Symposia & Debates

MONDAY, SEPTEMBER 23, 1100-1230

  • S2301: Emerging Drugs of Abuse; Emphasis on Designer Drugs
  • S2302: Clinical Pharmacometrics to Support Individualized Therapeutics
  • TUESDAY SEPTEMBER 24, 1100-1230

  • Debate S2401: Brand Name Immunosuppressive Drugs; Can They Easily be Substituted by Generic Drugs?
  • Debate S2402: Utility of Oral Fluid in Clinical Toxicology
  • WEDNESDAY SEPTEMBER 25, 1100-1230

  • S2501: Metal on Metal Toxicity
  • S2502: Pharmacodynamic Monitoring

  • THURSDAY, SEPTEMBER 26, 1100-1230

  • S2601: TDM for Special Populations
  • S2602: Alternative Approaches to TDM and Toxicology



    Symposium S2301: Emerging Drugs of Abuse; Emphasis on Designer Drugs

    Moderator: Matthew McMullin, Toxicology, National Medical Services, USA


    Synthetic Cannabinoids: Trends in Europe and Current Knowledge on Metabolism

    Volker Auwärter, Institute of Forensic Medicine, University Medical Center Freiburg, Germany


    • Describe the latest changes on the European market regarding ‘smoking mixtures’ containing synthetic cannabinoids.
    • Name the main metabolic pathways of the different classes of synthetic cannabinoid receptor agonists.
    • Apply strategies for targeting suitable diagnostic metabolites in urine samples without having reference standards.

    Products containing synthetic cannabimimetic compounds continue to be widely abused as substitutes for cannabis and almost weekly new substances were identified in the last years. From a clinical point of view it is evident that these products can cause intoxications much more severe than typical intoxications caused by cannabis use, which is in part due to the high potency and efficacy of the drugs but could also be a consequence of metabolism with a number of metabolites retaining both strong binding affinity and intrinsic activity at the CB1 receptor.
    For abstinence control in many environments urine is the preferred test material. However, for effective urine screening methods the main metabolites of the synthetic cannabinoids have to be the analytical targets because only very low concentrations of the parent compounds are usually present in urine samples due to extensive metabolism. Given the high frequency of appearance of new compounds and the huge variety of chemical substructures, keeping up with identifying and sensitively detecting these metabolites presents a continuous challenge for clinical and forensic toxicologists.
    The major metabolites suitable for sensitive detection using Electrospray Ionization and a strategy for valid method development in view of lacking reference standards are presented


    Cathinones, Phenylethylamines, Piperazines and Other Emerging Drugs: European Trends and Toxicological Challenges

    Robert Kronstrand, National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden


    • Summarize and categorize emerging drugs and identify trends.
    • Exemplify and evaluate strategies for the analysis of emerging drugs.
    • Recognize difficulties in interpreting toxicological results

    Initially the term designer drugs was used as a synonym for a range of phenylethylamines and tryptamines. Currently trends in designer drugs show a spread into analogs of common abuse drug classes such as amphetamines, cannabinoids, cocaine, opiates and benzodiazepines. In fact, some of the new designer drugs are difficult to categorize. Emerging drugs is offered as a more accurate term to describe this phenomenon. Even though many of the emerging drugs are advertised as or believed to be safe alternatives, the toxicity of these drugs is a matter of public safety with many life threatening adverse effects. Many of the emerging drugs are proving to be more acutely dangerous than the established drugs of abuse.
    In Europe clinical and forensic toxicology laboratories must put in tremendous effort to keep up with these emerging drugs. Our experience has been that testing by LC-Q-TOF it an alternative to allow for rapid testing with for both screening as well as confirmatory testing in a single analysis.
    In this lecture I will present European trends for emerging drugs and exemplify these with case reports mainly from a forensic perspective. I will also present strategies for the analysis of new drugs and how to interpret results.


    Synthetic Cannabinoids and Bath Salts in the United States

    Matthew McMullin, Toxicology, National Medical Services, USA


    • Know the history, current trends and legal responses to the designer drug phenomenon in the United States.
    • Be familiar with the physiological effects and the toxicological significance of synthetic cannabinoids and bath salts
    • Understand the analytical approaches available to test for synthetic cannabinoids and bath salts in blood and urine.

