MONDAY, SEPTEMBER 23, 1700-1830
- W2301: TDM of Immunosuppressants and Options for Biomarkers
- W2302: Detection and Assessment of Toxic Element Exposures
- W2303: TDM in Oncology
- W2304: Young Scientist Workshop
WEDNESDAY, SEPTEMBER 25,1700-1830
- W2501: Therapeutic Monitoring of Perinatal Exposure to Drugs and Chemicals
- W2502: Advances in Antidoping Drug Testing
- W2503: Anti-infectives
- W2504: High Resolution Mass Spectrometry
Workshop W2301: TDM of Immunosuppressants and Options for Biomarkers
Moderator: Michael Oellerich, Lower Saxony Distinguished Professor, Department of Clinical Chemistry, George-August University Göttingen, Germany
- PK/PD of newer immunosuppressive agents.
- Endogenous biomarkers to achieve personalized immunosuppression.
- Implementation of pharmacogenomics to clinical management of immunosuppressive agents.
Pharmacokinetics of New Immunosuppressive Drugs and Monitoring Opportunities
Teun van Gelder, Internist, Erasmus Medical Center, NetherlandsObjectives:
- Understand the added value for PK/PD monitoring of the recently approved drug belatacept.
- Learn the reasons for discontinuation of the development of a number of immunosuppressive compounds, and how TDM might have prevented these failures.
- Speculate on potential new compounds which are in the pipeline.
Pharmacogenomics for Adequate Dosage Regimens of Immunosuppressants in Liver Transplant Patients
Satohiro Masuda, Associate Professor/Vice Director, Department of Pharmacy, Kyoto University Hospital, JapanObjectives:
- Understand the usefulness of genomic information to set individualized dosage adjustment of tacrolimus.
- Learn the importance of combination in genetic backgrounds of recipients (small intestine) and donors (graft liver) to explanation of large inter-individual variation in tacrolimus pharmacokinetics.
- Understand the pharmacological importance of lymphocytic expression of MDR1 on tacrolimus PD.Description:Factors limiting long-term outcomes in transplantation include irreversible chronic rejection and side effects of standard immunosuppression (e.g. nephrotoxicity, cardiovascular disease, opportunistic infection, malignancy). Over- and under-immunosuppression is still common. Against this background, numerous attempts have been made to develop biomarkers and new compounds (e.g. belatacept) to achieve personalized immunosuppression. Biomarkers are of interest, because pharmacokinetic monitoring of immunosuppressive drugs does not precisely predict pharmacological effects on immune cells, and ultimately clinical outcome. A new approach for non-invasive early detection of acute rejection is based on the determination of organ donor and recipient circulating cellfree DNA in plasma. Cytokine production by T cells is a specific marker for the effects of cyclosporine and tacrolimus. Various tolerance-specific peripheral blood gene sets have been described. Pharmacogenomics and the discussed biomarkers could facilitate personalized immunosuppression. In this workshop, the latest developments will be presented.
Biomarkers to Achieve Personalized Immunosuppression in Transplantation
Michael Oellerich, Lower Saxony Distinguished Professor, Department of Clinical Chemistry, George-August University Göttingen, GermanyObjectives:
- Understand the usefulness of using the donor/recipient circulating cellfree DNA ratio as an early indication of organ damage.
- Interpretation of specific markers for the effects of calcineurin inhibitors (e.g. proportion of IL-2 producing CD8+ T-cells, NFAT-regulated gene expression).
