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European Journal of Clinical Pharmacology

, Volume 72, Issue 9, pp 1091–1098 | Cite as

Pharmacokinetic patterns of risperidone-associated adverse drug reactions

  • Georgios Schoretsanitis
  • Benedikt Stegmann
  • Christoph Hiemke
  • Gerhard Gründer
  • Koen R. J. Schruers
  • Sebastian Walther
  • Sarah E. Lammertz
  • Ekkehard Haen
  • Michael Paulzen
Pharmacokinetics and Disposition

Abstract

Purpose

The aim of the study was to investigate a correlation between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety (AM) (RIS + 9-OH-RIS), and adverse drug reactions (ADRs) in a naturalistic sample.

Methods

Plasma concentrations of RIS, 9-OH-RIS, and AM in patients out of a therapeutic drug monitoring (TDM) database complaining ADRs were categorized according to the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 97) and compared to patients without ADRs (n = 398).

Results

Patients in the ADR group received a significantly lower daily dosage of risperidone (trimmed mean 3.64 mg/day) than patients without ADRs (4.40 mg/day). No differences were found for active moiety plasma concentrations between the groups (p = 0.454). Differences were detected only in the case of dose-adjusted plasma concentration values (concentration-by-dose, C/D) for 9-OH-RIS, being higher in patients reporting ADRs (4.78 ng/mL/mg) than in patients without ADRs (4.3 ng/mL/mg) (p = 0.037 for Mann-Whitney U test). Note that differences for non-adjusted 9-OH-RIS plasma levels between groups failed to reach significance (p = 0.697).

Conclusions

Our findings are consistent with previous data supporting a prominent role of 9-hydroxyrisperidone, but not of risperidone with regard to ADRs. When studying the various subgroups of reported ADRs separately, the size of these subsamples offers some plausible limitations by reducing the power of the analysis.

Keywords

Antipsychotics Drug metabolism Psychopharmacology Schizophrenia Pharmacokinetics 

Notes

Acknowledgments

The authors wish to express their gratitude to the number of people who contributed with excellent professional technical as well as pharmacological competence to build up the KONBEST database with 50,049 clinical pharmacological comments as of February 2, 2016 (ranked among the professional groups in historical order):

- A. Köstlbacher created the KONBEST software in his Ph.D. thesis based on the idea of E. Haen, C. Greiner, and D. Melchner along the workflow in the clinical pharmacological laboratory at the Department of Psychiatry and Psychotherapy of the University of Regensburg. He, together with his colleague A. Haas, currently maintains the KONBEST software and its data mining platform (Haas & Köstlbacher GbR, Regensburg, Germany).

- The following lab technicians performed the quantitative analysis: D. Melchner, T. Jahner, S. Beck, A. Dörfelt, U. Holzinger, and F. Pfaff-Haimerl.

- The clinical pharmacological comments to drug concentrations were composed by licensed pharmacists (C. Greiner, W. Bader, R. Köber, A. Hader, R. Brandl, M. Onuoha, N. Ben Omar, K. Schmid, A. Köppl, M. Silva, B. Fay, S. Unholzer, C. Rothammer, S. Böhr, F. Ridders, D. Braun, and M. Schwarz) and medical doctors (M. Dobmeier, M. Wittmann, M. Vogel, M. Böhme, K. Wenzel-Seifert, B. Plattner, P. Holter, R. Böhm, and R. Knorr).

The research study did not receive funds or support from any source.

Compliance with ethical standards

Conflict of interest

Ekkehard Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is the managing director of AGATE, a non-profit working group to improve drug safety and efficacy in the treatment of psychiatric diseases. He reports no conflict of interest with this publication. Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Astra Zeneca, Janssen-Cilag, Pfizer, Lilly, and Servier. He is the managing director of the Psiac GmbH which provides an Internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, IN, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen-Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorff (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is a co-founder of PharmaImage GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). Georgios Schoretsanitis received grant from the bequest “in memory of Maria Zaoussi,” State Scholarships Foundation, Greece, for clinical research in Psychiatry for the academic year 2015–2016. All other authors declare no conflicts of interest as well.

