For more information about TNOs solutions to address the critical factors in bioavailability and PK, please contact

us.

Looking for ways to address critical factors in bioavailability and PK?

Christiaan Kalk, MSc E Christiaan.kalk@tno.nl T +31 306 94 44 99 Steven Erpelinck, BSc E steven.erpelinck@tno.nl T +31 30 694 43 18 Tineke Meijers, PhD Email: tmeijers@tnopharma.com T +1 41 68 37 75 00

About TNO
TNO is one of Europes largest research and technology organizations. We aim to provide our customers with the best possible advice and research based on a multidisciplinary approach and a strong drive to give you the information you need to optimize your drug development portfolio. In the US, we have a strategic collaboration with the consultancy based CRO, Seventh Wave, and Rutgers University concerning our gastrointestinal model TIM.

Visiting address Utrechtseweg 48 3704 HE Zeist The Netherlands

Postal address P Box 360 .O. 3700 AJ Zeist The Netherlands

www.tno.nl/pharma

TNO | Innovation for Life

TNO services
As an expert in the critical factors in biovailability and kinetics, TNOs objective is to deliver the detailed information you need for your drug development programs. We help you address the luminal performance and availability for absorption of formulated APIs, biodistribution and metabolism. We offer: Dynamic in vitro model of the gastrointestinal tract (TIM system, see illustration below) Unique transporter assays (e.g. based on HEK or MDCK cells) In vivo and in vitro ADME studies via all routes of application In silico modeling (TIMpk, PBPK) Microdosing Consultancy

Addressing critical factors in bioavailability and PK

Many of todays drug candidates pose challenges during development, for example because of their poor permeability or drug-drug interactions.

If you are looking for a partner to help determine and then address these challengesbe it a single factor or a whole chain of different factors limiting the bioavailability and metabolism of your drug e candidatewe at TNO would like to speak with you. clear insight into th al tract Crystalstrointestin f the ga dynamics o gastrointestinal tract when food is digested ro-Intestinal
TNO gast on in the and small n for TIM, the tly that goes What is it exacswallowed? Thats a questiomodels, one for the stomachmodels e simulation n, TIM-2. Thes or medication are two separate large intestine or colo y temperature but also the Model. There sporting bile at bod and one for the ading and tran various enzymes and stine, TIM-1, of inte t: kne only the action the gastrointestinal trac ly be adapted for simulate not can fairly easi lt or the hing activity of most eye-catc es for a realistic model thatsystem of a baby or an adu to simulate the digestive and TIM-2 are also suitable food. This mak oses, whether ulation. TIM-1 like dogs. research purp ach creatures from a form other single stom release of a drug inal tract for the gastrointest es

TNO at the AAPS FIP World Congress

November 1418, 2010, the AAPS and the FIP World Congress will be joining forces to organize a conference in New Orleans, USA. TNO is looking forward to attending the conference. It is a prime opportunity to meet others, both new contacts and old friends, to discuss hot topics in their companies, within TNO and in the field of drug formulation. If you will also be attending, feel free to make an appointment to meet with one of the TNO experts. Alternatively, visit our booth 2737 where we will be explaining our approach to tackling the challenges of drug development. Our posters: In vitro evaluation of postprandial disintegration of immediate release fosamprenavir tablets using the dynamic gastrointestinal system TIM Assessment of species differences in the inhibition of the human and murine ABC transporters MDR1 (ABCB1) and Mdr1a (Abcb1a) by registered drugs in vitro Assessment whether ABC transporters are involved in the transport of the oxime HI-6 across the bloodbrain barrier Dynamic GI tract system predicts the bioavailability of formulated dissolution rate API in dogs and humans. Join poster with Abbott.

Gastrointestina Peristalsis
using wall is simulated The intestinal sleeves that are flexible plastic this water pressure; compressed by in the lates peristalsis therefore simu l tract. gastrointestina
Water supply and discharge re Nitrogen pressu ltic closes the perista valves

move and intestine of the stomach they The contents model, just as ns through the in small portio through the happens here do in reality. This valves. located peristaltic vertically
Contents of the intestine

l transit

The flexible sleeve is closed by nitrogen pressure

Glass

Flexible plastic

sleeve

TIM-2
Intestine conten ts allows small compartment A sensor in this colon model to be the the volume in regulated

Digestive juic

juices and saliva, gastric Enzymes from the are supplied for hydrates. pancreatic juice proteins and carbo digestion of fats,
Stomach

simulates the d system that This system TIM-2 is a close (large intestine). action of the colon particular adjusted for a can be specifically porate the , and can incor target study group , an adult or even flora of a child intestinal micro a dog.

contents with of By flushing the is cleared nitrogen, the colon oxygen

can A pH electrode measure the acidity level

The undigested small material of the here in intestine arrives model the colon

pH electrode

Duodenum

Duodenum

added Bicarbonate is to in the duodenum of the enable the pH ach supplied stom to 6.3, content to rise bile and together with pancreatic juice.

Coloncompar timent

Dialysis
Jejunum

Jejunum

Membrane system

a little In the jejunum again bicarbonate is is 6.8. added; the pH

is system that is also a dialys cules In TIM-2 there water and mole absorption of simulates the the colon) by the the bacteria in (as formed by of the colon. intestinal wall

m A dialysis syste simulates the water, absorption of and digested food released drugs through the in intestinal wall the jejunum and ileum.

Contents of the intestine

Flexible plastic sleeve

Ileum
Ileum

pH In the ileum the gh rises to 7.2 throu the addition of bicarbonate.

Dialysis system

aar@tno.nl, Info: rob.haven r@tno.nl evelijn.zeijdne

ts Compartmen

specific ent has its own Each compartm ly as possible resemble as close conditions that l tract. For l gastrointestina those of the actua ach has a very lly empty stom instance, a virtua g and goes down rises during eatin low pH, which ic acid secretion. again by gastr

Body tempera

peristalsis also to simulate the The water used temperature. l at the right body keeps the mode

ture

Water supply system peristalsis

for the