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Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes

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Abstract

Background and Objectives

The genetic polymorphism of cytochrome P450 (CYP) 2D6 is characterized by an excessive impact on positive and adverse drug reactions to antipsychotics, such as risperidone. Consequently, the pharmacokinetics of the drug and metabolite can be substantially altered and exhibit a high variability between the different phenotypes. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model considering the CYP2D6 genetic polymorphism for risperidone and 9-hydroxyrisperidone (9-OH-RIS) taking CYP3A4 into account. Additionally, risperidone dose adjustments, which would compensate for genetically caused differences in the plasma concentrations of the active moiety (sum of risperidone and 9-OH-RIS) were calculated.

Methods

Based on available knowledge about risperidone, 9-OH-RIS, and relevant physiological changes according to different CYP2D6 phenotypes, several PBPK models were built. In addition, an initial model was further evaluated based on the plasma concentrations of risperidone and 9-OH-RIS from a single-dose study including 71 genotyped healthy volunteers treated with 1 mg of oral risperidone.

Results

PBPK models were able to accurately describe risperidone exposure after single-dose administration, especially in the concentration range ≥ 1 µg/L, illustrated by a minimal bias and a good precision. About 90.3% of all weighted residuals versus observed plasma concentrations ≥ 1 µg/L were in the ± 30% range. The risperidone/9-OH-RIS ratio increased progressively according to reduced CYP2D6 activity, resulting in a mean ratio of 4.96 for poor metabolizers. Simulations demonstrate that dose adjustment of the drug by − 25% for poor metabolizers and by – 10% for intermediate metabolizers results in a similar exposure to that of extensive metabolizers. Conversely, the risperidone/9-OH-RIS ratio can be used to determine the phenotype of individuals.

Conclusion

PBPK modelling can provide a valuable tool to predict the pharmacokinetics of risperidone and 9-OH-RIS in healthy volunteers, according to the different CYP2D6 phenotypes taking CYP3A4 into account. These models are able to ultimately support decision-making regarding dose-optimization strategies, especially for subjects showing lower CYP2D6 activity.

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References

  1. World Health Organization. Schizophrenia—fact sheet. 2018. http://www.who.int/news-room/fact-sheets/detail/schizophrenia. Accessed 14 Aug 2018.

  2. World Health Organization. The world health report 2001: mental health: new understanding, new hope. 2018. http://www.who.int/whr/2001/en/whr01_en.pdf. Accessed 14 Aug 2018.

  3. Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther. 1988;244(2):685–93.

    CAS  PubMed  Google Scholar 

  4. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–62.

    Article  CAS  PubMed  Google Scholar 

  5. Bo Q-J, Li X-B, Wang Z-M, Li A-N, Ma X, Wang C-Y. Extrapyramidal symptoms during risperidone maintenance treatment in schizophrenia: a prospective, multicenter study. J Clin Psychopharmacol. 2016;36(2):125–9.

    Article  CAS  PubMed  Google Scholar 

  6. Kasper S, Tauscher J, Küfferle B, Barnas C, Pezawas L, Quiner S. Dopamine- and serotonin-receptors in schizophrenia: results of imaging-studies and implications for pharmacotherapy in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1999;249(Suppl 4):83–9.

    Article  PubMed  Google Scholar 

  7. Huang ML, van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther. 1993;54(3):257–68.

    Article  CAS  PubMed  Google Scholar 

  8. Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol. 1999;359(2):147–51.

    Article  CAS  PubMed  Google Scholar 

  9. Yasui-Furukori N, Hidestrand M, Spina E, Facciolá G, Scordo MG, Tybring G. Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos. 2001;29(10):1263–8.

    CAS  PubMed  Google Scholar 

  10. Bork JA, Rogers T, Wedlund PJ, Leon Jd. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A. J Clin Psychiatry 1999;60(7):469–76.

    Article  CAS  PubMed  Google Scholar 

  11. Spina E, Avenoso A, Facciolà G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate. Ther Drug Monit. 2000;22(4):481–5.

    Article  CAS  PubMed  Google Scholar 

  12. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008;13(1):27–35.

    Article  CAS  PubMed  Google Scholar 

  13. Schoretsanitis G, de Leon J, Haen E, et al. Pharmacokinetics of risperidone in different application forms—comparing long-acting injectable and oral formulations. Eur Neuropsychopharmacol. 2018;28(1):130–7.

    Article  CAS  PubMed  Google Scholar 

  14. Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1–02):9–62.

    CAS  PubMed  Google Scholar 

  15. Balant-Gorgia AE, Gex-Fabry M, Genet C, Balant LP. Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors. Ther Drug Monit. 1999;21(1):105–15.

    Article  CAS  PubMed  Google Scholar 

  16. Aravagiri M, Marder SR, Wirshing D, Wirshing WC. Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection. Pharmacopsychiatry. 1998;31(3):102–9.