    Both the synthetic cannabinoids and bath salts have historically originated in Asia and moved into the European continent before arriving in the US. The response in the US has been to schedule individual drugs and classes of drugs at the federal, state and local levels. To counter these scheduling the elicit market has replaced the controlled chemicals with uncontrolled analogues. This cat and mouse game continues today.
    The changes in the mix of synthetic cannabinoids drugs being used have been dramatic. Based on testing of confiscated and purchased materials the initial wave contained JWH-018/073/250 which have cycled out; JWH-081 and JWH-122 were in a second wave but are fading away; AM-2201 is a major second wave drug and has gained in popularity and continues to be a major player; JWH-022 & 210 are showing signs of increasing popularity. Newest on the scene are XLR-11 and UR-144 which are ahead of the latest scheduling attempts. AM-1248 is an adamantoyl analog that is just appearing. Changes in the prevalence of drugs being used have large implications for clinical and forensic toxicology laboratory. The most up to date trends will be presented as well as the procedures to test blood for parent drugs and the identification of metabolites in urine.
    Similar to the synthetic cannabinoids the bath salts are scheduled and then quickly replaced in the illicit market with unscheduled chemicals. The analytical challenges for a toxicology laboratory include the large number of drugs, lack of ADME data in man, their structural simplicity, and their structural similarities. Our experiences to date will be presented for roughly 60 “bath salt” drugs in obtained products, blood, and urine using LC-MS-TOF, LC/MS/MS and GC/MS.


    Symposium S2302: Clinical Pharmacometrics to Support Individualized Therapeutics

    Moderator: Alexander A. Vinks, Professor and Division Director, Division of Clinical Pharmacology, Cincinnati Children’s Hospital and Medical Center, USA

    • Provide an overview of clinical pharmacometrics and available tools.
    • To survey available electronic medical record (EMR) integrated decision support systems for application of pharmacometrics to manage individual therapy in the clinical setting.
    • To describe the use of point of care technology (paper-spray LC-MS/MS, clinical software, web-based tools) at the bedside.
    • To demonstrate selected tools from the perspective of the physician, the patient and the clinical laboratory.


    There is an increasing need for personalized medicine both in the clinical and research settings. This symposium will introduce attendees to several of the ongoing efforts to deliver clinical pharmacometrics to the point-of-care and electronic decision support technologies. While models to manage therapy in individual patients are available, approaches to integrate and deliver reporting of results and recommendations in real-time to the point-of-care are just emerging. This symposium will focus on applications of clinical pharmacometrics to manage individual therapy. Topics to be covered include: 1) Examples of available software, 2) Web-based decision support and bedside application and 3) Electronic medical record (EMR) integrated decision support tools.


    PK-based Dose Adjustment Service When Offered on a Consultation Basis: the Case of Antibiotics
    Franck Saint-Marcoux, Pharmacist–Researcher, Department of Pharmacology and Toxicology, University Hospital of Limoges, France

    • To demonstrate the feasibility of integrating a decision support system dedicated to aminoglycosides monitoring.
    • To demonstrate the added-value of such a system to improve patient care.

    Aminoglycosides represent a typical candidate to discuss the feasibility and the utility of using PK/PD modelling for individual dose adjustments. Relying on common sense, a TDM strategy is most often applied where a patient given gentamicin or amikacin, is sampled at the end of an infusion and just before the next one. However, there are major limitations with such an approach: (i) no intervention in the choice of the starting dose; (ii) loss of time while waiting for the presumed steady-state; (iii) the necessity of respecting strict sampling times to interpret concentrations and (iv) nothing more than vague recommendations for a decrease or increase in the dose. In this context, strategies where aminoglycosides dosing is preceded and immediately followed by individualized PK-PD monitoring are more powerful.


