Identification of Cytochrome P450-Mediated Drug–Drug Interactions at Risk in Cases of Gene Polymorphisms by Using a Quantitative Prediction Model

  • Nicolas Fermier
  • Laurent Bourguignon
  • Sylvain Goutelle
  • Nathalie Bleyzac
  • Michel Tod
Original Research Article


Background and Objective

The magnitude of drug–drug interactions mediated by cytochrome P450 (CYP) may depend on the genotype of polymorphic cytochromes. The objective of this study was to identify drug–drug interactions with greater magnitude in CYP variant groups than in extensive metabolizers.


The in-vivo mechanistic static model was used to predict the area under the curve ratio of drug–drug interactions. Five cytochromes (CYP3A4/5, 2D6, 2C9, 2C19, 1A2) and five groups of genotypes for each polymorphic cytochrome (CYP2D6, 2C9, 2C19) were considered. The area under the curve ratios were calculated for all combinations and all genotypes for 196 substrates and 96 inhibitors. Among the strongest interactions (area under the curve ratio greater than 5), two levels of gene sensitivity of drug–drug interactions were defined: the intermediate sensitivity, with a three- to five-fold stronger interaction in genotype groups other than in extensive metabolizers, and the high sensitivity, with a more than five-fold stronger interaction than in genotype groups other than extensive metabolizers.


A red list of 104 interactions with a sensitivity greater than 3, involving 13 substrates and 24 interactors was obtained. There were 59 and 45 cases of high and intermediate sensitivity, respectively. The genotypes associated with a high sensitivity were CYP2D6 *3–8 *3–8 (sensitivity up to 24.3) and CYP2C19 *2–3*2–3 (sensitivity up to 37.8).


A cytochrome polymorphism may lead to major drug–drug interactions in poor metabolizers, while these interactions may not be significant in extensive metabolizers. Among the 104 cases studied, the interaction could be of ca. 30-fold larger magnitude in the worst case. Genotyping of the patient and/or therapeutic drug monitoring of the substrate should be carried out when an association mentioned in the red list is prescribed. The concept of gene sensitivity of drug–drug interactions appears promising for the development of precision medicine.


Compliance with Ethical Standards


No external funding was received for the conduct of this study.

Conflict of interest

Nicolas Fermier, Laurent Bourguigon, Sylvain Goutelle, Nathalie Bleyzac, and Michel Tod have no conflicts of interest directly relevant to the content of this article.