    Article  CAS  PubMed  Google Scholar 

  17. Zhou S-F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 2009;48(11):689–723.

    Article  CAS  PubMed  Google Scholar 

  18. Snoeck E, van Peer A, Sack M, et al. Influence of age, renal and liver impairment on the pharmacokinetics of risperidone in man. Psychopharmacology. 1995;122(3):223–9.

    Article  CAS  PubMed  Google Scholar 

  19. Puangpetch A, Vanwong N, Nuntamool N, Hongkaew Y, Chamnanphon M, Sukasem C. CYP2D6 polymorphisms and their influence on risperidone treatment. Pharmgenomics Pers Med. 2016;9:131–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234–42.

    Article  CAS  PubMed  Google Scholar 

  21. Xie H-G, Feng X, editors. Applying pharmacogenomics in therapeutics. Boca Raton: CRC Press; 2016.

    Google Scholar 

  22. de Leon J, Susce MT, Pan R-M, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15–27.

    Article  PubMed  Google Scholar 

  23. Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry. 1996;57(Suppl 11):12–25.

    CAS  PubMed  Google Scholar 

  24. Wu AH. Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteomics. 2011;8(1):12.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bozina N, Jovanović N, Lovrić M, Medved V. Clinical significance of a CYP2D6 poor metabolizer–a patient with schizophrenia on risperidone treatment. Ther Drug Monit. 2008;30(6):748–51.

    Article  PubMed  Google Scholar 

  26. Bertilsson L, Dahl M-L, Dalén P, Al-Shurbaji A. Molecular genetics of CYP2D6: Clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53(2):111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Olesen OV, Licht RW, Thomsen E, Bruun T, Viftrup JE, Linnet K. Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit. 1998;20(4):380–4.

    Article  CAS  PubMed  Google Scholar 

  28. Scordo MG, Spina E, Facciolà G, Avenoso A, Johansson I, Dahl ML. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone. Psychopharmacology. 1999;147(3):300–5.

    Article  CAS  PubMed  Google Scholar 

  29. Roh HK, Kim CE, Chung WG, Park CS, Svensson JO, Bertilsson L. Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients. Eur J Clin Pharmacol. 2001;57(9):671–5.

    Article  CAS  PubMed  Google Scholar 

  30. Mihara K, Kondo T, Yasui-Furukori N, et al. Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia. Ther Drug Monit. 2003;25(3):287–93.

    Article  CAS  PubMed  Google Scholar 

  31. Open Systems Pharmacology. Software PK-Sim®: 7.3.0. 2018. https://github.com/Open-Systems-Pharmacology/Suite/releases/tag/v7.3.0. Accessed 7 Sep 2018.

  32. Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. BIOSILICO. 2003;1(4):121–4.

    Article  CAS  Google Scholar 

  33. Open Systems Pharmacology. PK-Sim® software manual. http://www.open-systems-pharmacology.org. Accessed 7 Sep 2018.

  34. Willmann S, Höhn K, Edginton A, et al. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007;34(3):401–31.

    Article  PubMed  Google Scholar 

  35. Eissing T, Kuepfer L, Becker C, et al. A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front Physiol. 2011;2:4.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kuepfer L, Niederalt C, Wendl T, et al. Applied concepts in PBPK modeling: how to build a PBPK/PD model. CPT Pharmacometrics Syst Pharmacol. 2016;5(10):516–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Novalbos J, López-Rodríguez R, Román M, Gallego-Sandín S, Ochoa D, Abad-Santos F. Effects of CYP2D6 genotype on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers. J Clin Psychopharmacol. 2010;30(5):504–11.

    Article  CAS  PubMed  Google Scholar 

  38. Janssen Pharmaceutical Ltd. Product information Risperdal® (risperidone) tablets. FDA Accessdata. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020272s042,020588s030,021444s016,021346s010lbl.pdf. Accessed 7 Sep 2018.

  39. Sheehan JJ, Sliwa JK, Amatniek JC, Grinspan A, Canuso CM. Atypical antipsychotic metabolism and excretion. Curr Drug Metab. 2010;11(6):516–25.

    Article  CAS  PubMed  Google Scholar 

  40. Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, de Gaspari IF, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007;46(5):359–88.

    Article  CAS  PubMed  Google Scholar 

  41. Ejsing TB, Pedersen AD, Linnet K. P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments. Hum Psychopharmacol. 2005;20(7):493–500.

    Article  CAS  PubMed  Google Scholar 

  42. Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94(6):1259–76.

    Article  CAS  PubMed  Google Scholar 

  43. Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.

    Article  CAS  PubMed  Google Scholar 

  44. Cabaleiro T, Ochoa D, López-Rodríguez R, et al. Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers. Hum Psychopharmacol. 2014;29(5):459–69.

