oral

A New Era of Oral BE

• BCS Class/Subclass

• In Vitro Standards

• Professional and Public Acceptance

• Scientific Research Needs

Absorption (BE) Science View:

THE BCS View

If two products, same drug, present

the same surface concentration profile

over time => They will be

Bioequivalent (BE)

0

M(t)

t

w w

A

w w w

P C dAdt

j P C

Predicting Mass (Dose)

Absorbed

w eff wj P C

BCS SubClasses

BCS Class 0.1 N HCl pH 6.5 Permeability Media*

I High High High PIB**

IIa Low High High 15 and 30 min in PGB** then PIB**

IIb*** High Low High 15 or 30 min in PGB** , then PIB**

IIc Low Low High Dissolution 15 and 30 min in PGB** ,

Then PIB** + surfactant to match in vivo

solubilization

III High High Low Same as I

IVa Low High Low Same as IIa

IVb** High Low Low Same as IIb**

IVc Low Low Low Same as IIc

‘In Silico’ BCS Class IIa,b,c

Dissolution

BE Dissolution Sub-Classification Proposal

BCS

Class

Drug Solubility

pH 1.2

Drug Solubility

pH 6.8

Drug

Permeability Preferred Procedure

I High High High >85% Dissolution in 15 min; 30 min, f2., pH =

6.8.

II-A Low High High

15 min at pH=1.2, then 85% Dissolution in 30

min., pH = 6.8; F2>50; 5 points minimum; not

more than one point > 85%.

II-B High Low High >85% Dissolution in 15 min., pH = 1.2.

II-C Low Low High

15 min at pH=1.2; then 85% Dissolution in 30

min., pH = 6.8 plus surfactant*; F2>50; 5 points

minimum, not more than one point > 85%.

III High High Low >85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8.

IV-A Low High Low

15 min. at pH = 1.2; then 85% Dissolution in 30

min., pH = 6.8,; F2>50; 5 points minimum.; not

more than one point > 85%.

IV-B High Low Low >85% Dissolution in 15 min., pH = 1.2.

IV-C Low Low Low

15 min at pH=1.2; then 85% Dissolution in 30

min., pH = 6.8 plus surfactant*; F2>50; 5 points

minimum, not more than one point > 85%.

In Vivo Predictive Dissolution (IPD):

GastroIntestinal Simulator (ASD/GIS)

Two-Phase Dissolution

• Mass Transport Analysis

• Not Curve Fitting

• Physical Chem. & Transport

Variables

• Can be mechanistically set-

up

• Preformulation-Formulation

• In Vivo Predictive

ho [R-]

a

[RH]a

[R-]a,s

[RH]a,s

[RH]o,s

[R]o,s

[RH]o, [R]o -ha Well-

mixed

aqueous

buffer

Organic

medium 0

Drug transport

Mechanistic analysis of solute partitioning in the two-phase

apparatus

16

Fa,t =1

1+ b( )e

-AI

VaPI 1+b( )t

+ bé

ëêê

ù

ûúú

Fo,t =1

1+ b( )1- e

-AI

VaPI 1+b( )té

ëêê

ù

ûúú

Fa,t

= Fraction of dose in aqueous medium

Fo,t = Fraction of dose in organic medium

t = time, s

β = Va/(K*Vo)

Vo = Volume of octanol, ml

V = Volume of water, ml

K = Apparent octanol-water partition coefficient

Pi = Interface permeation rate, cm/sec

A = Area of the interface, cm2

Physical transport parameters defined by experimental set up, or can be measured

or estimated a priori

Previous kinetic models (e.g. Grassi et al. 2002) rely on fitting mathematical constants

with no physical basis

Ref: D.M. Mudie, Y. Shi, H.L. Ping, P. Gao, G.L. Amidon, and G.E. Amidon. Mechanistic Analysis of Solute Transport in an In Vitro Physiological

Two-Phase Dissolution Apparatus. Mol Pharmaceutics. 33: 378-402 (2012).

In Vivo Predictive Dissolution

(IPD) : Need

• In vivo GI Physiology variables

– Transit, Lumenal contents ([H+], η, S*),

volumes

• Mean and Statistical distribution

• Time Dependences

• Reflective in vitro Methods

• Full Mass Transport Analysis

In Vivo Predictive Dissolution:

IPD

• Methods (10-15) based on BCS Subclass

• Not a QC method

– Though QC method would be based on IPD

• Partial basis for BE determination

– As used today for biowaivers vs. dose

• Pharmaceutical Standards Institute

– Widely accepted by Pharmaceutical and Health

community

https://Pharmacy.umich.edu/invivodissolution

https://pharmacy.umichh.edu/invivodissolution

BE Regulatory Science

• Mass transport Analysis (absorption): All

routes

• Many routes more complex than Oral

– Topical, lung, etc.