- Understand the concept of tolerance specific peripheral blood gene sets (e.g. NK-related transcripts, B-cell differentiation genes, number of natural regulatory T cells).Description:Tacrolimus is used as a primary immunosuppressant in liver transplantation. We identified the mRNA expression level of MDR1 in small intestine was a biological marker to set the initial dosage of tacrolimus immediately after transplantation. Especially, the average trough concentration of tacrolimus of 7 ng/mL was found to be the target concentration of tacrolimus to prevent acute cellular rejection during postoperative 14 days. On the other hand, CYP3A5 genotype in the native intestine and graft liver was found to be a marker for understanding the inter-individual difference of tacrolimus pharmacokinetics. In the pediatric patients and whole liver transplant patients, CYP3A5 genotype in the graft liver rather than native intestine was revealed be a major factor to explain the large inter-individual difference in tacrolimus pharmacokinetics. In contrast, the intestinal genotype of CYP3A5 rather than that of graft liver was showed to act as a marker in the adult patients receiving living-donor partial liver transplantation. The weight of graft liver as well as CYP3A5 genotype was suggested to be a factor to affect tacrolimus pharmacokinetics in patients after liver transplantation. Since MDR1 is expressed in lymphocytes as well as intestine and liver, MDR1 mRNA expression level closely associated with its inhibitory activity of lymphocytic calcineurin, suggesting the individualized target concentration of tacrolimus was associated with the mRNA expression level of MDR1 in lymphocytes. In this workshop, I will talk about the several molecular markers to contribute the individualized dosage adjustment of tacrolimus after liver transplantation
Workshop W2302: Detection and Assessment of Toxic Element Exposures
Moderator: Gwen McMillin, Associate Professor (Clinical), Department of Pathology, University of Utah, Medical Director of Toxicology, Co-Medical Director of Pharmacogenomics, ARUP Laboratories, USA
Exposures to Metals in the Workplace
Lee Blum, Assistant Laboratory Director, Scientific Director-FUDT, NMS Labs, USAObjectives:
- Describe health concerns from chronic exposures to metals in the workplace.
- Explain biological monitoring and its use in occupational exposure monitoring.
- Discuss possible limitations in evaluating biological monitoring test results for metals.Description:This course will discuss metal exposures in the workplace. A historical perspective of metals used at work will be explored and the diseases associated with chronic metal toxicities will be examined. The concept of biological monitoring will be introduced and its role in preventing occupational metal exposure will be discussed. Agencies involved in biological monitoring will also be identified. The course will describe types of specimens used to assess workplace exposures and the concerns about potential sources of specimen contamination with their impact on test results.
Non-Occupational Exposures and Analytical Methods
Frederick Strathmann, Assistant Professor of Pathology, Department of Pathology, University of Utah, Medical Director of Toxicology, ARUP Laboratories, USAObjectives:
- List several elements commonly assessed in non-occupational toxic exposures.
- Describe several components of clinical ICP-MS assays used to ensure data quality.
- Compare various specimen types for the assessment of non-occupational toxic exposures.Description:Inductively coupled plasma-mass spectrometry (ICP-MS) is a powerful yet underutilized tool in the field of toxicology. Unique from other types of clinical mass spectrometry, most ICP-MS based assays require little to no sample preparation for whole blood, serum/plasma and urine specimens, yet offer highly sensitive and specific multiplex assays. ICP-MS can be used to assess pediatric blood lead levels, monitor metal-on-metal toxicity in prosthetic device wear, determine occupational exposures to toxic metals, and even provide tissue concentrations of nutritional elements in diseases of excess absorption and storage. An overview of ICP-MS will be provided through a series of clinical cases and laboratory quality scenarios.
Clinical Case Examples of Toxic Element Exposures
Paul Jannetto, Pathology and Laboratory Medicine, Mayo Clinic, USAObjectives:
- Recognize and correlate the physical, clinical laboratory, and anatomic findings related to occupational, environmental and/or intentional toxic element exposure.
- Identify the appropriate specimen type and tests which should be used to detect and/or monitor exposure to some common toxic elements.
- Correctly interpret the toxic element test results, summarize the mechanism of toxicity, and suggest appropriate treatment/management.Description:Diagnosis of toxic element exposure can be difficult since the signs and symptoms are similar to a number of other diseases. In addition, the toxicity of various elements depends on a number of different factors. As a result, this lecture will present two clinical case studies illustrating the clinical presentation and laboratory findings of people exposed to toxic elements.
Workshop W2303: TDM in Oncology
Moderator: Salvatore Salamone, Chief Scientific Officer, Saladax Biomedical Inc., USA
Chemotherapy Drug Management: Addressing an Unmet Medical Need
Jan Beumer, Assistant Professor, Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Pittsburgh, USAObjectives:At the end of the session, the participants will be able to:
- Discuss the opportunities for TDM provided by the peculiar pharmacokinetic properties of tyrosine kinase inhibitors.
- Discuss the data supporting the exposure-response relationships for tyrosine kinase inhibitor anticancer agents, with a focus on imatinib.