    Article  CAS  PubMed  Google Scholar 

  45. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS. Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clin Pharmacol Ther. 2002;72(1):76–89.

    Article  CAS  PubMed  Google Scholar 

  46. Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 2017;46(D1):D1074–D1082.

    Article  PubMed Central  CAS  Google Scholar 

  47. Viswanadhan VN, Ghose AK, Revankar GR, Robins RK. Atomic physicochemical parameters for three dimensional structure directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput Sci. 1989;29(3):163–72.

    Article  CAS  Google Scholar 

  48. Mannens G, Meuldermans W, Snoeck E, Heykants J. Plasma protein binding of risperidone and its distribution in blood. Psychopharmacology. 1994;114(4):566–72.

    Article  CAS  PubMed  Google Scholar 

  49. de Leon J, Susce MT, Johnson M, et al. DNA microarray technology in the clinical environment: the AmpliChip CYP450 test for CYP2D6 and CYP2C19 genotyping. CNS Spectr. 2009;14(1):19–34.

    Article  PubMed  Google Scholar 

  50. Heykants J, Huang ML, Mannens G, et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry. 1994;55(Suppl):13–7.

    PubMed  Google Scholar 

  51. Janssen-Cilag GmbH. Fachinformation RISPERDAL® 0.5 mg, Filmtabletten. 2018. https://www.gelbe-liste.de/produkte/RISPERDAL-0-5-mg-Filmtabletten_355913. Accessed 10 Aug 2018.

  52. Zhou Z-l, Li X, Peng H-y, et al. Multiple dose pharmacokinetics of risperidone and 9-hydroxyrisperidone in Chinese female patients with schizophrenia. Acta Pharmacol Sin 2006;27(3):381–6.

    Article  CAS  PubMed  Google Scholar 

  53. Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol. 1993;13(1):25–40.

    Article  CAS  PubMed  Google Scholar 

  54. European Medicines Agency. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation: draft. London. 2016. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500211315.pdf. Accessed 24 Aug 2018.

  55. R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2008. ISBN 3-900051-07-0. http://www.R-project.org.

  56. Spina E, de Leon J. Clinical applications of CYP genotyping in psychiatry. J Neural Transm (Vienna). 2015;122(1):5–28.

    Article  CAS  Google Scholar 

  57. de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006;47(1):75–85.

    Article  PubMed  Google Scholar 

  58. Mas S, Gassò P, Alvarez S, Parellada E, Bernardo M, Lafuente A. Intuitive pharmacogenetics: spontaneous risperidone dosage is related to CYP2D6, CYP3A5 and ABCB1 genotypes. Pharmacogenomics J. 2012;12(3):255–9.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. Williams R. Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry. 2001;62(4):282–9.

    Article  CAS  PubMed  Google Scholar 

  61. Schoretsanitis G, Spina E, Hiemke C, de Leon J. A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone. Expert Rev Clin Pharmacol. 2017;10(9):965–81.

    Article  CAS  PubMed  Google Scholar 

  62. Poulin P, Schoenlein K, Theil FP. Prediction of adipose tissue: plasma partition coefficients for structurally unrelated drugs. J Pharm Sci. 2001;90(4):436–47.

    Article  CAS  PubMed  Google Scholar 

  63. Poulin P, Theil FP. A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. J Pharm Sci. 2000;89(1):16–35.

    Article  CAS  PubMed  Google Scholar 

  64. Deutscher Apotheker Verlag. Monographien H - Z. 9. Ausgabe, Grundwerk 2017. Europäisches Arzneibuch, 9.2017, Band 3. Stuttgart: Deutscher Apotheker Verlag; Govi-Verlag—Pharmazeutischer Verlag. 2017.

  65. Okubo M, Morita S, Murayama N, Akimoto Y, Goto A, Yamazaki H. Individual differences in in vitro and in vivo metabolic clearances of antipsychotic risperidone from Japanese subjects genotyped for cytochrome P450 2D6 and 3A5. Hum Psychopharmacol. 2016;31(2):93–102.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Institute of Pharmaceutical and Medical Chemistry, University of Münster, Corrensstr. 48, 48149, Munster, Germany

    Lisa Alina Kneller & Georg Hempel

  2. Clinical Pharmacology Department, Instituto de Investigación Sanitaria La Princesa (IP), Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Diego de León 62, 28006, Madrid, Spain

    Francisco Abad-Santos

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Correspondence to Georg Hempel.

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Lisa Alina Kneller, Francisco Abad-Santos, and Georg Hempel have no potential conflicts of interest to declare.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Kneller, L.A., Abad-Santos, F. & Hempel, G. Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes. Clin Pharmacokinet 59, 51–65 (2020). https://doi.org/10.1007/s40262-019-00793-x

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