• Focus on in vitro tests reflecting in vivo

Nasal Topical: Skin

0 ( )

Dose Absorbed=M(t) ( ) ( )

( ) ( )

t

w w

A t

w w w

P t C t dAdt

j P t C t

Predicting Mass (Dose)

Absorbed

• Time Dependence

Bioequivalence (BE) Today: Oral

• Historically a Relative Bioavailability (BA) Based View

– Misses the underlying scientific issues

• IN Vivo Dissolution

• BE Testing is Same Drug

– Once Absorbed PK is the Same

• The Science of BE is at the Absorption Site

– For Oral Dosage Form in the GI Tract

• The Question is: What is the Best BE Test

BE Can Not be waived

Only the in vivo test can

be waived

There is no Drug on the Market

There is only product on the market

BE

Plasma Paradigm vs. Mechanism

(Oral)

==

Todays ‘Gold’ standard Todays Science (oral)

Oral BE: The Science

Buffer (CO2) Effect on ketoprofen Dissolution

Buffer components pH Mean flux*

(S.D.)

USP 50mM phosphate 6.8 0.783 (0.01)

29 mM phosphate

(FaSSIF)

6.5 0.386 (0.01)

5.0 mM bicarbonate 6.5 0.134 (0.003)

15 mM bicarbonate 6.5 0.231 (0.002)

20 mM bicarbonate 6.5 0.312 (0.009)

SGF, 0.1N HCl 1.2 0.022 (0.001)

*: initial drug flux /dissolution rate of ketoprofen (mg/cm2/min) at 37C,

100rpm, n = 3. The drug disk was prepared with 150mg of bulk drug and

compressed under 2000LBS for 60s.

Stomach

10mM

4-

21mM

avg

15mM

30mM

70mM

Human GI Bicarbonate

Duodenal: PCO2 ~20-30%

In Vivo Predictive Dissolution

• In Vivo Environment

– Medium Composition

– Fasted/Fed

• Variation in Environment

• Simulation

GI Volumes

• MRI Study*: Gastrointestinal Volumes following 8 oz

(240) ml of water

*Marciani,L., Mol. Pharmaceutics 2014 (submitted)

MRI Images

• A= Stomach after 240 ml drink

• B= Abdomen

• C= Small bowel water pockets

A B C

Liver

Stomach

Spleen

Spine

Duodenum

Jejunum

Ileum

Liver

Duodenum

Jejunum

Ileum

Mean Volume

Stomach Small Intestine

Equilibrium (?) In the Intestine • Bicarbonate Equilibrium

• H2CO3 HCO3− + H+ Ka1 = 2.5×10−4 ; pKa1 = 3.60 at 25 °C.

•

• HCO3− CO3

2− + H+ Ka2 = 5.61×10−11 ; pKa2 = 10.33 at 25 °C

•

• Gas Phase Equilibrium

• – CO2(gas) = CO2(dissolved)

•

• where kH=29.76 atm/(mol/L) at 25°C (Henry constant)

•

• CO2(aq) + H2O = H2CO3 (aq)

•

• Then of course we have CO2 transport in the Intestine Transporters, Exchangers, intracellular equilibrium

CO2 + H2O =

H2CO3

CO2

http://en.wikipedia.org/wiki/Henry's_law

Tablet, HA

Bicarbonate Buffer Physiological

Relevance

• Equilibrium Prevails in

the Bulk (pKa=6.04)

• H2CO3 undergoes a

irreversible reaction in the

Boundary Layer (BL)

due to the slow hydration

CO2 + H2O reaction

• The irreversible reaction

consumes H+ in the BL

and increases the

buffering

𝑪𝑶𝟐 +𝑯𝟐𝑶⇌ 𝑯+ +𝑯𝑪𝑶𝟑−

GI Lumen

Bulk Solution

HA->H+ + A-

𝐶𝑂2 + 𝐻2𝑂𝑘𝑑 𝐻2𝐶𝑂3 ⇌𝐻𝐶𝑂3

− + 𝐻+

BL

BE ‘Generic’ Product Science

• Science is at the absorption site

– All Routes

• Oral -> IPD

• GI Physiology: MRI

• Computational Software

– Much Needed Information

• Pharmaceutical Standards institute

BCS Subclass Proposal

Generic Drugs -> Generic Drug

Products

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