    Clinical Pharmacometrics to Optimize Busulfan Dosing – Role of PMetrics and RightDose
    Michael Neely, Associate Professor of Pediatrics, Division of Pediatric Infectious Diseases, University of Southern California, USA

    • To introduce Pmetrics and BestDose.
    • To show how pharmacometrics can be applied directly to patient care.
    • To reduce the number of samples required for busulfan TDM.
    Busulfan is used in the preparative phase for bone marrow transplantation. Busulfan has a narrow therapeutic index, with underdosing increasing the risk of graft rejection, and overdosing increasing the risk of hepatic veno-occlusive disease (VOD). According to the package insert, the suggested target is a steady-state AUC of 1125 microM/min (4.6 mg*h/L). To calculate the AUC, three to nine precisely timed samples are typically used, with a trapezoidal approximation and linear extrapolation to infinity after the first dose. We will demonstrate the use of Pmetrics, our package for R, to build a non-parametric population model for busulfan, and then use that model in our BestDose software to optimize busulfan dosing using real patient data. We will show how only two samples of busulfan can be used to accurately achieve target concentrations, without the need for precise timing of the samples.


    Role of Point of Care Technology in Optimizing PK/PD Target Controlled Individualized Chemotherapy and Immunosuppression
    Alexander A. Vinks, Professor and Division Director, Division of Clinical Pharmacology, Cincinnati Children’s Hospital and Medical Center, USA

    • This presentation will highlight the implementation of dry blood spot sampling with a model based dosing strategy and will review new developments in the reporting of laboratory results that include therapeutic recommendations through web-based decision support.
    • To demonstrate an Electronic Health Record (EHR) integrated decision support tool for individualized immunosuppression.


    This presentation will highlight the implementation of dry blood spot sampling with a model based dosing strategy and will review new developments in the reporting of laboratory results that include therapeutic recommendations through web-based decision support.




    Debate S2401: Brand Name Immunosuppressive Drugs; Can They Easily be Substituted by Generic Drugs?

    Moderator: Teun van Gelder, Internist, Erasmus Medical Center, Netherlands

    The patents for a number of cornerstone immunosuppressive drugs used in the field of solid organ transplantation have expired. Generic formulations are now available and several professional societies and individual physicians and pharmacists have given their opinions on the issue of generic substitution. In this Debate two experts will discuss a number of hot topics related to the registration and implementation of generic immunosuppressive drugs in clinical practice. They will show you different perspectives.

    Pro Speaker:
    Uwe Christians, IC42 Integrated Solutions in Systems Biology for Clinical Research & Development, USA

    • What is special about immunosuppressants and why is there the lingering suspicion among physicians and patients that generic versions may differ in quality and therapeutic efficacy from the brand name drug.
    • That the innovator’s and the generic active drug molecule are exactly the same and are produced following exactly the same tight rules of good manufacturing practice.
    • The principles of clinical bioequivalence testing and why testing in healthy volunteers is also valid for drugs that are used in complex patient population such as transplant patients.
    • Why establishing therapeutic equivalence of brand and generic immunosuppressants in transplant patients is an unrealistic concept.
    • That many of current brand post-approval versions of immunosuppressants on the market were approved based on exactly the same guidelines used for approval of generics.
    • That the FDA has issued specific guidelines describing the requirements for approval of generic versions of tacrolimus, sirolimus and mycophenolic acid. The standard average bioequivalence approach is recommended and in the cases of tacrolimus and sirolimus, the effect of food should also be tested. No studies in the patient population are requested. Immunosuppressants are not regarded as drugs that require a special status to establish bioequivalence between generic and the innovator’s versions.

    Con Speaker:
    Pierre Marquet, Pharmacology and Toxicology, University Hospital Limoges, France


    At the conclusion of this presentation, the participant will be able to:

    • Know and understand the limitations of bioequivalence studies with regards to their extrapolation to clinical practice in transplantation.
    • Understand the risks represented by substitution between generics of a same drug.
    • Understand the economic background behind the promotion of generics and its implications in terms of quality and safety.


