Intelligent Systems for Personalized Medicine

ISyPeM II

Administration and monitoring of medical treatments

enrico.accastelli@epfl.
ch

Intelligent Systems for Personalized Medicine

ISyPeM II

Administration and monitoring of medical treatments

enrico.accastelli@epfl.
ch

Intelligent Systems for Personalized Medicine

ISyPeM II

Administration and monitoring of medical treatments

enrico.accastelli@epfl.
ch

es of medical treatment for which monitoring is highly critical

Imatinib exposure
(ng/ml)

IMMUNOSUPPRESSIVE
DRUGS

CANCER TARGETED
THERAPIES

IV ANTIBIOTICS

enrico.accastelli@epfl.
ch

Patient

time after dose (hrs)

Courtesy of N. Widmer

Only
Qualitative!
Drug
concentration
needs to be
quantified with
Syva RapidTest
15% accuracy
for TDM

es of medical treatment for which monitoring is highly critical

IMMUNOSUPPRESSIVE
DRUGS

Towards distributed bioanalytics

Physiological parameters, DNA
analysis

Hand-held

CANCER TARGETED
THERAPIES

Accu-Chek product
iSTAT, Abbott lines.
Roche Diagnostics

Top bench
IV ANTIBIOTICS

enrico.accastelli@epfl.
ch

cobas Lab-in-a
tube
Roche
Diagnostics

Clonit
StMicroelectronics
5

Intelligent Systems for Personalized Medicine

ISyPeM II

Reduce volume samples

Monitoring of treatment
is often needed in
newborn and child care

BIOCHEMICAL/ANALYTICAL CHALLENGES
Compact, affordable
analytical systems

Measurement performed at
the MD
integrated with decision
support software

DATA INTERPRETATION AND MANAGEMENT CHALLENGES

BIOCHEMICAL/ANALYTICAL CHALLENGES
Interaction and
Interoperability

enrico.accastelli@epfl.
ch

Gather data for decision

on dosage and enrich
population data
6

Affordability of the analytical system

Meet the microsample challenge

Renaud Lab

J-M Segura
M Geiser

Immunoassays
(FPIA,
CMIA, MIA)

25 cm

20 cm

Abbott "Architect ci8200"

enrico.accastelli@epfl.
ch

Affordability of the analytical system

Meet the microsample challenge

Renaud Lab

J-M Segura
M Geiser

Immunoassays
(FPIA,
CMIA, MIA)
Abbott "Architect ci8200"

ISyPeM II demonstrator
Low-cost
Fully integrated
Based on High sensitive FPIA
Works on capillaries
enrico.accastelli@epfl.
ch

Microsample analytics in capillaries

Plasma extraction from whole
blood

Yield outperforms any passive on-chip

method reported to date. Extraction
from ejection.

Renaud Lab

http://dbs-system.ch

enrico.accastelli@epfl.
ch

Microsample analytics in capillaries

FPIA of Tobramycin performed in glass
microcapillaries
Therapeutic range
0.260
Squared glass capillary
0.240

reference system

0.220
Anisotropy

300 m

capillary

0.200

Renaud Lab

0.180
0.160
0.140
0

10

12

Concentration [g/ml]

http://dbs-system.ch

J-M Segura

enrico.accastelli@epfl.
ch

10

TACROLIMUS

IMATINIB

TOBRAMYCIN

Lack of availability of ligands for drug

molecules
Drugs are small molecules
They can have very different solubility and
biochemical and metabolic characteristics
In vivo raised antibody against drugs have
poor affinities and in some case are not
available at all

We develop in vitro approaches for the

selection of ligands for different classes
of drugs

enrico.accastelli@epfl.
ch

11

- NNN...NNN 460 possible variants

=
1.33 1036 sequences

In vitro selection of aptamers

IMATINIB

TOBRAMYCIN

Streptavidin-coated
magnetic beads

Docking region (12nt)

CCTTACCTAGGTGTAG- 5'

