Abstract
Objective: The cytochrome P450 superfamily is an important enzyme complex which aids in the metabolization of approximately 80% of pharmaceuticals currently on the market. Genetic variation leads to different phenotypes of metabolization: extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM) and ultra-rapid metabolizer (UM). Depending on polymorphism, different doses are appropriate. The information about 2D6, 2C9 and 2C19 is especially relevant from an economic point of view. The authors aim to determine how large the economic savings can be for the statutory health insurance by adapting the dose rate according to the CYP450 genotype. Therefore, they explored the top ten groups of the Anatomical Therapeutic Chemical (ATC) Classification System in sales in 2010.
Methods: To calculate potential savings, a formula was designed, which includes the relevant agents, the frequency in which polymorphisms occur, the average defined daily doses and their costs, the number of patients, and the average intake period.
Results: 36 appropriate agents were identified for calculation. They incurred a total cost of h2.3 billion for the statutory health insurance in 2010. The maximum saving potential lies in the ATC-group of psychoanaleptics, amounting to h96.1 million. Aripiprazol (h948.60), perphenazin (h352.40) and thiordiazin (€319.10) head the list of agents with the best saving potential per patient and treatment phase. Regarding the costs of diagnostic tests (€100 or €300), only four out of eight drugs are cost-covering.
Conclusion: Pharmacogenetic testing and subsequent dose optimization is partially efficient. Mainly for agents with high €/DDD (DDD: Defined Daily Dose) and long duration of treatment, positive cost-aspects have been calculated in total or on a per patient basis. For final economic appraisal, further information is needed, such as the effect on adverse drug reaction or synergy effects for multi-medicated patients. Finally, dose optimization based on genetic information is likely to be efficient for several agents.
Access this article
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
Similar content being viewed by others
Literatur
Mutschler E, Geisslinger G, Kroemer HK, et al. Mutschler Arzneimittelwirkungen: Lehrbuch der Pharmakologie und Toxikologie. 9. Auflage. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 2008
Ingleman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci 2004; 25(4): 193–200
Wilkinson GR. Drug metabolism and variability in drug response. N Engl J Med 2005; 352(21): 2211–21
Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002; 360(9340): 1155–62
Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286(5439): 487–91
Roots I, Laschinski G, Meyer UA. Pharmakogenetik und Pharmakogenomik. In: Ganten D, Ruckpaul K. Grundlagen der molekularen Medizin. 3. Auflage. Berlin/Heidelberg: Springer, 2008: 315–31
Kirchheiner J, Seeringer A, Brockmöller J. Stand der Pharmakogenetik in der klinischen Arzneimitteltherapie. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2006; 49(10): 995–1003
Seeringer A, Kirchheiner J. CYP2D6-, CYP2C9- und CYP2C19-basierte Arzneimitteldosisanpassungen. Der Internist 2008; 7: 877–83
Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116(3): 496–526
Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278(1): 441–6
Bertilsson L, Dahl ML, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341(8836): 63
Kirchheiner J, Meisel C, Goldammer M, et al. Pharmako-genetik als Basis neuer Therapiekonzepte. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2003; 46(10): 835–44
Scott SA. Personalizing medicine with clinical pharmacogenetics. Genet Med 2011; 13(12): 987–95