    Debate S2402: Utility of Oral Fluid in Clinical Toxicology

    Moderator: Christophe Stove, Laboratory of Toxicology, Ghent University, Belgium

    Pro Speaker: Marilyn A. Huestis, Chief, Chemistry & Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, University of Maryland, USA


    After attending this session, participants will be able to:
    • Describe the advantages and limitations of oral fluid as a biological sample for workplace, treatment, pain management and driving under the influence of drugs
    • Describe the mechanisms of drug disposition into oral fluid
    • Describe how selection of analytes and cutoffs can produce longer or shorter windows of drug detection appropriate for different drug monitoring programs
    The advantages and limitations of oral fluid for drug monitoring, and the choice of drug analytes and drug concentration cutoffs will be discussed. The needs of different drug monitoring programs will be described.


    Con Speaker: Pirjo Lillsunde, National Institute for Health and Welfare, Finland

    At the end of the session, the participants will be able to:
    • Understand the origin and characteristics of oral fluid and its relationship to other biofluids (blood, urine).
    • Understand the relative time course of drugs and drug concentrations in comparative specimens (oral fluid, blood and urine).
    • Understand the advantages of oral fluid as an adjunct in workplace drug testing and the evaluation of subjects treated with complex pain medications.
    Oral fluid is a mixed specimen consisting primarily of saliva combined with other secretions of the mouth. Salivary glands have a high associated blood flow; hence, drugs and metabolites in blood are distributed rapidly through the salivary glands and appear in the oral fluid. The relative acidity of the oral fluid (compared to blood) generally facilitates higher concentrations of drugs (particularly organic bases) in oral fluid. Oral fluid is commonly collected using a commercially available collection device consisting of an absorbent pad on a handle.
    Many scientific studies have established the validity of oral fluid as an alternate test matrix offering advantages over blood and urine as a test specimen. These include the presence of parent drug in oral fluid, the correlation of oral fluid with blood time lines, hence, a greater correlation with drug effects, and the fact that the collection is witnessed thus eliminating the need for phlebotomy or the uncertainties of urine. Therefore, oral fluid is finding application in workplace testing, pain management testing and driving under the influence of drugs.




    Symposium S2501: Metal on Metal Toxicity

    Moderator: Robert Middleberg, VP, Quality Assurance, Lab Director and Forensic Toxicologist, NMS Labs, USA

    Does Chromium or Cobalt Exposure from Metal-on-Metal Implant Cause Toxicity? The Incidence, the Evidence, the Clinical Response
    Thomas P. Moyer, Mayo Clinic, USA


    At the end of the session, the participants will be able to:
    • Recognize the importance of the correct clinical workup of patients with suspected ARMD.
    • Understand the critical role of serum chromium and cobalt analysis in the diagnosis of ARMD.
    • Educate clinical staff on known associations between chromium and cobalt exposure through orthopedic implant and chromium or cobalt toxicity.
    Joint replacement is a successful treatment for advanced joint disease. More than 1 million total hip replacements are performed worldwide each year. While most recipients benefit with improved mobility and quality of life, a small number experience implant-specific local and systemic adverse effects. Wear of the metal-on-metal (MoM) surfaces can cause release of micro-particles of metal debris into the surrounding tissues which can corrode, resulting in the release of metal ions into circulation. The condition causing adverse effects related to sensitivity to the metal or due to the wear of the metal surfaces is called Adverse Reaction to Metal Debris (ARMD). The majority of patient with joint pain do not have ARMD. Evaluation to rule out implant loosening, infection, or pseudotumor should be carried out before considering ARMD. Numerous reports indicate that ARMD can be assessed by evaluation of serum chromium and cobalt concentration. DeSmet provided well-founded data relating serum and joint fluid concentrations to orthopedic implant status.
    Elevated chromium and cobalt concentrations may indicate implant wear, but they are not indications for toxicity. While the toxicity and carcinogenic properties of chromium+6 are well known, chromium+3 compounds released from MoM wear are not considered a health hazard. There are a number of internet blogs and websites relying on the experience with chromium+6 exposure from the electroplating industry to make comments on the toxicity of chromium from hip implant deterioration. It is inappropriate to make that comparison because chromium+6 is not released during implant wear.
    Cobalt is an essential element. It is integral to vitamin B-12 and required for carbonic anhydrase activity. Cobalt toxicity, known as cobaltism, can occur after ingestion of large amounts of cobalt. Symptoms associated with cobaltism include renal failure, hypothyroidism, myocardial damage, erythrocytosis, and interstitial lung disease (if inhaled). Regarding ARMD, there are only a few case reports suggesting any deleterious effect from orthopedic implant wear and high cobalt serum concentrations.
    All patients with MoM implant will have serum cobalt and chromium concentration higher than unexposed (ie, no implant) individuals. Following implant, serum cobalt and chromium concentration increases, reaching a steady state around 3 years after implant; after that, concentrations remain steady or slowly decline unless ARMD develops. This is important when evaluating patients, especially those who are asymptomatic. Only those patients symptomatic for ARMD with serum cobalt >10 ng/mL and serum chromium >15 ng/mL are likely to have significant implant deterioration. It is recommended to repeat serum cobalt and chromium at 6 months to a year after symptoms develop. If the concentrations decrease significantly, revision may not be necessary.
    De Smet K, De Haan R, Calistri A, et al: Metal ion measurement as a diagnostic tool to identify problems with metal-on-metal hip resurfacing. J Bone Joint Surg 2008;90:202-208