- Discuss barriers to utilization of exposure-response relationships in cancer therapy.
Focus on Paclitaxel and 5-Fluorouracil
Markus Joerger, Medical Oncology & Clinical Pharmacology, Department of Internal Medicine and
Clinical Research Facility, Cantonal Hospital. St. Gallen, SwitzerlandObjectives:At the end of the session, the participants will be able to:
- Understand threshold models as a surrogate for paclitaxel-related hematological and non-hematological toxicity
- Understand steady-state plasma concentrations as a surrogate for 5FU-related toxicity and clinical activity
- Know logistical issues and practical issues that have to be dealt when performing TDM of 5FUDescription:This Session will discuss therapeutic drug monitoring (TDM) of paclitaxel and 5FU in patients with solid tumors. Threshold models have been used retrospectively to describe the relationship between 3-weekly paclitaxel pharmacokinetics and hematological as well as non-hematological toxicity. Only recently, the clinical value of TDM of 3-weekly paclitaxel is undergoing prospective testing. With 5FU, several non-randomized and one randomized study suggest a clinical benefit from TDM. Still, some logistical and practical issues have to be considered when implementing TDM of continous-intravenous 5FU.
Scientific and Cultural Challenges in Implementing an Oncology TDM Program
Salvatore Salamone, Chief Scientific Officer, Saladax Biomedical Inc., USAObjectives:At the end of the session, the participants will be able to:
- Identify the unmet medical need of TDM in the field of oncology.
- Identify the current challenges in implementing TDM in oncology.
- Have an overview of recent clinical data demonstrating the value of TDM.
- Outline key pharmacokinetic information for selected chemotherapeutic drugs and application of this information in clinical studies.
- Understand the pre-analytical, logistical and cultural challenges that can impact testing in support of chemotherapy management.
Workshop W2304: Young Scientist Workshop
Chair: Denise McKeown
Moderator: Denise McKeown, Forensic Toxicologist, Forensic Medicine and Science, University of Glasgow, UK
- Recognize the (non)sense of blood concentration determination in clinical toxicology.
- Understand the use of and identify the advantages of LC-MS(/MS) on-line extraction methods for clinical chemistry and toxicology applications
- Understand the steps involved in biomarker development and to appreciate the challenges in determining in utero substance exposures and the clinical management of substance-exposed neonates.
Determination of Blood Concentrations in Emergency Toxicology? When and How Accurate?
Markus Meyer, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, GermanyObjectives:At the end of the session, the participants will be able to:
- Understand the scope of methods used to determine blood concentrations in CT.
- Understand the (lack of)relationships between blood concentrations and clinical outcome for mentioned drugs.
- Engage in a critical discussion on the (non)sense of blood concentration determination in CT.Description:The discussion will focus on the sense and nonsense of blood concentration determination in Clinical Toxicology(CT). The session will present methods suitable for “drug monitoring” in CT and highlight drawbacks as well as pitfalls of such methods. Certain drugs such as paracetamol will be presented where knowledge of blood concentrations is helpful for therapy optimization and drugs where such knowledge is not that helpful. Furthermore, examples will be given where repeated determinations of blood concentrations might be useful. All aspects will be discussed considering the pharmacology of the mentioned compounds.
Overview of the Available On-line Sample Preparation Techniques Coupled to LC-MD/MD – Benefits for Clinical Laboratories
Lewis Couchman, Clinical Scientist, King’s College Hospital, UKObjectives:At the end of the session, the participants will be able to:
- Understand the basic theory and principles of on-line extraction methods, including on-line SPE and turbulent flow chromatography.
- Identify the advantages of on-line extraction methods over other sample preparation techniques.
- Understand the use of on-line extraction for clinical chemistry and toxicology applications, including endogenous compounds and drugs/metabolites.Description:Manual (off-line) sample preparation techniques, such as liquid-liquid extraction (LLE) and solid-phase extraction (SPE), can be time-consuming, laborious processes. Others, such as protein precipitation (PPT), or ‘dilute-and-shoot’ approaches may impact analysis by mass spectrometry due to the presence of remaining matrix components after the sample preparation process. For high-throughput analyses, such as in therapeutic drug monitoring (TDM) and clinical chemistry, automating the sample preparation process, whilst maintaining effective sample clean-up (e.g. removal of matrix components known to cause ion suppression) is clearly beneficial. Therefore, on-line methods such as on-line SPE and turbulent flow chromatography are gaining in popularity.