  1. 1.
    European Medicines Agency. Guideline on the investigation of drug interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2. 2012.Google Scholar
  2. 2.
    Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Drug interaction studies: study design, data analysis, implications for dosing, and labeling recommendations. 2012.Google Scholar
  3. 3.
    Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Clinical pharmacogenomics: premarket evaluation in early-phase clinical studies and recommendations for labeling. 2013.Google Scholar
  4. 4.
    Hamelin BA, Bouayad A, Méthot J, Jobin J, Desgagnés P, Poirier P, et al. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther. 2000;67:466–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Lim KS, Cho J-Y, Jang I-J, Kim B-H, Kim J, Jeon J-Y, et al. Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects. Br J Clin Pharmacol. 2008;66:660–6.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, et al. The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone. Br J Pharmacol. 2010;160:907–18.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Madadi P, Hildebrandt D, Gong IY, Schwarz UI, Ciszkowski C, Ross CJD, et al. Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. Pediatrics. 2010;126:e986–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Puech R, Gagnieu M-C, Planus C, Charpiat B, Boibieux A, Ferry T, et al. Extreme bradycardia due to multiple drug-drug interactions in a patient with HIV post-exposure prophylaxis containing lopinavir-ritonavir. Br J Clin Pharmacol. 2011;71:621–3.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Charpiat B, Tod M, Darnis B, Boulay G, Gagnieu M-C, Mabrut J-Y. Respiratory depression related to multiple drug-drug interactions precipitated by a fluconazole loading dose in a patient treated with oxycodone. Eur J Clin Pharmacol. 2017;73:787–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Cerdelga 84 mg capsules. Summary of Product Characteristics. eMC. Accessed 19 Mar 2018.
  11. 11.
    Ohno Y, Hisaka A, Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharmacokinet. 2007;46:681–96.CrossRefPubMedGoogle Scholar
  12. 12.
    Ohno Y, Hisaka A, Ueno M, Suzuki H. General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information. Clin Pharmacokinet. 2008;47:669–80.CrossRefPubMedGoogle Scholar
  13. 13.
    Tod M, Goutelle S, Clavel-Grabit F, Nicolas G, Charpiat B. Quantitative prediction of cytochrome P450 (CYP) 2D6-mediated drug interactions. Clin Pharmacokinet. 2011;50:519–30.CrossRefPubMedGoogle Scholar
  14. 14.
    Tod M, Goutelle S, Gagnieu MC, Group TGIW. Genotype-based quantitative prediction of drug exposure for drugs metabolized by CYP2D6. Clin Pharmacol Ther. 2011;90:582–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Goutelle S, Bourguignon L, Bleyzac N, Berry J, Clavel-Grabit F, Tod M, et al. In vivo quantitative prediction of the effect of gene polymorphisms and drug interactions on drug exposure for CYP2C19 substrates. AAPS J. 2013;15:415–26.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Castellan A-C, Tod M, Gueyffier F, Audars M, Cambriels F, Kassaï B, et al. Quantitative prediction of the impact of drug interactions and genetic polymorphisms on cytochrome P450 2C9 substrate exposure. Clin Pharmacokinet. 2013;52:199–209.CrossRefPubMedGoogle Scholar
  17. 17.
    Tod M, Nkoud-Mongo C, Gueyffier F. Impact of genetic polymorphism on drug-drug interactions mediated by cytochromes: a general approach. AAPS J. 2013;15:1242–52.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Tod M. DDI-predictor. Available from: Accessed 17 Mar 2018.
  19. 19.
    Tod M, Bourguignon L, Bleyzac N, Goutelle S. A model for predicting the interindividual variability of drug-drug interactions. AAPS J. 2017;19:497–509.CrossRefPubMedGoogle Scholar
  20. 20.
    Small D, Loghin C, Lucas R, Knadler MP, Zhang L, Chappell J, et al. Pharmacokinetic evaluation of combined duloxetine and fluvoxamine dosing in CYP2D6 poor metabolizers. Clin Pharmacol Ther. 2005;77:P37.CrossRefGoogle Scholar
  21. 21.
    Paulzen M, Finkelmeyer A, Grözinger M. Augmentative effects of fluvoxamine on duloxetine plasma levels in depressed patients. Pharmacopsychiatry. 2011;44:317–23.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhu L, Brüggemann RJ, Uy J, Colbers A, Hruska MW, Chung E, et al. CYP2C19 genotype-dependent pharmacokinetic drug interaction between voriconazole and ritonavir-boosted atazanavir in healthy subjects. J Clin Pharmacol. 2017;57:235–46.CrossRefPubMedGoogle Scholar
