In Vitro and In Vivo Correlations and BiorelevantDissolution Using Computers

Simulations in a QbDEnvironment

November 14, 2016

Raimar Löbenberg

Outline

• Fundamentals in QbD

• Fundamentals of the BCS

• API vs. Formulation controlled dissolution

• How to identify clinically relevant product specifications

–Example lysosomal trapping

–Permeability vs dissolution controlled absorption

• Conclusions

Quality by DesignProduct Quality Implementation Lifecycle Initiative (PQLI)

• Quality by Design is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management.

– ICH Q8 Pharmaceutical Development

– ICH Q9 Quality Risk Management

– ICH Q10 Quality Systems

– FDA Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach. Final Report

16-07-06 7

IVIVC 1997

16-07-06

9

BCS Classification Lifecycle Management

BCS Biowaiver 2000

QbD

SUPAC 1995/ 1997 Level 1/2/3 Changes

Level A CorrelationBio-

waiver

BSC Class waiver

Design Space

How things started…

Fundamental 1

Only what is dissolved can be absorbed

Fundamental 2Only what is absorbed can be studied in

vivo

Solubility directly influences the dissolution behavior of oral dosage forms in gastrointestinal tract

Biopharmaceutical Drug Classification System (BCS)

8

Class Solubility Permeability

I High High

II Low High

III High Low

IV Low Low

When to use Dissolution/Disintegration?

ICH Guideline Q6A “Specifications: Test procedures and acceptance criteria for new drug substances and new drug products” outlines acceptance criteria for different dosage forms and routes of administration. The guidance document contains decision tree #7.1, which allows disintegration testing to be used as a performance/quality control test if a relationship between dissolution and disintegration has been establishedU.S. Department of Health and Human Services, 1999

FDA Study 2009

FDA Study 2009

However, no direct correlation was observed between the

disintegration and the dissolution

For certain Formulations Disintegration and Dissolution are Sequential ProcessesNo correlation other than the Sequence should be found if API controls Dissolution

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Cs

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F=kKP*tn

Drug release mechanism

KorsmeyerPeppas equation:

Exponent n of the power law and drug release mechanism from polymeric controlled delivery systems of different geometry

n values Drug release mechanism

Thin Film Cylinder Sphere

0.5 0.45 0.43 Fickian Diffusion

0.5 <n<1.0 0.45<n<0.89 0.43<n<0.85 Anomalous Transport

1 0.89 0.85 Case-II Transport

Fast Disintegrating slow eroding Tablet

0

20

40

60

80

100

120

0 20 40 60

% D

isso

luti

on

Time

25 rpm observed50 rpm observed75 rpm observed

0

20

40

60

80

100

120

0 20 40 60

% D

isso

luti

on

Time

25 rpm observed50 rpm observed75 rpm observed

Korsmeyer-Peppas n values75 0.11150 0.29325 0.413

Korsmeyer-Peppas n values75 1.1150 0.93825 0.924

Sphere<0.43

0.43<n<0.85>0.85

Sequential EventsTablet Disintegration

• After you pull the handle the valve opens fully

• Water will flush down the pipe

• The rate depends only on the hydrostatic pressure and diameter of the pipe

• The extend is 100%• If you only pull a little and do

not trigger the valve to open you can control the amount and rate of water

Flushing a Toilet

Dissolution TestDisintegration Test

Direct compression

Dry granulation

Powder blend

Wet granulation

Fluid bed granulation

Sinter granulation

Melt extrusion

Dissolution Test

API controls

dissolution

excipients

have no

significant

impact

Capsule

Tablet or ODT/FDT

Formulation

significantly

controls

dissolution

Dosage form

Manufacturing process

R&DDevelopment

QC Method

PHASE 1/2 R&D DEVELOPMENT

Proposed New Formulation

Classification:

API vs.Formulation

Controlled Dissolution

Release mechanism Modeling

In vitro: Dissolution Testand Clinical relevance?