In this session, on-line sample preparation methods will be described. The theory of turbulent flow chromatography, and the use of column-switching techniques will be discussed, and relevant examples from the fields of clinical chemistry (vitamin D metabolites and steroid hormones) and toxicology/TDM (antipsychotics, antifungals and tyrosine kinase inhibitors) will be shown, detailing the application of both methods in routine practice. Practical considerations for developing and implementing such techniques, as well as potential pitfalls, such as interference from metabolites and problems associated with carryover, will also be covered.
Overview of the Steps Involved in Biomarker Development/identification – With Focus on In Utero Substance Exposure
Joey Gareri, Laboratory Manager, Division of Clinical Pharmacology & Toxicology, Hospital for Sick Children, CanadaObjectives:At the end of the session, the participants will be able to:
- Identify the unique pharmacokinetic considerations associated with in utero substance exposure presented by the placenta
- Understand the development of fatty acid ethyl esters (FAEE) in meconium as an example of biomarker development.
- Recognize the unique challenges presented in the clinical management of substance abusing women and substance-exposed neonates.Description:This session will review basic embryologic development with a focus on the development of meconium and neonatal hair. The metabolic activity/capacity of the placenta will be discussed, including the ex vivo placental perfusion model of pharmacological experimentation. The clinical relevance of developing biomarkers of prenatal alcohol exposure will be discussed. Alcohol biomarkers in meconium will be reviewed; with a focus on fatty acid ethyl esters (FAEE); demonstrating the role for various experimental approaches in the development of an in utero biomarker. Analytical, physiological, and neurodevelopmental aspects of biomarker development will be discussed.
WEDNESDAY, SEPTEMBER 25
Workshop W2501: Therapeutic Monitoring of Perinatal Exposure to Drugs and Chemicals
Moderator: Gideon Koren, Director, The Motherisk Program, The Hospital for Sick Children, Professor of Pediatrics, Pharmacology, Pharmacy and Medical Genetics, The University of Toronto, Canada
Clinical and Social Work Yield of Urine and Meconium Testing of the Newborn
Matthew Krasowski, Assistant Professor, Pathology, Laboratory Director, Clinical Chemistry, University of Iowa, USAObjectives:
- Define the limitations of newborn drug screening using urine and meconium as specimens.
- Identify the prescription medications to mother or infant likely to be detected in meconium specimens.
- Describe the screening criteria that are of highest yield in determining which infants to perform newborn drug testing.Description:Non-medical drug use in pregnancy can lead a variety of complications. This session will describe the results of a four year retrospective analysis at an academic medical center of newborn drug screening using meconium and urine as specimens. Detailed chart review of both the newborn and mother’s medical record was performed on all cases for which one or more drug(s) or metabolite(s) were identified and confirmed in meconium or urine. Meconium testing identified 229 cases of maternal non-medical drug use reported to child protective services. Meconium samples in 283 infants were positive for drug and/or metabolites explainable by prescription medications given to mother or infant. Urine drug testing failed to identify any case of non-medical drug use not seen in meconium, and in general urine screening had low yield of detection (only 12 cases of non-medical drug use identified). History of maternal substance abuse and/or tobacco use in pregnancy was present in 90.8% of non-medical drug use cases. Addition of social risk factors (e.g., domestic violence, prior child protective services involvement) and poor prenatal care increased the yield to 96.9%. Unexplained prematurity and untreated maternal psychiatric illness in the absence of other risk factors were not predictive of non-medical drug use. This study support focused screening criteria to detect prenatal non-medical drug exposure. Health care professionals should be aware that newborn meconium drug testing commonly detects prescribed medications, necessitating thorough and careful review of pharmacy and hospital medication records.
New Frontiers in Fetal TDM
Gideon Koren, Director, The Motherisk Program, The Hospital for Sick Children, Professor of Pediatrics, Pharmacology, Pharmacy and Medical Genetics, The University of Toronto, CanadaObjectives:
- To inform participants on methods for detecting and monitoring drug and chemical exposure during pregnancy.