    Current Laboratory Capabilities and Method Performance for Monitoring Co and Cr in Whole Blood   A U.S. Perspective
    Patrick J. Parsons, Deputy Director, Wadsworth Center Division of Environmental Health Sciences; Lab Chief, Wadsworth Center, Laboratory of Inorganic & Nuclear Chemistry; Professor and Chair, University at Albany, School of Public Health, Environmental Health Sciences, USA


    At the end of the session, the participants will be able to:
    • Grasp the basic principles of current ICP-MS methods used to measure Co and Cr in blood, including the optimal use of dynamic reaction cell (or collision cell) technology to reduce polyatomic interferences.
    • Become familiar with the NYSDOH PT program for clinical trace elements and, in particular, its operation for Co and Cr in whole blood.
    • Understand the consensus criteria used to evaluate performance for Co and Cr in whole blood, and appreciate the limitations of current analytical methods.
    In 2012 the FDA issued guidance on monitoring patients with metal-on-metal (MoM) implants. The FDA’s guidance included specific advice for US clinical laboratories that measure cobalt (Co) and chromium (Cr) in whole blood, and they recommend labs participate in a CMS-approved proficiency testing (PT) program. Currently, the New York State Department of Health’s (NYSDOH) Wadsworth Center operates a PT program for trace metals in whole blood that includes Co and Cr at levels consistent with those expected in patients with failing MoM implants. The NYSDOH PT program began grading lab performance for Co and Cr in 2013 based on consensus criteria that were developed in consultation with other trace element PT program providers. At present grading is conducted on an educational basis such that participants can evaluate their own performance relative to others. Most of the participants are using methods based on inductively coupled plasma mass spectrometry (ICP-MS) although there are marked differences in the manner in which ICP-MS is implemented. This presentation will review current analytical methods for measuring Co and Cr in blood, summarize interlaboratory performance in the NYSDOH PT program based on the consensus criteria. Recommendations for future work will be discussed.


    Metal Ion Measurements in UK Patients with Metal-on-Metal Hip Replacements
    Andrew Taylor, Clinical Laboratory, Royal Surrey County Hospital, UK

