Review Thieme Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 Authors C. Hiemke1, 2, N. Bergemann3, H. W. Clement4, A. Conca5, J. Deckert6, K. Domschke7, G. Eckermann8, K. Egberts9, M. Gerlach9, C. Greiner10, G. Gründer11, E. Haen12, U. Havemann-Reinecke13, G. Hefner14, R. Helmer15, G. Janssen16, E. Jaquenoud17, G. Laux18, T. Messer19, R. Mössner20, M. J. Müller21, M. Paulzen11, B. Pfuhlmann22, P. Riederer6, A. Saria23, B. Schoppek24, G. Schoretsanitis25, M. Schwarz26, M. Silva Gracia12, B. Stegmann12, W. Steimer27, J. C. Stingl10, M. Uhr28, S. Ulrich29, S. Unterecker6, R. Waschgler30, G. Zernig23, 31, G. Zurek32, P. Baumann33 Affiliations 19 Danuviuskliniken, Psychiatric Hospital, Pfaffenhofen, 1 Department of Psychiatry and Psychotherapy, University Germany Medical Center of Mainz, Mainz, Germany 20 Department of Psychiatry and Psychotherapy, University 2 Institute of Clinical Chemistry and Laboratory Medicine, of Tübingen, Tübingen, Germany University Medical Center of Mainz, Mainz, Germany 21 Psychiatric Hospitals Oberberggruppe, Berlin, Germany 3 Kitzberg Hospitals, Center for Psychosomatic Medicine 22 Psychiatric Hospital Weisser Hirsch, Dresden, Germany and Psychotherapy, Bad Mergentheim, Germany 23 Experimental Psychiatry Unit, Department of Psychiatry 4 Department of Child and Adolescent Psychiatry, 1, Medical University of Innsbruck, Innsbruck, Austria University of Freiburg, Freiburg, Germany 24 kbo-Isar-Amper Klinikum München-Ost, Psychiatric 5 Servizio Psichiatrico del Comprensorio Sanitario di Hospital, Munich-Haar, Germany Bolzano, Bolzano, Italy 25 Department of Psychiatry, University of Bern, Bern, 6 Department of Psychiatry, Psychotherapy and Psychoso- Switzerland matics, University Hospital of Würzburg, Germany 26 Department of Laboratory Medicine, Ludwig Maximilian 7 Department of Psychiatry and Psychotherapy, Medical University, Munich, Germany Center - University of Freiburg, Faculty of Medicine, 27 Institute of Clinical Chemistry and Pathobiochemistry, University of Freiburg, Freiburg, Germany Technical University Munich, Munich, Germany 8 Psychiatric Hospital, Kaufbeuren, Germany 28 Max Planck Institute of Psychiatry, Munich, Germany 9 Department of Child and Adolescent Psychiatry, 29 Aristo Pharma GmbH, Berlin, Germany Psychosomatics and Psychotherapy, Center of Mental 30 Psychiatric Hospital, Feldkirch, Austria Health, University Hospital of Würzburg, Germany 31 Private Practice for Psychotherapy and Court-Certified 10 Federal Institute for Drugs and Medical Devices (BfArM), Witness, Hall in Tirol, Austria Bonn, Germany 32 Medical Laboratory Bremen, Bremen, Germany 11 Department of Psychiatry, Psychotherapy and Psychoso- 33 Department of Psychiatry, University of Lausanne, matics, RWTH Aachen University, Aachen, and JARA – Prilly-Lausanne, Switzerland Translational Brain Medicine, Aachen, Germany 12 Clinical Pharmacology, Department of Psychiatry and Psycho- Key words therapy and Department of Pharmacology and Toxicology, antidepressant drugs, antiepileptic drugs, antiparkinson University of Regensburg, Regensburg, Germany drugs, antipsychotic drugs, concentration in blood, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 13 Department of Psychiatry and Psychosomatics, University consensus guidelines, drug analysis, genotyping, neurologic of Göttingen, Göttingen, Germany drugs, pharmacogenetics, pharmacokinetics, phenotyping, 14 Psychiatric Hospital, Vitos Klinik, Eichberg, Eltville, Germany plasma concentration, psychiatric drugs, reference range, 15 Center of Epilepsy, Bielefeld, Germany serum concentration, therapeutic drug monitoring, 16 Medical Laboratory Stein, Limbach Group, therapeutic window Mönchengladbach, Germany 17 Psychiatric Hospital, Königsfelden, Brugg, Aargau, received 15.05.2017 Switzerland revised 08.07.2017 18 Institute of Psychological Medicine, Haag in Oberbayern, accepted 10.07.2017 Germany Hiemke C et al. Consensus Guidelines for Therapeutic … Pharmacopsychiatry 2018; 51: 9–62 9 Review Thieme Bibliography 2. Drug Concentrations in Blood to Guide DOI http://dx.doi.org/10.1055/s-0043-116492 Neuropsychopharmacotherapy 22 Published online: 14.9.2017 2.1 The therapeutic reference range 22 2.1.1 Estimation of the lower limit of the therapeutic Pharmacopsychiatry 2018; 51: 9–62 reference range 33 © Georg Thieme Verlag KG Stuttgart · New York 2.1.2 Estimation of the upper limit of the therapeutic ISSN 0176-3679 reference range 33 2.1.3 From population-based to subject-based reference values 33 Correspondence 2.1.4 Laboratory alert level 34 C. Hiemke, PhD, Univ.