- To critically discuss short and long term effects of xenobiotic exposure on outcome of the offspring.
- To update participants on new developments in maternal-fetal TDM.Description:
In this session we will describe the risks associated with in utero exposure to drugs of abuse, alcohol and environmental toxins on short and long term development of the offspring.
Workshop W2502: Advances in Antidoping Drug Testing
Moderator: Marilyn Huestis, Chief, Chemistry & Drug Metabolism, Intramural Research Program, NIDA, NIH, Biomedical Research Center, USA
- Describe anti-doping testing for the London Olympics
- Describe new developments in anti-doping testing and the latest research at the Sports Medicine Research Testing Laboratory
- Describe the possibility of oral fluid monitoring for “in competition” testing
State of the Art of Antidoping Drug Testing in 2012
Bryan Finkle, Chairman and Founder, Sports Medicine Research & Testing Laboratory, Salt Lake City, USA
Use of UHPLC-HRMS in Bioanalysis – Screening for Substances Prohibited in Sport
David Cowan, Director, King’s College London Drug Control Centre, UKObjectives:
- Understand the use of high resolution high mass accuracy UHPLC mass spectrometry
- Understand the advantages, limitations and precautions
- Ion suppression/enhancement – what to watch out for and how to controlDescription:Ultra high performance liquid chromatography coupled to mass spectrometry is becoming one of the most important tools available to the scientist working in the areas of therapeutic drug monitoring and toxicology whether for clinical or forensic applications. The separating power and speed of analysis of complex biological matrices permitted by UHPLC coupled with the sensitivity and information content provided by mass spectrometry have enabled new assays to be readily implemented by the laboratory. More recently, the availability of sensitive relatively low cost high resolution high mass accuracy, mass spectrometers has added a further order of precision to the information that can be obtained. Furthermore, working in full scan enables retrospective analysis of data to detect the use of “designer compounds”. This workshop presentation will give some practical insights into our work in these areas.
Individual Reference Range Evaluation – How to Catch the Sophisticated Doper
Daniel Eichner, Executive Director, Sports Medicine Research & Testing Laboratory, USAObjectives:
- Use of biomarkers in detection doping.
- Use of longitudinal evaluations with respect to anti-doping.Description:
Anti-doping laboratories have historically focused on detecting known prohibited substances or their metabolites. With the emergence of more sophisticated doping techniques being practiced by some unscrupulous athletes and their entourage, anti-doping laboratories have recently began focusing on “indirect” methods of detection by monitoring select biomarkers longitudinally. This approach has been deemed the Biological Passport. It is now possible to determine and thereby sanction an athlete that has committed an anti-doping rule violation without specifically detecting the suspected drug or metabolite. Data will be presented to demonstrate the techniques used in both blood and urine to identify prohibited blood manipulation and steroid administration respectively.
Is Oral Fluid the Answer to Identifying In-competition Drug Use in Sport?
Moderator: Marilyn Huestis, Chief, Chemistry & Drug Metabolism, Intramural Research Program, NIDA, NIH, Biomedical Research Center, USAObjectives:After attending this session, participants will be able to:
- Describe how oral fluid testing may pose a better solution for “in-competition” testing for anti-doping drug monitoring than urine testing.
- Compare the disposition of cannabinoids into oral fluid from chronic frequent and occasional cannabis smokers.
- Describe the disposition of cocaine and benzoylecgonine into oral fluid.
Workshop W2503: Anti-infectives
Moderator: Jan-Willem Alffenaar, Pharmacist, University Medical Center Groningen, Netherlands
TDM of Antifungal Drugs; an Update
Eliane Billaud, Laboratoire de Pharmacologie-Toxicologie, Hôpital Européen Georges Pompidou, FranceObjectives:At the end of the session, the participants will be able to:
- Provide a description of some key elements and targets in the management of these antiinfectious drugs TDM;
- Get a description of significant items in the management of drug to drug interactions involving this class of drugs;
- Get some considerations on the potential role of TDM in the real-life management of these drugs in clinical practice.Description:This presentation will cover clinical cases to describe situations regarding azole antifungal drugs TDM (hepatic model) and other antiinfectious situations (renal model).