    At the end of the session, the participants will be able to:
    • Recognize the clinical problems associated with metal on metal hip replacements.
    • Appreciate the role of the laboratory in patient investigations.
    • Consider where further work is required.
    Problems with MOM prostheses were reported in the 1970s but it is only since 2006 that it was recognised that there was a serious clinical issue. Patients report groin and hip pain, and may have large sterile green/yellow joint fluid effusions, soft tissue damage which can be extensive involving muscles and nerves, and bony destruction (osteolysis). Following concerns at the growing number of revisions necessary due to failure of the implant and the high concentrations of cobalt and chromium in blood which we and others were reporting the UK Medicines and Healthcare products Regulatory Authority issued a Medical Device Alert in 2010 stating that patients with painful hips should be investigated with evaluation of blood cobalt and chromium ion levels and cross sectional imaging including MRI or ultrasound scan. A subsequent alert recommended blood measurements of all MOM patients. The Alerts specified concentrations of 7 ppb as a trigger for further investigation. There are approximately 60 to 70,000 such patients in the UK. During 2006-2012 we analysed 27,346 samples, some from replicates from the same patients. Twelve other laboratories in the UK, all using ICP-MS, also analyse samples. In additional clinical investigations it has been shown that results from serum and blood provide better information than from blood alone and that failure of titanium components in the prosthesis can also be detected.
    The MHRA stated that analysis of blood should be carried out at laboratories participating in the Trace Element External Quality Assessment Scheme (TEQAS). TEQAS participants analyse blood, serum and urine samples monthly. Performance reports show their own results compared to assigned values and with Z-scores calculated against a quality specification. The specifications now used for Co and Cr were determined in collaboration with other scheme organizers and are based on performance RSDs between 2011 and 2012. Part of our remit as the TEQAS organizer is to report poor performance to an independent panel. This has not been necessary for Co and Cr.


    Symposium S2502: Pharmacodynamic Monitoring

    Moderator: Leslie M. Shaw, William Pepper Laboratory, Hospital of the University of Pennsylvania, USA


    Biomarkers of Immunosuppression in Transplantation
    Mercè Brunet, Head of Pharmacology and Toxicology Laboratory, Hospital Clinic of Barcelona, Spain

    At the end of the session, the participants will be able to:
    • Know the pros and contras of the most promising biomarkers related with immunosuppressive treatment response and graft clinical outcome.
    • Understand the biomarkers validation procedure.
    • Know how to implement biomarkers monitoring in the field of ytransplantation.
    Pharmacodynamic monitoring by direct measurement of immunomodulatory drug-effect (biomarkers), combined with pharmacokinetics, has the potential to personalize immunosuppression therapy. Treatment of transplant patients according to surrogate markers and assays may allow (1) a better pre-transplant risk evaluation with subsequent risk stratification, (2) personal drug-response monitoring and (3 improved predictions of long-term graft outcome. The purpose of this review is to provide the audience with an overview of the clinically promising biomarkers in the field of immunosuppression in transplantation.


    Cell Free Circulating DNA as Biomarker in Chronic Diseases
    Ekkehard Schütz, Chief Technology Officer and, Senior Vice President Research, Chronix Biomedical Inc., Germany

    At the end of the session, the participants will be able to:
    • Understand the origin and use of circulating cell-free DNA (cfDNA) in different diseases.
    • Describe the technical developments in molecular diagnostics (e.g. digital PCR) to use it as biomarkers.
    • Discuss the association of graft derived cfDNA in transplantation with clinical observations and PK of ISDs.

    The liquid part of blood e.g. plasma has been shown to contain small, but consistently detectable amounts of DNA, which mainly stems from apoptotic processes naturally going on in the body. The amount can vary in diseases and – in particular if the disease is associated with a genetic makeup different form the germline – the cfDNA coming from the affected tissue can be differentiated. Examples are cancer, aneuploid pregnancies and solid organ grafts. Recent technical advances (droplet digital PCR) have made the use of cfDNA as quantitative biomarker more reliable and inexpensive compared to older sequencing based methods. The use in solid organ recipients seems promising due to the direct interrogation of graft integrity.


    Clinical Utility and Analytical Challenges in Measurement of Cerebrospinal Fluid Amyloid-b1-42 and Tau Proteins as Alzheimer’s Disease Biomarkers
    Leslie M. Shaw, William Pepper Laboratory, Hospital of the University of Pennsylvania, USA

    At the conclusion of this presentation, the participant will be able to:
    • Describe the known biomarker and pathologic hallmarks of Alzheimer’s disease.
    • Understand the challenges of developing and validating CSF biomarkers.
    • Learn about the current state of Alzheimer’s disease treatment trials and the potential roles of CSF biomarkers in them.

