Isypem2

ISyPeM II Giulia Cappi École polytechnique fédérale de Lausanne

Annual Plenary Mee;ng of the Nano-­‐Tera program May 4th, 2015

Therapeu;c drug monitoring (TDM)

Ima;nib exposure (ng/ml)

Candidates for therapeutic drug monitoring Modern anticancer agents Immunosuppressants Antiretrovirals Antibiotics

Courtesy of N. Widmer

time after dose (hrs)

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Therapeu;c Drug Monitoring Today Transfer to and measurement at central clinical labs

Interpretation of the result by a specialized doctor

Drug Concentra0on

Blood sample taken at the doctor’s office or at the hospital

Target

?

Pa0ent Treatment dura0on (days)

hQp://e-­‐sante.futura-­‐sciences.com

AbboQ "Architect ci8200"

Today this procedure severely restricts the applicability of TDM ISyPeM II -­‐ G. Cappi

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Drug quan;fica;on in body fluids Used in Clinical facilities

Agilent LC-MS/MS

Abbott "Architect ci8200” FPIA (fluorescence polarization immunoassay) CMIA (chemiluminescent microparticle immunoassay) MIA (magnetic immunoassay)

ISyPeM II -­‐ G. Cappi

Point-of-need

Syva RapidTest® EMIT (Enzyme multiplied immunoassay technique)

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Point-­‐of-­‐need therapeu;c drug Hand-held monitoring The In-Check® system integrates amplification and microarray detection processes for end-point PCR-based molecular testing in a single lab-on-chip.

The In-Check system is intended to address the qualitative identification of multiple extracted nucleic-acid analytes, through PCR amplification and hybridization on a low-density microarray.

Amplification of extracted nucleic acids

Detection through low-density microarray

The integrated silicon heaters, temperature sensor and miniaturized 25 µl volume allow the In-Check PCR module to perform the rapid heating and cooling cycles required for highly reliable, end-point PCR.

The In-Check microarray module is used to detect the amplified labeled DNA sequences through hybridization on a low-density microarray composed of 126 spots.

The In-Check PCR module is thermally driven by the In-Check temperature control system (TCS). This allows fast and programmable temperature ramps together with independent random access for 5 different tests simultaneously.

iSTAT, Abbott

Accu-Chek product lines.

Roche Diagnostics User-friendly operation

ISyPeM approach toTDM

The microarray module includes a set of control probes at fixed positions, as well as specific probes located according to customer requirements.

The microarray module is fluidically connected to the PCR module and is thermally driven by the temperature control system. After hybridization, the microarray module is read by the In-Check optical reader (OR) in a few seconds.

In-Check system

The microfluidic integration of the PCR and hybridization modules ensures that system operation does not require highly-trained personnel, and greatly simplifies the typical lab procedures.

The In-Check system is extremely userfriendly and allows unskilled operators to perform all steps from sample to result.

Top bench

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Cobas product lines Roche Diagnostics

Clonit StMicroelectronics

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ISyPeM. A solu;on to enable drug-­‐ based therapeu;c drug monitoring

• Low-sample volumes • Miniaturized reader • Cartridge that can be stored with stable reagents

• Monitoring and prediction interface for clinicians and practitioners • Local or remote

ISyPeM II -­‐ G. Cappi

• Extension of eHealth medical standards • Data integrity

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ISyPeM: A solu;on to enable drug-­‐ based therapeu;c drug monitoring

HOMOGENEOUS AND HETEROGENEOUS ASSAY

• Cartridge that can be stored with stable reagents

In vitro selection of capture molecules for drug targets ISyPeM II -­‐ G. Cappi

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In vitro selec;on of monoclonal an;bodies for Tacrolimus Antibody phage display

Heinis Lab

Target: tacrolimus

Sangram Kale

Phage-antibodies were successfully selected for Tacrolimus and expressed ISyPeM II -­‐ G. Cappi

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In vitro selec;on of DNA-­‐ aptamers for Tobramycin

Guiducci Lab

DNA beacon aptamers Capture Selex

F. M. Spiga Now with Creoptix Sensors

Spiga F. M. et al. ACS Comb. Sci. 2015, featured on the cover of May Issue ISyPeM II -­‐ G. Cappi

No drug derivatization High affinity Specific Functional in serum 9

Low-­‐volume sample prepara;on on chip Plasma extraction from whole blood Renaud Lab

Yield outperforms any passive on-chip method reported to date

David Forchelet

http://dbs-system.ch

FPIA of Tobramycin performed in glass microcapillaries Squared glass capillary

300 µm

Anisotropy

0.260 0.240

reference system

0.220

capillary

0.200 0.180 0.160 0.140 0

2

4

6

8

10

12

Concentra;on [µg/ml]

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Diana Burghelea J-M Segura

Measurement system: miniaturiza;on of an Polarization established assay technique Fluorescence Immunoassay Competitive assay Highly-sensitive Compatible with small volumes

Martial Geiser team

20 cm

25 cm

*

Requires derivatization of drug molecules ISyPeM II -­‐ G. Cappi

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Label-­‐free quan;fica;on of drug from serum s amples Heterogeneous assay based on binding kinetics

Guiducci Lab

No drug derivatization No additional reagents

Transmission Surface Plasmon Resonance Change of optical properties of the interface

200 nm

Giulia Cappi

Layers of functionalized gold nanoislands Cappi G. et al. Sensors and Actuators 2013

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Hue r eadout o f s urface p lasmonics Compact read-out system

CMOS image sensor Guiducci Lab

Hue readout of surface plasmonics

Cappi G. et al. Analyt. Chem. 2015

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Measurement of binding kine;cs of DNA aptamer-­‐Tobramycin Guiducci Lab

Transmission SPR signal

KD = 200 nM, same as extracted from commercial SPR

Cappi G. et al. Analyt. Chem. 2015

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Tobramycin quan;fica;on from ✔ Small molecules serum ✔ Complex Matrix ✔ Small molecules ✖ Complex Matrix

Chang, A. L. et al., Anal. Chem.

2014, 86, 3273−3278.

✖ Small molecules ✔ Complex Matrix

Jang, H. R., et al. Anal. Chem. 86, 814–819 (2013)

Cappi G. et al. Analyt. Chem. 2015

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Suppor;ng clinical interpreta;on EzeCHiel interface Population-based percentiles

Dosing schedule suggestion

Individual concentration vs time profile Yann Thoma

Div. Clin. Pharmac.

Aline Fuchs ISyPeM II -­‐ G. Cappi

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Data management Health data Medical DB POC

Data security Dynamic Health Data Aggregation

Alevtina Dubovitskaya

Data Exchange between EzeCHiel and DB of the Medical “translate” from one representation to another

Institution

RSDB

EzeCHiel

MOLIS, CHUV

Dubovitskaya, A. Privacy Preserving Interoperability for Personalized Medicine, in: Swiss Medical Informa;cs, Swiss Society for Medical Informa;cs, Switzerland, 2014

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Popula;on pharmacokine;cs

Meta-analysis.

Implementation and validation

Div. Clin. Pharmac.

Aline Fuchs

Aziz Chaouch

Pharmacokinetic models

Br J Clin Pharmacol. 2014 Nov;78(5):1090-­‐101

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Acknowledgements

Guiducci Lab

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