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
World Health Organization. Schizophrenia—fact sheet. 2018. http://www.who.int/news-room/fact-sheets/detail/schizophrenia. Accessed 14 Aug 2018.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008;13(1):27–35.
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.
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.
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.
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.
Zhou S-F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 2009;48(11):689–723.
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.
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.
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.
Xie H-G, Feng X, editors. Applying pharmacogenomics in therapeutics. Boca Raton: CRC Press; 2016.
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.
Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry. 1996;57(Suppl 11):12–25.
Wu AH. Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteomics. 2011;8(1):12.
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.
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.
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.
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.
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.
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.
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.
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.
Open Systems Pharmacology. PK-Sim® software manual. http://www.open-systems-pharmacology.org. Accessed 7 Sep 2018.
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.
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.
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.
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.
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.
Sheehan JJ, Sliwa JK, Amatniek JC, Grinspan A, Canuso CM. Atypical antipsychotic metabolism and excretion. Curr Drug Metab. 2010;11(6):516–25.
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.
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.
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.
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.
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.
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.
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.
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.
Mannens G, Meuldermans W, Snoeck E, Heykants J. Plasma protein binding of risperidone and its distribution in blood. Psychopharmacology. 1994;114(4):566–72.
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.
Heykants J, Huang ML, Mannens G, et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry. 1994;55(Suppl):13–7.
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.
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.
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.
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.
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.
Spina E, de Leon J. Clinical applications of CYP genotyping in psychiatry. J Neural Transm (Vienna). 2015;122(1):5–28.
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.
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.
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.
Williams R. Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry. 2001;62(4):282–9.
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.
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.
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.
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.
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.
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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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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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DOI: https://doi.org/10.1007/s40262-019-00793-x