World Health Organization. International drug monitoring: the role of national centres. Report of a WHO meeting. World Health Organ Tech Rep Ser 1972; 498: 1–25
Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356(9237): 1255–9
Beubler E. Kompendium der Pharmakologie: Gebräuchliche Arzneimittel in der Praxis. 3. Auflage. Wien: Springer, 2011
Thürmann PA. Unerwünschte Arzneimittelwirkungen — Diagnostik und Bewertung. Der Pathologe. 2006; 27(1): 6–12
Dormann H, Neubert A, Criegee-Rieck M, et al. Readmissions and adverse drug reactions in internal medicine: the economic impact. J Intern Med 2004; 255(6): 653–63
Classen DC, Pestotnik SL, Evans RS, et al. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1997; 277(4): 301–6
Schnurrer JU, Frölich JC. Zur Häufigkeit und Vermeidbarkeit von tödlichen unerwünschten Arzneimittelwirkungen. Der Internist 2003; 44(7): 889–95
Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group. JAMA 1997; 277(4): 307–11
Beijer HJ, de Blaey CJ. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies. Pharm World Sci 2002; 24(2): 46–54
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med 2006; 57: 119–37
Kirchheiner J. Arzneitherapieempfehlungen auf pharmakogenetischer Basis [Habilitation]. Berlin: Charité — Universitätsmedizin Berlin, 2003
Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotypeguided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008; 83(3): 460–70
Liberato NL, Marchetti M, Barosi G. Cost effectiveness of adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2007; 25(6): 625–33
Neyt M, Albrecht J, Cocquyt V. An economic evaluation of Herceptin in adjuvant setting: the Breast Cancer International Research Group 006 trial. Ann Oncol 2006; 17(3): 381–90
Tappenden P, Jones R, Paisley S, et al. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess 2007; 11(12): 1–128, iii-iv
Brown B, Diamantopoulos A, Bernier J, et al. An economic evaluation of cetuximab combined with radiotherapy for patients with locally advanced head and neck cancer in Belgium, France, Italy, Switzerland, and the United Kingdom. Value Health 2008; 11(5): 791–9
Debnath M, Prasad GBKS, Bisen PS. Molecular Diagnostics: Promises and Possibilities. 1. Auflage. Dordrecht: Springer, 2010
Wong WB, Carlson JJ, Thariani R, et al. Cost Effectiveness of Pharmacogenomics: A Critical and Systematic Review. PharmacoEconomics 2010; 28(11): 1001–13
Patrick AR, Avorn J, Choudhry NK. Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2009; 2(5): 429–36
Eckman MH, Rosand J, Greenberg SM et al. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009; 150(2): 73–83
Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12(3): 251–63
Sachse C, Brockmöller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60(2): 284–95
Schwabe U, Paffrath D. Arzneiverordnungs-Report 2011. Berlin: Springer, 2011
Gesundheitsberichterstattung des Bundes. Mitglieder und mitversicherte Familienangehörige der gesetzlichen Krankenversicherung am 1.7. eines Jahres (Anzahl). Gliederungsmerkmale: Jahre, Deutschland, Alter, Geschlecht, Kassenart, Versichertengruppe. Erhältlich unter URL: http://www.gbe-bund.de [Abgerufen 11.07.2011]
Niehaus F. Versicherung von Kindern im Vergleich zwischen GKV und PKV. WIP Diskussionspapier 9/09. Erhältlich unter URL: http://www.wip-pkv.de/uploads/tx_nppresscenter/Versicherung_von_Kinder_im_Vergleich_ PKV_und_GKV.pdf [Abgerufen 15.06.2011]
Hagenmeyer EG, Gothe H, Höer A, et al. Management of Rheumatoid Arthritis in Germany: Findings of a Claims Database Analysis. Erhältlich unter URL: http://www.iges.de/publikationen/poster__abstracts/ispor_arlington/e5661/infoboxContent5662/IGES_Poster_RA_ISPOR_2007_ ger.pdf [Abgerufen 05.06.2011]
Ziegler S, Huscher D, Karberg K, et al. Trends in treatment and outcomes of rheumatoid arthritis in Germany 1997–2007: results from the National Database of the German Collaborative Arthritis Centres. Ann Rheum Dis 2010; 69(10): 1803–8