Contributions of the authors

GS, MP, GG, CH, EH, BS, KRJS, and SW participated in the research design. GS, MP, and SEL performed the data analysis. GS, MP, GG, CH, EH, BS, KRJS, SEL, and SW wrote or contributed to the writing of the manuscript.

Supplementary material

228_2016_2085_MOESM1_ESM.docx (16 kb)
ESM 1 (DOCX 15 kb)

References

  1. 1.
    Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF (1988) Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244(2):685–693PubMedGoogle Scholar
  2. 2.
    Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, Macqueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M (2013) Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 15(1):1–44. doi: 10.1111/bdi.12025 CrossRefPubMedGoogle Scholar
  3. 3.
    Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, Antony, MM, Bouchard S, Brunet A, Flament M, Grigoriadis S, Mendlowitz S, O’Connor K, Rabheru K, Richter, PM, Robichaud M, Walker JR Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles a, McGill U (2014) Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry 14 Suppl 1:S1. doi: 10.1186/1471-244X-14-S1-S1
  4. 4.
    Fang J, Bourin M, Baker GB (1999) Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3 A4. Naunyn Schmiedeberg’s Arch Pharmacol 359:147–151CrossRefGoogle Scholar
  5. 5.
    Xiang Q, Zhao X, Zhou Y, Duan JL, Cui YM (2010) Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety. J Clin Pharmacol 50(6):659–666. doi: 10.1177/0091270009347867 CrossRefPubMedGoogle Scholar
  6. 6.
    Heykants J, Huang ML, Mannens G, Meuldermans W, Snoeck E, Van Beijsterveldt L, Van Peer A, Woestenborghs R (1994) The pharmacokinetics of risperidone in humans: a summary. The Journal of Clinical Psychiatry 55(Suppl):13–17PubMedGoogle Scholar
  7. 7.
    Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, Fric M, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Jaquenoud Sirot E, Kirchherr H, Laux G, Lutz UC, Messer T, Muller MJ, Pfuhlmann B, Rambeck B, Riederer P, Schoppek B, Stingl J, Uhr M, Ulrich S, Waschgler R, Zernig G (2011) AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 44(6):195–235CrossRefGoogle Scholar
  8. 8.
    Yasui-Furukori N, Saito M, Nakagami T, Sugawara N, Sato Y, Tsuchimine S, Furukori H, Kaneko S (2010) Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 34(3):537–540. doi: 10.1016/j.pnpbp.2010.02.014 CrossRefGoogle Scholar
  9. 9.
    Yasui-Furukori N, Saito M, Tsuchimine S, Nakagami T, Sato Y, Sugawara N, Kaneko S (2008) Association between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients. Prog Neuro-Psychopharmacol Biol Psychiatry 32(6):1491–1495. doi: 10.1016/j.pnpbp.2008.05.006 CrossRefGoogle Scholar
  10. 10.
    Knegtering R, Baselmans P, Castelein S, Bosker F, Bruggeman R, van den Bosch RJ (2005) Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels. Am J Psychiatry 162(5):1010–1012. doi: 10.1176/appi.ajp.162.5.1010 CrossRefPubMedGoogle Scholar
  11. 11.
    Melkersson KI (2006) Prolactin elevation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite. Human Psychopharmacology 21(8):529–532. doi: 10.1002/hup.811 CrossRefPubMedGoogle Scholar
  12. 12.
    Eberhard J, Lindstrom E, Holstad M, Levander S (2007) Prolactin level during 5 years of risperidone treatment in patients with psychotic disorders. Acta Psychiatr Scand 115(4):268–276. doi: 10.1111/j.1600-0447.2006.00897.x CrossRefPubMedGoogle Scholar
  13. 13.
    Zhou ZL, Li X, Peng HY, Yu XY, Yang M, Su FL, Wang F, Zhu RH, Deng CY, Lin QX, Wang CY, Li WB, Lin SG, Li HD (2006) Multiple dose pharmacokinetics of risperidone and 9-hydroxyrisperidone in Chinese female patients with schizophrenia. Acta Pharmacol Sin 27(3):381–386. doi: 10.1111/j.1745-7254.2006.00256.x CrossRefPubMedGoogle Scholar
  14. 14.