  23. 23.
    Mikus G, Schowel V, Drzewinska M, Rengelshausen J, Ding R, Riedel K, et al. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther. 2006;80:126–35.CrossRefPubMedGoogle Scholar
  24. 24.
    DeSilva KE, Le Flore DB, Marston BJ, Rimland D. Serotonin syndrome in HIV-infected individuals receiving antiretroviral therapy and fluoxetine. AIDS (London, England). 2001;15:1281–5.Google Scholar
  25. 25.
    Pollack TM, McCoy C, Stead W. Clinically significant adverse events from a drug interaction between quetiapine and atazanavir-ritonavir in two patients. Pharmacotherapy. 2009;29:1386–91.CrossRefPubMedGoogle Scholar
  26. 26.
    Kelly DV, Béïque LC, Bowmer MI. Extrapyramidal symptoms with ritonavir/indinavir plus risperidone. Ann Pharmacother. 2002;36:827–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Lee SI, Klesmer J, Hirsch BE. Neuroleptic malignant syndrome associated with use of risperidone, ritonavir, and indinavir: a case report. Psychosomatics. 2000;41:453–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Jover F, Cuadrado J-M, Andreu L, Merino J. Reversible coma caused by risperidone-ritonavir interaction. Clin Neuropharmacol. 2002;25:251–3.CrossRefPubMedGoogle Scholar
  29. 29.
    Gonzalez LS, Kothari K, Kasle DA. Three cases of late onset angioedema in nursing home human immunodeficiency virus patients on ritonavir and risperidone. J Clin Psychopharmacol. 2016;36:95–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Wolfsperger M, Greil W. Galactorrhea during treatment with trimipramine: a case report. Pharmacopsychiatry. 2005;38:326–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Benazzi F. Severe anticholinergic side effects with venlafaxine-fluoxetine combination. Can J Psychiatry. 1997;42:980–1.CrossRefPubMedGoogle Scholar
  32. 32.
    Benazzi F. Venlafaxine-fluoxetine-nortriptyline interaction. J Psychiatr Neurosci. 1997;22:278–9.Google Scholar
  33. 33.
    Benazzi F. Venlafaxine-fluoxetine interaction. J Clin Psychopharmacol. 1999;19:96–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Bhatara VS, Magnus RD, Paul KL, Preskorn SH. Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms. Ann Pharmacother. 1998;32:432–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Loue C, Tod M. Reliability and extension of quantitative prediction of CYP3A4-mediated drug interactions based on clinical data. AAPS J. 2014;16:1309–20.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Gabriel L, Tod M, Goutelle S. Quantitative prediction of drug interactions caused by CYP1A2 inhibitors and inducers. Clin Pharmacokinet. 2016;55:977–90.CrossRefPubMedGoogle Scholar
  37. 37.
    Ambrosioni J, Coll S, Manzardo C, Nicolás D, Agüero F, Blanco JL, et al. Voriconazole and cobicistat-boosted antiretroviral salvage regimen co-administration to treat invasive aspergillosis in an HIV-infected patient. J Antimicrob Chemother. 2016;71:1125–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Toy J, Giguère P, Kravcik S, la Porte CJL. Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia. AIDS (London, England). 2011;25:541–2.Google Scholar
  39. 39.
    Liu P, Foster G, Gandelman K, LaBadie RR, Allison MJ, Gutierrez MJ, et al. Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects. Antimicrob Agents Chemother. 2007;51:3617–26.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gareri P, De Fazio P, Gallelli L, De Fazio S, Davoli A, Seminara G, et al. Venlafaxine-propafenone interaction resulting in hallucinations and psychomotor agitation. Ann Pharmacother. 2008;42:434–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44(6):195–235.CrossRefGoogle Scholar
  42. 42.
    Regenthal R, Krueger M, Koeppel C, Preiss R. Drug levels: therapeutic and toxic serum/plasma concentrations of common drugs. J Clin Monit Comput. 1999;15(7–8):529–44.CrossRefPubMedGoogle Scholar
  43. 43.
    Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56(9):4793–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Nicolas Fermier
    • 1
  • Laurent Bourguignon
    • 1
    • 2
    • 3
  • Sylvain Goutelle
    • 1
    • 2
    • 3
  • Nathalie Bleyzac
    • 4
  • Michel Tod
    • 1
    • 2
    • 4
  1. 1.Pharmacie, Groupement Hospitalier NordHospices Civils de LyonLyonFrance
  2. 2.Faculté de pharmacieUniversité Lyon 1LyonFrance
  3. 3.UMR 5558, EMETUniversité Lyon 1LyonFrance
  4. 4.EMR 3738, Faculté de médecine Lyon-sudUniversité Lyon 1OullinsFrance

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