Guiducci Lab

In vitro selection results

- CCTTACCTAGGTGTAG- 5'
5' - GGAATGGATCCACATC-

(A) Loading
Conversion to ssDNA
conjugation beads-aptamers

(B) Selection
exposition of the small
molecule to the aptamers' pool
Binding aptamers - drug

(C) Partitioning
Separation of binding
aptamers from the pool

R2=0.993
LOD=0.15 M

Spiga F. M. et al. ACS Comb. Sci. 2015,

featured on the cover of May Issue
enrico.accastelli@epfl.
ch

Clin. Pharmac.
DNA aptamers can
be obtained in a
few steps that are
better or equal to
existing RNA
aptamers

Functional in serum
and proved on
patient samples,
meeting the clinical
range
Specificity
demonstrated
Method can be
applied to different
drugs

12

TOBRAMYCIN

Measuring Tobramycin concentration

from serum on a palm-sized devices
DNA aptamers are
stable and functional
on surfaces
Sensitivity is
demonstrated in
undiluted serum
undergoing minimal
sample treatments
o Can meet on
relatively high
clinical ranges

Guiducci Lab

Clin. Pharmac.

G. et al. Analytical Chemistry, April 2015 . Contributed by EPFL, CHUV and STMicroelectronics
enrico.accastelli@epfl.
ch

13

TACROLIMUS

In vitro selection of antibodies

Heinis Lab

J-M Segura
First in vitro
selection of
antibodies
against
Tacrolimus ever
performed
Two approached
deployed to
competition
assay

Peptide
macrocyclesbased approach
C. Heinis, Bicyclic peptide phage display, 10th Peptide Therapeutics Symposium,
enrico.accastelli@epfl.
for assays
ch23.10.2015, The Salk Institute, La Jolla, USA

14

DATA INTERPRETATION
AND MANAGEMENT
enrico.accastelli@epfl.
ch

15

Drug decision support system

developed by ISyPeM II partners
Yann Thoma

Now in use at
CHUV and
connected with
MOLIS database

Div. Clin. Pharmac.

Largely
outperforming
any existing
support systems

FIT grant for start-up creation:

http://www.fondation-fit.ch

Validation and
Clinical trials in
progress for
certification and
commercializatio
n

Lab Innovation Award, Lausanne 2016

enrico.accastelli@epfl.
ch

16

AMINOGLYCOSIDES EFAVIRENZ

IMATINIB

Meta-analysis approaches to build

population pharmacokinetics models
Div. Clin. Pharmac.

Consolidation of
population studies for
TDM
Statistical combination
of independent
population studies

Br J Clin Pharmacol. 2014

Nov;78(5):1090-101

enrico.accastelli@epfl.
ch

17

P2P approach for data storage

Cryptographic
Module

LDB
metadata

Anonymization
Module
RSDB

Query/Ex
change
Data

ch

RSDB

LDB

Initiator
A1
Negotiat
e
Tuple-center

No centralized
system for
data storage
Contributors
can share
their data and
get
anonymized
data from the
enrico.accastelli@epfl.
others

Contributor

P2P Network
Publish/Subscribe

Contributor

RSDB

"Multi-Agent System for Dynamic Data

Aggregation in Medical Research A.
Dubovitskaya,V. Urovi, I. Barba, K.
Aberer, M. I. Schumacher, in preparation
Dubovitskaya, A. Privacy Preserving
Interoperability for Personalized
Medicine, in: Swiss Medical Informatics,
Swiss Society for Medical Informatics,
Switzerland, 2014, Contributed by AIS
18
Lab, Thoma Lab and CHUV

Output and outlook

More than 15 peer reviewed papers published (only ISyPeM II)

First demonstrator is functional

CTI on going with a Pharma company (Debiopharm International)

nterest in the diagnostics field

enrico.accastelli@epfl.
ch

19

enrico.accastelli@epfl.
ch

20

enrico.accastelli@epfl.
ch

21

Therapeutic Drug Monitoring Today

Interpretation and
recommendations by
clinical
pharmacologists

Measurement of drug
concentration

Immunoassays
(FPIA,
CMIA, MIA)
Abbott "Architect ci8200"