-Prof. 2.2 The dose-related reference range 34 Department of Psychiatry and Psychotherapy 2.3 Concentration to dose ratio 44 University Medical Center, Mainz 2.4 Metabolite to parent compound ratios 44 Untere Zahlbacher Str. 8 2.5 Probe drug phenotyping 46 D-55101 Mainz 2.6 Indications for measuring drug concentrations in blood 47 Germany 2.7 Recommendations for measuring drug [email protected] concentrations in blood 50 3. Practical Aspects of TDM in Psychiatry and Neurology 52 Abstract 3.1 TDM request for quantification of drug concentrations in blood 52 Therapeutic drug monitoring (TDM) is the quantification and 3.2 Specimen collection 53 interpretation of drug concentrations in blood to optimize 3.2.1 Blood sample collection 53 pharmacotherapy. It considers the interindividual variability of 3.2.2 Oral fluid for TDM 54 pharmacokinetics and thus enables personalized pharmaco- 3.3 Storage and shipment of blood samples 55 therapy. In psychiatry and neurology, patient populations that 3.4 Laboratory measurements 55 may particularly benefit from TDM are children and adoles- 3.5 Computing of trough steady-state concentrations 56 cents, pregnant women, elderly patients, individuals with intel- 3.6 Interpretation and communication of results and lectual disabilities, patients with substance abuse disorders, recommendations 56 forensic psychiatric patients or patients with known or sus- 3.6.1 How to use the TDM guidelines for interpretation of results – cases 57 pected pharmacokinetic abnormalities. Non-response at ther- 3.7 Pharmacogenetic tests in addition to TDM 59 apeutic doses, uncertain drug adherence, suboptimal tolerabil- 3.8 Clinical decision making 60 ity, or pharmacokinetic drug-drug interactions are typical 3.9 Cost-effectiveness of TDM 61 indications for TDM. However, the potential benefits of TDM to 4. Conclusions and Perspectives 61 optimize pharmacotherapy can only be obtained if the method References 62 is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid informa- tion on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie Abbreviations (AGNP) issued their first guidelines for TDM in psychiatry in BBB blood-brain-barrier 2004. After an update in 2011, it was time for the next update. C/D concentration to dose ratio Following the new guidelines holds the potential to improve CL total clearance neuropsychopharmacotherapy, accelerate the recovery of CL/F apparent total clearance many patients, and reduce health care costs. Cav average concentration Cmax maximal concentration Cmin trough or minimal concentration CYP cytochrome P450 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Table of Contents DRC dose-related concentration EMA European Medicines Agency Abbreviations 10 F bioavailability (fraction absorbed) Background 11 FDA Food and Drug Administration Objectives of the Consensus Document 12 GeKO German Commission Genetic Testing Preparation of the Consensus Document 12 MPR metabolite to parent compound ratio 1. Pharmacokinetics and pharmacogentics 12 PET positron emission tomography 1.1 Pharmacokinetic aspects 12 1.1.1 Absorption, distribution and elimination of P-gp P-glycoprotein neuropsychiatric drugs 12 t1/2 elimination half-life 1.1.2 Drug concentrations in blood 17 TDM therapeutic drug monitoring 1.1.3 Drug concentrations in brain and cerebrospinal fluid 19 tmax time of maximal drug concentrations 1.2 Pharmacogenetic aspects 20 tmin time of minimal drug concentration 10 Hiemke C et al. Consensus Guidelines for Therapeutic … Pharmacopsychiatry 2018; 51: 9–62 Pharmacodynamics Pharmacokinetics Interactions with Absorption neurotransmitter receptors, Distribution transporters, metabolizing Metabolism enzymes and signal Excretion transduction systems Drug Drug Prescribed Drug concentration concentration dose effects in blood in brain Age, gender, disease, Neurogenesis, brain maturation, Drug lipophilicity, pregnancy, pharmacokinetic pharmacodynamic genotype drug transporter affinity, genotype, adherence, (neurotransmitter receptors, re- blood-brain-barrier medication error, interactions uptake transporters and permeability with other drugs, diet, smoking metabolizing enzymes) ▶Fig. 1 From prescribed dose to drug effects modulated by multiple factors leading to marked pharmacokinetic and pharmacodynamic variability. of a drug’s concentration in blood plasma or serum to titrate the Background dosage of individual patients to a drug concentration in blood that For the treatment of psychiatric and neurologic patients, more than is associated with the highest possible probability of response and 200 drugs are available which have been discovered and developed a low risk of adverse drug reactions/toxicity. Moreover, TDM has during the last 60 years