    Wang L, Yu L, Zhang AP, Fang C, Du J, Gu NF, Qin SY, Feng GY, Li XW, Xing QH, He L (2007) Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia. J Psychopharmacol 21(8):837–842. doi: 10.1177/0269881107077357 CrossRefPubMedGoogle Scholar
  15. 15.
    Ginovart N, Kapur S (2012) Role of dopamine D(2) receptors for antipsychotic activity. Handb Exp Pharmacol 212:27–52. doi: 10.1007/978-3-642-25761-2_2 CrossRefPubMedGoogle Scholar
  16. 16.
    Mauri MC, Laini V, Boscati L, Rudelli R, Salvi V, Orlandi R, Papa P (2001) Long-term treatment of chronic schizophrenia with risperidone: a study with plasma levels. Eur Psychiatry: J Assoc Eur Psychiatrists 16(1):57–63CrossRefGoogle Scholar
  17. 17.
    Riedel M, Schwarz MJ, Strassnig M, Spellmann I, Muller-Arends A, Weber K, Zach J, Muller N, Moller HJ (2005) Risperidone plasma levels, clinical response and side-effects. Eur Arch Psychiatry Clin Neurosci 255(4):261–268. doi: 10.1007/s00406-004-0556-4 CrossRefPubMedGoogle Scholar
  18. 18.
    Chen PS, Yang YK, Su SF, Liao YC, Chang JW, Yeh TL (2004) Correlation between scores on continuous performance test and plasma concentration for schizophrenic patients on risperidone. Psychiatry Clin Neurosci 58(2):168–172CrossRefPubMedGoogle Scholar
  19. 19.
    Schoretsanitis G, Haen E, Hiemke C, Gründer G, Stegmann B, Schruers RJK, Vesenlinovic T, Lammertz S, Paulzen M (2016) Risperidone-induced extrapyramidal side effects: is the need for anticholinergics the consequence of high plasma concentrations? Int Clin Psychopharmacol. doi: 10.1097/YIC.0000000000000131 PubMedGoogle Scholar
  20. 20.
    Yoshimura R, Ueda N, Nakamura J (2001) Possible relationship between combined plasma concentrations of risperidone plus 9-hydroxyrisperidone and extrapyramidal symptoms. Preliminary study. Neuropsychobiology 44(3):129–133CrossRefPubMedGoogle Scholar
  21. 21.
    Kakihara S, Yoshimura R, Shinkai K, Matsumoto C, Goto M, Kaji K, Yamada Y, Ueda N, Ohmori O, Nakamura J (2005) Prediction of response to risperidone treatment with respect to plasma concentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. Int Clin Psychopharmacol 20(2):71–78CrossRefPubMedGoogle Scholar
  22. 22.
    Jovanovic N, Bozina N, Lovric M, Medved V, Jakovljevic M, Peles AM (2010) The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naive patients with first-episode schizophrenia treated with risperidone. Eur J Clin Pharmacol 66(11):1109–1117. doi: 10.1007/s00228-010-0850-1 CrossRefPubMedGoogle Scholar
  23. 23.
    Odou P, Levron JC, Luyckx M, Brunet C, Robert H (2000) Risperidone drug monitoring: a useful clinical tool? Clin Drug Investig 19(4):283–292CrossRefGoogle Scholar
  24. 24.
    Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Ancione M, Madia AG, Perucca E (2001) Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology 153(2):238–243CrossRefPubMedGoogle Scholar
  25. 25.
    Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987) The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 334:1–100CrossRefPubMedGoogle Scholar
  26. 26.
    Olesen OV, Licht RW, Thomsen E, Bruun T, Viftrup JE, Linnet K (1998) Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 20(4):380–384CrossRefPubMedGoogle Scholar
  27. 27.
    Yasui-Furukori N, Saito M, Nakagami T, Furukori H, Suzuki A, Kondo T, Kaneko S (2010) Clinical response to risperidone in relation to plasma drug concentrations in acutely exacerbated schizophrenic patients. J Psychopharmacol 24(7):987–994. doi: 10.1177/0269881109104849 CrossRefPubMedGoogle Scholar
  28. 28.
    Haen E (2011) Therapeutic drug monitoring in pharmacovigilance and pharmacotherapy safety. Pharmacopsychiatry 44(6):254–258CrossRefPubMedGoogle Scholar
  29. 29.
    Köstlbacher A, Haen E (2008) Konbest—a Web-based laboratory information management system (LIMS) for TDM-laboratories. Pharmacopsychiatry 41(05):A23Google Scholar