    In this presentation the neuropathologic basis for Alzheimer’s disease (AD) will be discussed including the contrasts amongst the other major neurodegenerative diseases. The development, analytical performance assessment and qualification of CSF biomarkers will be described for several intended uses including: (a) as indices of underlying neuropathology; (b) as measures of risk for AD neuropathology; (c) to exclude the presence of AD neuropathology; (d) as biomarkers of likelihood of disease progression in patients with mild cognitive impairment or in cognitively normal individuals; (e) as markers of treatment effects.




    Symposium S2601: TDM for Special Populations

    Moderator: Steven Soldin, Laboratory Medicine, National Institutes of Health, USA


    The Expanding Roles of TDM and Tandem Mass Spectrometry in the Diagnosis and Treatment of Thyroid Diseases

    Steven Soldin, Laboratory Medicine, National Institutes of Health, USA

    At the end of the session, the participants will be able to:
    • comprehend why we should employ tandem mass spectrometry for the measurement of FT4,FT3 and TT3 (as the alternative to immunoassays) for optimization of diagnosis and treatment of hypo and hyperthyroidism.
    • Good assays for FT4 and FT3 should correlate well with TSH measured by immunoassay.
    • TT3 measured by MSMS is frequently low in hypothyroid patients treated with T4. These patients probably are heterozygous for a defective deiodinase ,a disorder with variable expression and present in 30-60% of the population. Dosing with T3 is needed.
    The current challenge in optimizing the treatment of patients with thyroid diseases will be reviewed. Shortcomings of immunoassays for measurement of FT4,FT3 and TT3 will be addressed. Advantages of employing tandem mass spectrometry will be highlighted resulting in “Recommendations for optimal laboratory assessment of thyroid disorders.”


    The Challenges of TDM in Pediatrics
    Catherine Sherwin, Assistant Professor, Department of Pediatrics, University of Utah School of Medicine, USA


    At the end of the session, the participants will be able to:
    • Understand the impact of TDM in pediatrics remains relatively understudied and gaps resulting in difficulty in establishing initial doses and PK/PD and pharmacogenetic relationships.
    • Describe the issues and challenges such as associated with pediatric pharmacology/toxicology, and why TDM remains a challenge in this population.
    • Discuss the need to improve relevant drug research in pediatrics and enhance integration between clinical and research areas.
    Therapeutic Drug Monitoring (TDM) has been a mainstay of management for many drugs including antimicrobials and immunosuppressants to establish initial doses and PK/PD relationships. There are a number of challenges faced when using TDM to determine clinical endpoints and to make clinical decisions in special populations specifically some disease states and in pediatric age groups. The application and utility of TDM has been traditionally understudied in pediatrics and adult guidelines have been applied with no consideration to adapt specially to pediatric patients. There is a need for integration between clinical and research outcomes as well as the Physician-Pharmacist-Patient triad interactions.


    The Challenges of TDM in the Elderly
    Andrew McLachlan, Professor of Pharmacy, Faculty of Pharmacy, University of Sydney, Australia

    At the end of the session, the participants will be able to:
    • Appreciate the impact of aging on the pharmacokinetics and pharmacodynamics of medicines.
    • Understand that comorbid disease, frailty and polypharmacy contribute to variability in response to medicines in older people.
    • Appreciate the impact role that therapeutic drug monitoring plays optimizing drug therapy in older people.
    Older people display considerable variability in response to medicines. This clinical variability is a likely consequence of age-associated changes in organ function and body composition, declining homeostatic reserve, and comorbid diseases, all of which alter drug and metabolite pharmacokinetics and pharmacodynamics. Multiple concomitant medications and geriatric syndromes, such as frailty, contribute to variability is response because of drug-drug and drug-syndrome interactions. An understanding of the clinical pharmacology of medicines in older people and the judicious and appropriate use of therapeutic drug monitoring can inform the safe and effective use of medicines in older people to achieve optimal health outcomes.