Prediction Software

• DDDPlus

• MembranePlus

• GastroPlus

Computer Simulations

Using ACAT and PK models

• In vitro data can be used as input function into Gastro Plus™ to simulate the absorption profiles of the drugs

• Gastro Plus™ uses a mathematical model called Advanced Compartmental, Absorption and Transit (ACAT), model which is based on the principles of the BCS

• The 3 major data input tabs are:– Compound tab

– Physiology tab

– Pharmacokinetics tab

SmallIntestine

Portalvein

GastroPlus Sodware

• Physicochemical Data as Input

• Dissolution Data as Input

• Permeability

GastroPlus Software

GastroPlus Software

How you get it wrong doing the right thing

“NO STRAIT LINE PLEASE”• Lysosomal trapping of

weak bases with high pKa

• Example Dextromethorphane

• Pharmacokinetic differences EM/PM

Metabolism of dextromethorphan by CYP2D6 and CYP3A4 (P450 enzyme system)

CYP3A4 CYP3A4

CYP2D6

CYP2D6

GastroPlus Software

In Vivo Amount in SystemicCirculation

Dissolution simulation DDDPlus

pH 7.8App 4 Closed loop 20hrs

Dissolution simulation DDDPlus

Desired profile which

matches the in vivo

observed fraction

dose absorbed!

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Systemic Circulation

0

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40

60

80

100

120

0 5 10 15 20 25 30

Dextromethorphan Dissolution

R² = 0.9959

0

20

40

60

80

100

120

0 50 100 150

% dissolved vs.% absorbed

Classical IVIVC

Let Snoopy tell you…

I have heard you are writing

a book on theology

I hope you have a good title for it

I have the perfecttitle

“has it ever occured to you that you might be wrong?”

What really happens

Lysosomal-Trapping of weak bases pKa >7

Gut: pH 5.5 -7.0

Cytoplasm

Lysosome pH 4.5 -5.5

Cytoplasm

Blood 7.4

Membrane Plus

apical chamber

basolateral chamber

PBPK ModelTeorell (1937)Provide a clear physiologicaldescription of determinants of drug disposition.Over the years so-called compartmental PK analysis wasdeveloped to examinepharmacokinetic behavior. These simplified models give equations that have exact solutions and have provided many useful insights despite their very much simplified depiction of physiology.

(lung, liver, heart, brain, kidney, spleen, skin, reproductive organs, muscle, adipose, red/ yellow marrow and rest of body)

PO 30mg EM Gorski

2

3

4

1

5

F (not Fa!)Fa

D PV

FDp(not Fa!)Absorption

Metabolism

A

ACAT model PK models/PBPK

SC

Metabolism

Dextromethorphan in Extensive metabolizers

%Drug in SC

Drug Dissolved

Drug Absorbed%Drug in PV

Observed Drug in Plasma

Dextromethorphan in Extensive metabolizers

Drug Dissolved

Dextromethorphan in Extensive metabolizers

Drug Absorbed

F (not Fa!)

Dosage form interface

Biological System

Dextromethorphan in Extensive metabolizers

Drug in Portal vein

Dextromethorphan in Extensive metabolizers

Ca

Drug in Systemic circulation

Concentration

% of dose

SC

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Systemic Circulation

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Dextromethorphan Dissolution

R² = 0.9959

0

20

40

60

80

100

120

0 50 100 150

% dissolved vs.% absorbed

Classical IVIVC

Classical PK model

Classical IVIVC

Wagner Nelson: D0 = D body + D urine + D not Abs

% D Abs = D body + D urine

=SC

Dosage form impact is limited to the gut lumen / enterocyte interface!!!

Drug Dissolved & Absorbed

Product Dissolution Specification

%Drug in SC

Drug Dissolved

Drug Absorbed%Drug in PV

Observed Drug in Plasma

Q80 @ 2 hrs

Dissolution Specification

Summary of IVIVC• IVIVC - It works but you better knw what

you are doing!

• Software can assist the formulation scientist to identify critical formulation variables

• If Permeability controls absorption dissolution criteria might not be important.

• Lysosomal trapping can impact the appearance of the drug in the systemic circulation

Conclusions

• BCS allows us to ask the right questions to find the solutions in drugdevelopment and dissolution method development

• The BCS has changed the way we look at drugs and the drug development process

• Software can assist to establish IVIVIC• You must know what you are doing

16-07-06 62

YES, the generic is cheaper. But for

real savings take the placebo

Questions

https://www.ualberta.ca/pharmacy/about-us/contact-us-and-people/people/raimar-loebenberg

Acknowledgments

• Abbvie

• Simulations Plus

• DDIC

• University of Alberta

• Muhammad Sarfaz

• Gregory Webster, PhD

• Michael Bolger