  30. 30.
    US Food and Drug Administration (2014) Drug development and drug interactions: table of substrates, inhibitors and inducers. http://www.fda.gov/Drugs/Developmenvt-ApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed 06/13/2016
  31. 31.
    Feng Y, Pollock BG, Coley K, Marder S, Miller D, Kirshner M, Aravagiri M, Schneider L, Bies RR (2008) Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study. Br J Clin Pharmacol 66(5):629–639. doi: 10.1111/j.1365-2125.2008.03276.x PubMedPubMedCentralGoogle Scholar
  32. 32.
    Yasui-Furukori N, Hidestrand M, Spina E, Facciola G, Scordo MG, Tybring G (2001) Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos Biological Fate Chem 29(10):1263–1268Google Scholar
  33. 33.
    Umbricht D, Kane JM (1996) Medical complications of new antipsychotic drugs. Schizophr Bull 22(3):475–483CrossRefPubMedGoogle Scholar
  34. 34.
    Sweeney JA, Keilp JG, Haas GL, Hill J, Weiden PJ (1991) Relationships between medication treatments and neuropsychological test performance in schizophrenia. Psychiatry Res 37(3):297–308CrossRefPubMedGoogle Scholar
  35. 35.
    Krausz M, Moritz S, Lambert M, Naber D (2000) Dosage of conventional neuroleptic medication and subjective cognitive functioning in schizophrenia. Int Clin Psychopharmacol 15(2):77–81CrossRefPubMedGoogle Scholar
  36. 36.
    Moritz S, Woodward TS, Krausz M, Naber D, Group PS (2002) Relationship between neuroleptic dosage and subjective cognitive dysfunction in schizophrenic patients treated with either conventional or atypical neuroleptic medication. Int Clin Psychopharmacol 17(1):41–44CrossRefPubMedGoogle Scholar
  37. 37.
    Keedy SK, Reilly JL, Bishop JR, Weiden PJ, Sweeney JA (2015) Impact of antipsychotic treatment on attention and motor learning systems in first-episode schizophrenia. Schizophr Bull 41(2):355–365. doi: 10.1093/schbul/sbu071 CrossRefPubMedGoogle Scholar
  38. 38.
    Harvey PD, Keefe RS (2001) Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 158(2):176–184. doi: 10.1176/appi.ajp.158.2.176 CrossRefPubMedGoogle Scholar
  39. 39.
    Harvey PD (2006) Cognitive and functional effects of atypical antipsychotic medications. J Clin Psychiatry 67(10):e13CrossRefPubMedGoogle Scholar
  40. 40.
    Takeuchi H, Suzuki T, Remington G, Bies RR, Abe T, Graff-Guerrero A, Watanabe K, Mimura M, Uchida H (2013) Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study. Schizophr Bull 39(5):993–998. doi: 10.1093/schbul/sbt090 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Elie D, Poirier M, Chianetta J, Durand M, Gregoire C, Grignon S (2010) Cognitive effects of antipsychotic dosage and polypharmacy: a study with the BACS in patients with schizophrenia and schizoaffective disorder. J Psychopharmacol 24(7):1037–1044. doi: 10.1177/0269881108100777 CrossRefPubMedGoogle Scholar
  42. 42.
    Harris MS, Wiseman CL, Reilly JL, Keshavan MS, Sweeney JA (2009) Effects of risperidone on procedural learning in antipsychotic-naive first-episode schizophrenia. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 34(2):468–476. doi: 10.1038/npp.2008.79 CrossRefGoogle Scholar
  43. 43.
    Reilly JL, Harris MS, Keshavan MS, Sweeney JA (2006) Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Arch Gen Psychiatry 63(11):1189–1197. doi: 10.1001/archpsyc.63.11.1189 CrossRefPubMedGoogle Scholar
  44. 44.
    Seeman MV (2010) Schizophrenia: women bear a disproportionate toll of antipsychotic side effects. J Am Psychiatric Nurses Assoc 16(1):21–29. doi: 10.1177/1078390309350918 CrossRefGoogle Scholar
  45. 45.
    Seeman MV (2009) Secondary effects of antipsychotics: women at greater risk than men. Schizophr Bull 35(5):937–948. doi: 10.1093/schbul/sbn023 CrossRefPubMedGoogle Scholar
  46. 46.
    Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Remschmidt H, Krieg JC, Hebebrand J, Theisen FM (2009) Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res 43(6):620–626. doi: 10.1016/j.jpsychires.2008.11.001 CrossRefPubMedGoogle Scholar
  47. 47.
    Keepers GA, Casey DE (1991) Use of neuroleptic-induced extrapyramidal symptoms to predict future vulnerability to side effects. Am J Psychiatry 148(1):85–89CrossRefPubMedGoogle Scholar
  48. 48.
    Cabaleiro T, Ochoa D, Lopez-Rodriguez R, Roman M, Novalbos J, Ayuso C, Abad-Santos F (2014) Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers. Human Psychopharmacol 29(5):459–469. doi: 10.1002/hup.2420 CrossRefGoogle Scholar
  49. 49.
    Mas S, Gasso P, Ritter MA, Malagelada C, Bernardo M, Lafuente A (2015) Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: multilocus interaction in the mTOR pathway. Eur Neuropsychopharmacology: J Eur Coll Neuropsychopharmacology 25(1):51–59. doi: 10.1016/j.euroneuro.2014.11.011 CrossRefGoogle Scholar
  50. 50.
    Balant-Gorgia AE, Gex-Fabry M, Genet C, Balant LP (1999) Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors. Ther Drug Monit 21(1):105–115CrossRefPubMedGoogle Scholar
  51. 51.
    Paulzen M, Haen E, Gründer G, Lammertz SE, Stegmann B, Schruers RJK, Walther S, Schoretsanitis G (2016) Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients – thinking of clinically relevant CYP2D6 interactions. J Psychopharmacol. 2016 May 31.Google Scholar
  52. 52.
    Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA (2013) Applications of CYP450 testing in the clinical setting. Mol Diagn Ther 17(3):165–184. doi: 10.1007/s40291-013-0028-5 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Bader W, Melchner D, Nonenmacher T, Haen E (2005) Determination of five commonly used antipsychotics in human serum by high performance-liquid chromatography (HPLC) and electrochemical detection. Pharmacopsychiatry 38(01):4Google Scholar
  54. 54.
    Paul L, Musshoff F, Aebi B, Auwärter V, Krämer T, Peters F, Skopp G, Aderjan R, Herbold M, Schmitt G (2009) Richtlinie der GTFCh zur Qualitätssicherung bei forensisch-toxikologischen Untersuchungen. Toxichem Krimtech 76(3):142–176Google Scholar
  55. 55.
    US Food and Drug Administration. Center for Drug Evaluation and Research (2001) Guidance for industry on biomedical method validation. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm070107.pdf. Accessed 30 Mar 2016
  56. 56.
    ICH Expert Working Group, editor. Harmonised tripartite guideline, validation of analytical procedures: test and methodology. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (1996) ICH harmonised tripartite guideline validation of analytical procedures: test and methodology. Available from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf. Accessed 26 Apr 2016

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Georgios Schoretsanitis
    • 1
    • 2
  • Benedikt Stegmann
    • 3
  • Christoph Hiemke
    • 4
  • Gerhard Gründer
    • 1
  • Koen R. J. Schruers
    • 5
  • Sebastian Walther
    • 2
  • Sarah E. Lammertz
    • 1
  • Ekkehard Haen
    • 3
  • Michael Paulzen
    • 1
  1. 1.Department of Psychiatry, Psychotherapy and Psychosomatics and JARA–Translational Brain MedicineRWTH Aachen UniversityAachenGermany
  2. 2.University Hospital of PsychiatryBernSwitzerland
  3. 3.Clinical Pharmacology, Department of Psychiatry and Psychotherapy and Department of Pharmacology and ToxicologyUniversity of RegensburgRegensburgGermany
  4. 4.Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center of MainzMainzGermany
  5. 5.Faculty of Health, Medicine and Life Sciences, School for Mental Health and NeuroscienceMaastricht UniversityMaastrichtNetherlands

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