    The Role of Pharmacokinetics in Appropriate Dosing for Obese Patients with Cancer
    Jennifer H. Martin, Departments of Internal Medicine and Chemical Pathology, Pathology Queensland, Royal Brisbane and Women’s Hospital; Diamantina Institute, The University of Queensland, Australia

    At the end of the session, the participants will be able to:
    • Understand the difference between body surface area, lean body weight and total body weight
    • Understand the importance of these different parameters on pharmacokinetics of oncology drugs.
    • Appreciate the limitations of current dosing strategies and in particular the lack of data guiding cancer dosing in obesity.
    This presentation will discuss the pharmacokinetic changes in obesity and assumptions that are currently made about dose adjustments in this group, across the clinical spectrum. This includes areas such as dosing antimicrobials and oncology. Specifically, pharmacokinetic-guided data around dose adjustment in oncology will be presented with information regarding effects of toxicity and efficacy.


    Symposium S2602: Alternative Approaches to TDM and Toxicology

    Moderator: Christophe Stove, Laboratory of Toxicology, Ghent University, Belgium


    Dried Blood Spots
    Christophe Stove, Laboratory of Toxicology, Ghent University, Belgium

    At the end of the session, the participants will be able to:
    • Understand the potential value of the use of dried blood spots in toxicology and therapeutic drug monitoring.
    • Understand the main strengths and advantages associated with dried blood sampling and analysis.
    • Understand the weaknesses, limitations and special points of attention when aiming to use DBS sampling for quantitative bioanalysis.
    The potential of sampling via dried blood spots (DBS) as a minimally invasive alternative for classical venous blood sampling is increasingly being recognized by both academia and industry. Advantages such as ease of sampling, cost-effective transport and storage or automation capability of DBS analyses have resulted in many applications in the context of toxicology and therapeutic drug monitoring. Despite the many advantages, DBS sampling and analysis is associated with several issues, such as contamination risk, volume spotted, spot homogeneity and hematocrit.
    In this presentation, an overview will be given of the different application fields of DBS, with particular attention to toxicology and TDM. Selected case studies, both from own work, as from work published by others, will be used to illustrate the different aspects of DBS sampling for quantitative bioanalysis. Topics covered will include the advantages, limitations and challenges of DBS sampling and analysis, as well as proposed solutions for the latter, before proceeding to considerations on the future of DBS analysis.


    Dried Blood Spots and Oral Fluid in TDM
    Jan-Willem Alffenaar, Pharmacist, University Medical Center Groningen, Netherlands



    At the end of the session, the participants will:

    • Understand pro and cons of DBS and OF in TDM.
    • Be able to decide in which clinical situations DBS and OF can be preferred over traditional sampling.
    • Be able to apply DBS and OF in TDM in routine care.


    Dried blood spot (DBS) sampling has been used for neonatal screening for many years but has now entered the field of TDM as new tool for quantitative measurements. DBS sampling has a few advantages over conventional blood sampling. DBS sampling is easy to perform, and can be stored and transported without cooling facilities. Because it requires only a small amount of blood it is also suitable for pediatric sampling. A few drawbacks are that the analysis of DBS samples requires a more complex method development and validation process than conventional blood sampling. In addition, the influence of hematocrit, sampling paper characteristic and method of extraction must be thoroughly evaluated.
    Oral fluid is an alternative easy-to-obtain body fluid compared to plasma. It has been used for many years for detecting illicit drugs for on site testing. Although oral fluid sampling has the great advantage of being easy and non-invasive it faces practical problems like a dry mouth or lack of good correlation of the concentration of the drug of interest between between oral fluid and plasma.
    For both sampling strategies background, challenges in method development, clinical validation and use in routine care are discussed using actual cases.


    Potential of Using Exhaled Breath in Pharmacology and Toxicology
    Olof Beck, Karolinska University, Sweden

    After attending this session, participants will:
    • Understand the presence and formation mechanism behind non-volatiles to be part of exhaled breath.
    • Understand the potential of this non-invasive sampling procedure for biomarker use.
    • Be up-dated on the most recent findings about detection of drugs of abuse in exhaled breath.