Beta-lactams and Cipro; New Insights
Deborah Marriott, Microbiology and Infectious Diseases, St. Vincent’s Hospital, AustraliaObjectives:At the end of the session, the participants will be able to:
- Understand optimal dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients.
- Determine the role of therapeutic drug monitoring in beta-lactam and quinolone antibiotics.Description:The beta-lactam and quinolone antimicrobial agents are widely used in a range of clinical settings from ambulatory care to the critically ill patient. However the limited TDM data available suggests that under-dosing is common, especially in the haemodynamically unstable patient, resulting in treatment failure and the development of bacterial resistance. This session will review the current dosing regimens and highlight the importance of TDM, particularly in the Intensive Care setting.
IPK/PD of Anti-TB Drugs; Implications for Daily Practice
Jan-Willem Alffenaar, Pharmacist, University Medical Center Groningen, NetherlandsObjectives:At the end of the session, the participants will be able to:
- Understand PK/PD principles of TB drugs.
- Detect clinical situation in which patients are at risk for inadequate treatment.
- Apply PK/PD principles of TB drugs in TDM in routine care.Description:Diagnostic and treatment options for Tuberculosis (TB) have expanded in the past decades. Yet new efforts are required to prevent development of drug resistance and the threats of multidrug-resistant TB. Optimization of treatment with currently available drugs is therefore important. In vitro and in vivo modeling of TB drugs has increased our knowledge about pharmacokinetics and pharmacodynamics of TB drugs. As drug susceptibility may differ and pharmacokinetics may vary considerably between and within patients TDM may be appropriate to optimize treatment. Population pharmacokinetics has been used to identify and explain variability among patients. As TB patients fail on current treatment regimens important clinical parameters may be identified that can be related to drug exposure, safety and efficacy of TB drugs. TDM is not yet part of programmatic treatment of TB, so general guidelines are lacking. Tools to improve daily management of TDM of TB drugs like limited sampling and dried blood spot analysis are presented. Management of clinical cases will be used to explain routine TDM of TB drugs.
Workshop W2504: High Resolution Mass Spectrometry
Moderator: Paul Taylor, Department of Clinical Pharmacology, Princess Alexandra Hospital, Australia
The Role of LC-(HR)-MS in the Clinical Laboratory
Markus Meyer, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, GermanyObjectives:At the end of the session, the participants will be able to:
- Knowledge about general benefits of HRMS.
- Knowledge about particular benefits of HRMS in TDM and CT.
- Discussion on HRMS vs. LRMS in TMD and CT.Description:The workshop should focus on knowledge about general benefits and particular benefits of HRMS in TDM and CT. Principles of HRMS will and different instrument types will be introduced. Applications and strategies will be presented where HRMS was successfully used and particular benefits of these methods will be highlighted and discussed. Own experiences with HRMS in this context will be shown and final conclusions will be drawn on the future of HRMS in TDM and CT
Comparison of Methods for Drug Testing: is LC-(HR)-MS Truly Better?
Kara Lynch, Assistant Professor, Associate Chief of Chemistry and Toxicology, University of California San Francisco, San Francisco General Hospital, USAObjectives:At the end of the session, the participants will be able to:
- Describe how high resolution mass spectrometry can be used for drug screening.
- Explain the differences between targeted and general unknown screening workflows using high resolution mass spectrometry instruments.
- Identify the advantages and disadvantages of using high resolution mass spectrometry instrument for drug screening in toxicology laboratories compared to traditional approaches.Description:Many analytical tools have been used for broad spectrum drug screening in clinical toxicology. Recently, drug screening methods that utilize high resolution mass spectrometry (HRMS) have been developed and published. This talk will describe how HRMS can be used for drug screening and explain the differences between targeted and general unknown screening workflows using HRMS instruments. Despite the recent interest in these approaches, few studies have compared HRMS screening methods to targeted tandem mass spectrometry methods to determine if HRMS is truly capable of identifying more drugs and metabolites of interest compared to MS/MS methods. Results from a study comparing HRMS and LC-MS/MS broad spectrum drug screening methods and their ability to identify drugs and metabolites in routine clinical samples (n=100) will be presented. The advantages and disadvantages of both methodologies, as identified in this study, for broad spectrum drug screening will be discussed.