Petty DR, House A, Knapp P, et al. Prevalence, duration and indications for prescribing of antidepressants in primary care. Age Ageing 2006; 35(5): 523–6
Aletaha D, Stamm T, Kapral T, et al. Survival and effectiveness of leflunomide compared with methotrexate and sulfasalazine in rheumatoid arthritis: a matched observational study. Ann Rheum Dis 2003; 62(10): 944–51
Freeman J, Hutchison GB. Prevalence, incidence and duration. Am J Epidemiol 1980; 112(5): 707–23
Alho JM. On prevalence, incidence, and duration in general stable populations. Biometrics 1992; 48(2): 587–92
Ubink-Veltmaat LJ, Bilo HJ, Groenier KH, et al. Prevalence, incidence and mortality of type 2 diabetes mellitus revisited: a prospective population-based study in The Netherlands (ZODIAC-1). Eur J Epidemiol 2003; 18(8): 793–800
de Salvia D, Barbato A, Salvo P, et al. Prevalence and incidence of schizophrenic disorders in Portogruaro. An Italian case register study. J Nerv Ment Dis 1993; 181(5): 275–82
Kirchheiner J, Brøsen K, Dahl ML, et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001; 104(3): 173–92
Rudberg I, Mohebi B, Hermann M, et al. Impact of the ultrarapid CYP2C19∞17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 2008; 83(2): 322–7
Rudberg I, Hermann M, Refsum H, et al. Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Eur J Clin Pharmacol 2008; 64(12): 1181–8
Schöffski O, Greiner W. Grundprinzipien der Wirtschaftlichkeitsuntersuchung. In: Schöffski O, Graf v. d. Schulenburg JM. Gesundheitsökonomische Evaluationen. 3. Auflage. Berlin: Springer, 2007: 167–191
Rebsamen MC, Desmeules J, Daali Y, et al. The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J 2009; 9(1): 34–41
Rodríguez-Antona C, Gurwitz D, de Leon J, et al. CYP2D6 genotyping for psychiatric patients treated with risperidone: considerations for cost-effectiveness studies. Pharmacogenomics 2009; 10(4): 685–99
Matchar DB, Thakur ME, Grossman I, et al. Testing for cytochrome P450 polymorphisms in adults with non-psychotic depression treated with selective serotonin reuptake inhibitors (SSRIs). Evid Rep Technol Assess (Full Rep) 2007; (146): 1-77
Hüsing B, Hartig J, Bührlein B, et al. Individualisierte Medizin und Gesundheitssystem. TAB-Arbeitsbericht Nr. 126. Berlin: Büro für Technikfolgen-Abschätzung beim Deutschen Bundestag (TAB), 2008. Erhältlich von URL: http://www.tab-beim-bundestag.de/de/pdf/publikationen/ berichte/TAB-Arbeitsbericht-ab126.pdf [Abgerufen 11.04.2011]
Greiner W, Knittel M. Wirtschaftliche Potentiale individualisierter Medizin. PharmacoEconomics — German Research Articles 2011; 9(1): 45–54
Hermanns PM, Filler G, Roscher B. GOÄ (Gebührenordnung für Ärzte): Kommentar für Praxis und Klinik. 5. Auflage. München: ecomed Medizin, 2011
Marsden CD, Jenner P. The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med 1980; 10(1): 55–72
Casey DE. Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res 1991; 4(2): 109–20
Linnet K, Wiborg O. Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. Clin Pharmacol Ther 1996; 60(1): 41–7
Dahl ML, Sjöqvist F. Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics. Ther Drug Monit 2000; 22(1): 114–7
Hiemke C, Baumann P. Pharmakokinetik, Pharmakogenetik und therapeutisches Drug Monitoring. In: Holsboer F, Gründer G, Benkert O. Handbuch der Psychopharmakotherapie. Berlin/Heidelberg: Springer, 2008: 375–97
Manolopoulos VG, Ragia G, Tavridou A. Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective. Pharmacogenomics 2011; 12(8): 1161–91
Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry 2011 Nov 15. doi: 10.1038/mp.2011.146. [Epub ahead of print]
Fleeman N, McLeod C, Bagust A. The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation. Health Technol Assess 2010; 14(3): 1–157, iii
Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004; 329(7456): 15–9
Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279(15): 1200–5
Goettler M, Schneeweiss S, Hasford J. Adverse drug reaction monitoring-cost and benefit considerations. Part II: cost and preventability of adverse drug reactions leading to hospital admission. Pharmacoepidemiol Drug Saf 1997; 6 Suppl 3: S79–90
Schneeweiss S, Hasford J, Göttler M, et al. Admissions caused by adverse drug events to internal medicine and emergency depatments in hospitals: a longitudinal population-based study. Eur J Clin Pharmacol 2002; 58(4): 285–91
Sachverständigenrat zur Begutachtung der Entwicklung im Gesundheitswesen. Kooperation und Verantwortung. Voraussetzungen einer zielorientierten Gesundheitsversorgung. Jahresgutachten 2007. Erhältlich unter URL: http://www.svr-gesundheit.de/Gutachten/Gutacht07/Kurz fassung%202007.pdf
Stark RG, John J, Leidl R. Health care use and costs of adverse drug events emerging from outpatient treatment in Germany: a modelling approach. BMC Health Serv Res 2011; 11:9
Weiß J. Tabletten teilen — ein gefährliches Unterfangen. Dtsch med Wochenschr 2007; 132(15): 3
Rogausch A, Brockmöller J, Himmel W. Pharmakogenetische Tests in der zukünftigen medizinischen Versorgung: Implikationen für Patienten und Ärzte. Gesundheitswesen 2005; 67(4): 257–63
March R, Cheeseman K, Doherty M. Pharmacogenetics — legal, ethical and regulatory considerations. Pharmacogenomics 2001; 2(4): 317–27
Nebert DW, Bingham E. Pharmacogenomics: out of the lab and into the community. Trends Biotechnol 2001; 19(12): 519–23
Lindpaintner K. Pharmacogenetics and the future of medical practice. Br J Clin Pharmacol 2002; 54(2): 221–30
Norbert PW, Roses AD. Pharmacogenetics and pharmacogenomics: recent developments, their clinical relevance and some ethical, social, and legal implications. J Mol Med 2003; 81(3): 135–40
Burkhardt H, Wehling M. Probleme bei der Pharmakotherapie älterer Patienten. Der Internist 2010; 51(6): 737–48
Burkhardt H, Wehling M, Gladisch R. Prävention unerwünschter Arzneimittelwirkungen bei älteren Patienten. Z Gerontol Geriatr 2007; 40(4): 241–54
Thürmann PA. Geschlechtsspezifische Unterschiede in der Pharmakotherapie. In: Rieder A, Lohff B. Gender Medizin. Wien: Springer, 2008; 31–47
Findl I, Klaushofer K, Koller K. Medikamenten-Compliance geriatrischer Patienten. TopTipps — Ein Service der NÖGKK 2001; 3. Erhältlich unter URL: http://www.sozialversicherung.at/mediaDB/655175_Top_Tipps3_2001.pdf [Abgerufen 11.04.2011]
San Miguel MT, Martínez JA, Vargas E. Food-drug interactions in the summary of product characteristics of proprietary medicinal products. Eur J Clin Pharmacol 2005; 61(2): 77–83
Stein K. Herbal supplements and prescription drugs. A risky combination? J Am Diet Assoc 2000; 100(4): 412
Sari AB, Cracknell A, Sheldon TA. Incidence, preventability and consequences of adverse events in older people: results of a retrospective case-note review. Age Ageing 2008; 37(3): 265–9
Milton JC, Jackson SH. Inappropriate polypharmacy: reducing the burden of multiple medication. Clin Med 2007; 7(5): 514–7
Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch Intern Med 1997; 157(14): 1531–6
Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9(5): 442–73
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41(2): 89–295
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Meier, F., Kontekakis, A. & Schöffski, O. Bewertung der Einsparpotenziale in der Arzneimitteltherapie durch Dosisanpassung an die Polymorphismen im Cytochrom P450. Pharmacoeconomics-Ger-Res-Articles 10, 69–85 (2012). https://doi.org/10.1007/BF03320779
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03320779