New sampling Strategies Committee

New Sampling Strategies Committee

New sampling strategies in therapeutic drug monitoring
Last update: December 2011

Introduction

Venous sampling and consecutive assay of medicines in plasma, serum or sometimes in whole blood is common practice in therapeutic drug monitoring (TDM). However some possible draw-backs can be thought of for venous sampling. Venous sampling demands an experienced phlebotomist and usually  patients have to leave their home. Blood samples are bio-hazardous material and package for shipment and storage should cope with official guidelines. Limited stability of medicines in liquid blood samples during transport and storage is another problem with unstable medicines. Therefore there exists increasing interest for alternative sampling methods in TDM.

Alternative sampling methods are for example ‘dried blood spot sampling’ (DBS), ‘fingerprick sampling’ , transdermal reverse iontophoresis. More extensive information about these techniques is given below.

The IATDMCT Executive Committee has founded in 2007 a scientific committee for this subject:  ‘’New Sampling Strategies’’.

SCIENTIFIC COMMITTEE

The aims of the Committee are:

1. making up an inventory of available methods
2. evaluation,  stimulation and coordination of  new sampling strategies in TDM
3. information to the IATDMCT members of  new sampling strategies in TDM
4. development of guidelines

• Chair: Dr L Stolk, Maastricht, The Netherlands
lml.stolk@mumc.nl orlmlstolk@gmail.com

• Vice-Chair: Dr JW Alffenaar , Groningen, The Netherlands
j.w.c.alffenaar@umcg.nl

•   Members:

TECHNIQUES OF NEW SAMPLING STRATEGIES

The dried blood spot method (DBS)

The patient makes a fingerprick himself and whole blood is applied to sampling paper. After drying and shipment, the spot or part of it is extracted and analysed in the laboratory. Recently dried blood spot technology has been proposed for TDM of  many classes of drugs: immunosuppressive drugs, antiretroviral drugs, antimalarials, antiepileptic drugs, antibiotics and miscellaneous drugs, such as metformin, acetaminophen and theophylline. A wide range of assay techniques are used with DBS: HPLC-tandem MS, HPLC-UV and immunoassay. However there is need for standardization, quality assurance, basic research and development of more assays with the dried blood spot technology.

Review article about dried blood spot. Three members of our committee have published a review article about dried blood spot methods in therapeutic drug monitoring [1]. In this article the various aspects, methods and pitfalls of dried blood spot sampling are outlined. Also assays for therapeutic drug monitoring, already published in literature (52 references), based on dried blood spot methods,  are reviewed. The article is on line available for IATDMCT members on the IATDMCT website www.iatdmct.org. and for subscribers of Therapeutic Drug Monitoring at www.drug-monitoring.com. [1] Edelbroek P, van der Heijden J, Stolk L. Dried Blood Spot Methods in Therapeutic Drug Monitoring: Methods, Assays, and Pitfalls. Ther Drug Monitor 2009, 31:327-36.

Update review article. A 2010 update of above review on new TDM assays  based on dried blood spot method, has been written bij L Stolk. pdf 1

Many publications about the dried blood spot can be found in:
The journal Bioanalysis: www.future-science-group.com.
and The journal of pharmaceutical en biomedical analysis www.elsevier.com

Pdf files of the presentations about the dried blood spot method presented in the workshop of the committee during the 2009 Montreal congress:
• J Millership, “The use of dried blood spot sampling for the determination of drugs in children and neonates’’. pdf2
• B Ooms,  ‘’Finger prick TDM using on-line coupling of blood sample carriers to LC-MS/MS’’. pdf3
• L Stolk, ‘’Review of Therapeutic drug monitoring with the dried blood spot method’’. Pdf4
• P Edelbroek, ‘’DBS sampling in clinical epileptic practice and research’’ pdf5

Pdf files of the presentations about the dried blood spot method presented in the workshop of the committee during the 2011 Stuttgart congress:
Dr C Stove. DBS in Toxicology: On spot derivatisation and GC-MS determination in dried blood spots.pdf6
B Ooms. New developments in DBS: On line DBS analysis.pdf7
Dr Jeff Millership. DBS with children and neonates.pdf8
Prof Dr Yngve Bergqvist. DBS with antimalarials in third world countries.pdf9
Dr L Stolk. Some new developments and insights with the dried blood spot method. pdf10

Fingerprick sampling

Fingerprick sampling by the patients himself and consecutive transport of capillary blood is another alternative sampling method in TDM. Devices for transport of (diluted) capillary blood samples and sorbent sampling devices are being developed.

References:
-Keevil B, Fides J, Baynes A et al. Liquid chromatography-mass spectrometry measurement of tacrolimus in finger-prick samples compared with venous whole blood samples. Ann Clin Biochem 2009;46:144-5

Transdermal reverse iontophoresis

Initially developed for transdermal drug delivery, iontophoresis has also been investigated as an alternative, non-invasive samping technique. The potential application of this technique for monitoring drugs has been reviewed recently. Two mechanisms of transport are involved in iontophoresis. Electromigration involves the movement of ions, which carry charge across the skin and are driven (attracted) specifically toward the electrode of opposite polarity.

Electroosmosis is a net solvent flow in the anode to cathode direction, which enables much improved permeation of neutral species (eg glucose) and further enhances cationic transport.

References:
-Leboulanger B, Guy RH, Delgado-Charro MB. Reverse iontophoresis for non-invasive transdermal monitoring [review]. Phsiol Meas. 2004;25:R35-50
-Leboulanger B, Aubry J, Bondolfi G, Guy R, Delgado-Charro B.Lithium monitoring  by reverse iontophoresis in vivo.Clin Chem 2004;50:2091-2100.
PDF file of a presentation in the workshop during the 2009 Montreal congress:
-M Begona Delgado-Charro  Transdermal reverse iontophoresis in TDM pdf11
-Poster Stuttgart congress pdf.12

ACTIVITIES OF THE COMMITTEE

• Workshop: ‘’Dried blood spot in therapeutic drug monitoring’’. IATDMC congress Nice 2007.
• Information in  IATDMCT Compass: march 2008, september 2009, 2010 and 2011.
• Review article about dried blood spot sampling in therapeutic drug monitoring, which gives an overview of existing assays and methods, in the journal ‘’Therapeutic Drug Monitoring’’ june 2009. Ther Drug Monit 2009;31:327-3361
• 2010 update of a review on new TDM assays, described in literature, based on dried blood spot methods.
• We have held an enquiry by e-mail among our members about the new sampling techniques December 2008.
• A workshop and roundtable during the 2009 IATMCT congress in Montreal.
• Participation and presentations during the multiple international workshop in Brussels 17-18 june 2010 “Connecting strategies on dried blood spots’’. www.europeanbioanalysisforum.eu
• A workshop during the 2011 IATDMCT Congress in Stuttgart.

Recommendations from the new sampling strategies committee:

• Concentrations of drugs measures after dried blood spot sampling should be reported  in the same way as is usual in conventional sampling. This means for most drugs mg/l in plasma or serum and for immunosuppressive drugs mg/l in blood.
• There should be adequate instructions and training for dried blood spot sampling by patients themselves.
• Quality control of the sampling paper used in dried blood spot sampling is of essential interest.
• Proficiency programs for new sampling methods like dried blood spot sampling should become available.
• There is need for development of devices for application in reversed iontophoresis.

Stuttgart Congress 2011
There was a business meeting of committee during the 2011 Stuttgart Congress.
The minutes of this meeting: pdf13

Future activities of the committee:
-Update website committee on IATDMCT website and publication of all presentations of the workshop.
-New Update on the review of existing TDM assays by Leo Stolk.