Central clinical labs

Imatinib exposure
(ng/ml)

Blood sampling

Patient

LC-MS/MS
time after dose (hrs)
Courtesy of N. Widmer

Agilent

Lengthy procedure restricting the applicability of TDM

enrico.accastelli@epfl.
ch

http://e-sante.futura-sciences.com,

22

Bioanalytical systems for diagnostics

and monitoring

Physiological parameters, DNA analysis

ER Drug of abuse tests

Hand-held

Accu-Chek product
iSTAT, Abbott lines.
Roche Diagnostics

Top bench

cobas Lab-in-a
tube
Roche
enrico.accastelli@epfl.
Diagnostics
ch

Clonit
StMicroelectronics

Syva RapidTest
EMIT (Enzyme multiplied
immunoassay technique)

Only Qualitative!
Drug concentration
needs to be quantified
with 15% accuracy for
TDM
23

enrico.accastelli@epfl.
ch

24

enrico.accastelli@epfl.
ch

25

ISyPeM. Enabling drug-based

therapeutic drug monitoring.

Physiological parameters, DNA analysis

ISyPeM integrated
approach to TDM

Hand-held

Accu-Chek product
iSTAT, Abbott lines.
Roche Diagnostics

Top bench

cobas Lab-in-a
tube
Roche
enrico.accastelli@epfl.
Diagnostics
ch

Clonit
StMicroelectronics

eHealth
standar
ds
Data
security

Cartridge
with stable
reagents
Low sample
volume

Supported
Interpretation
for non
specialists
At the clinic
and outside
26

ISyPeM II: Objectives

Develop a top-bench stand-alone proof-of-concept
demonstrator for in vitro quantitative analysis of therapeutic
drug from whole blood.
The consortium is now focusing on antibiotics and
immunosuppressant drugs.

Our methodology

Develop and demonstrate the feasibility of in vitro selection techniques to identify suitable
probes for drug molecules
Achieve microvolume processing and analysis
Develop novel compact and fully-integrated assays proving their
Stability of molecules in complex matrix and in presence of sample treatment
reagents
Specificity
Accuracy
Equip local clinical institutions and selected cabinets with certified decision support
systems for drug dosage
Largely outperforming existing tools for usability and value of elaboration
approaches employed.
Connected with local databases, secure and connected in a P2P network to enrich
enrico.accastelli@epfl.
pharmacokinetic databases
ch

27

TOBRAMYCIN

Measurement system: miniaturization of

the assay

luorescence Polarization Immunoassay

J-M Segura
M. Pfeifer
M. Geiser

Competitive assay
(high sensitivity)
20 cm

25 cm

Designed for low

volumes (focalized)

enrico.accastelli@epfl.
ch

Renaud Lab

Functional on wells,
tested on capillaries
and paper

28

Progress of demonstrator

enrico.accastelli@epfl.
Not integrated
ch

Partially integrated

Integrated

29

BACK UP slides

enrico.accastelli@epfl.
ch

30

Therapeutic drug monitoring (TDM) for

imatinib has been suggested to improve
efficacy, assess compliance, and evaluate
drug-drug interactions
Teng et al., Therapeutic Drug Monitoring. 34(1):85-97,
February 2012.

enrico.accastelli@epfl.
ch

[Imatinib]

FPIA for tacrolimus TDM

Current status and next steps

enrico.accastelli@epfl.
ch

Population PK Meta-analysis of Imatinib

plasma concentration [ng/mL]

Systematic literature review

Best possible reference data

IP50% and IP90%

according to 9
population
PK studies
Metaanalysi
s

IP50%, IP75% and

IP90% of the
aggregated model
P95
P75

Simulatio
ns
and remodeling

P50
P25
P5

Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population

enrico.accastelli@epfl.
pharmacokinetic analyses
ch