Xenia M Hart1,2, Christoph Hiemke3,4, Luzie Eichentopf5, Xenija M Lense5, Hans Willi Clement6,4, Andreas Conca7,4, Frank Faltraco8,4, Vincenzo Florio7, Jessica Grüner6, Ursula Havemann-Reinecke9,4, Espen Molden10, Michael Paulzen11,4, Georgios Schoretsanitis12,13,14,4, Thomas G Riemer15, Gerhard Gründer5,4. 1. Department of Molecular Neuroimaging, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. xenia.hart@zi-mannheim.de. 2. Arbeitsgemeinschaft Für Neuropsychopharmakologie Und Pharmakopsychiatrie (AGNP), Work group Therapeutic Drug Monitoring, München, Germany. xenia.hart@zi-mannheim.de. 3. Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany. 4. Arbeitsgemeinschaft Für Neuropsychopharmakologie Und Pharmakopsychiatrie (AGNP), Work group Therapeutic Drug Monitoring, München, Germany. 5. Department of Molecular Neuroimaging, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. 6. Department of Child and Adolescent Psychiatry, University of Freiburg, Freiburg, Germany. 7. Sanitario Di Bolzano, Servizio Psichiatrico del Comprensorio, Bolzano, Italy. 8. Department of Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany. 9. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany. 10. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. 11. Department of Psychiatry, Psychotherapy and Psychosomatics, Alexianer Hospital Aachen, Aachen, Germany. 12. Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Psychiatric University Hospital Zurich, Zurich, Switzerland. 13. Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, New York, NY, USA. 14. Zucker School of Medicine at Northwell/Hofstra, Department of Psychiatry, Hempstead, NY, USA. 15. Institute of Clinical Pharmacology and Toxicology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin, Germany.
Abstract
RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.
RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.
Authors: J J Swen; M Nijenhuis; A de Boer; L Grandia; A H Maitland-van der Zee; H Mulder; G A P J M Rongen; R H N van Schaik; T Schalekamp; D J Touw; J van der Weide; B Wilffert; V H M Deneer; H-J Guchelaar Journal: Clin Pharmacol Ther Date: 2011-03-16 Impact factor: 6.875
Authors: Stefan Leucht; Magdolna Tardy; Katja Komossa; Stephan Heres; Werner Kissling; Georgia Salanti; John M Davis Journal: Lancet Date: 2012-05-03 Impact factor: 79.321