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Effects of Cytochrome P450 3A4 Inhibitors—Ketoconazole and Erythromycin—on Bitopertin Pharmacokinetics and Comparison with Physiologically Based Modelling Predictions

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Abstract

Objective

To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling.

Methods

The effects of ketoconazole and erythromycin were assessed in two male volunteer studies with open-label, two-period, fixed-sequence designs. Twelve subjects were enrolled in each of the studies. In period 1, a single dose of bitopertin was administered; in period 2, 400 mg ketoconazole was administered once daily for 17 days or 500 mg erythromycin was administered twice daily for 21 days. A single dose of bitopertin was coadministered on day 5. Pharmacokinetic parameters were derived by non-compartmental methods. Simulated bitopertin profiles using dynamic PBPK modelling for a typical healthy volunteer in GastroPlus® were used to predict changes in pharmacokinetic parameters.

Results

In healthy volunteers, coadministration of ketoconazole increased the bitopertin area under the plasma concentration–time curve (AUC) from 0 to 312 h (AUC0–312h) 4.2-fold (90 % confidence interval [CI] 3.5–5.0) and erythromycin increased the AUC from time zero to infinity (AUC0–inf) 2.1-fold (90 % CI 1.9–2.3). The peak concentration (C max) increased by <25 % in both studies. Simulated bitopertin profiles using PBPK modelling showed good agreement with the observed AUC ratios in both studies. The predicted AUC0–inf ratios for the interaction with ketoconazole and erythromycin were 7.7 and 1.9, respectively.

Conclusion

Strong CYP3A4 inhibitors increase AUC0–inf of bitopertin 7- to 8-fold and hence should not be administered concomitantly with bitopertin. Moderate CYP3A4 inhibitors double AUC0–inf.

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References

  1. Loftis JM, Janowsky A. The N-methyl-d-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther. 2003;97(1):55–85.

    Article  CAS  PubMed  Google Scholar 

  2. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158(9):1367–77.

    Article  CAS  PubMed  Google Scholar 

  3. Alberati D, Moreau JL, Lengyel J, Hauser N, Mory R, Borroni E, et al. Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology. 2012;62(2):1152–61. doi:10.1016/j.neuropharm.2011.11.008.

    Article  CAS  PubMed  Google Scholar 

  4. Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, Ostland M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry. 2014;71(6):637–46. doi:10.1001/jamapsychiatry.2014.163.

    Article  CAS  PubMed  Google Scholar 

  5. Committee for Medicinal Products for Human Use. Guideline in the investigation of drug interactions. London: European Medicines Agency; 2012.

    Google Scholar 

  6. Center for Drug Evaluation and Research. Guidance for industry. Drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. Bethesda: US Food and Drug Administration; 2012.

  7. Parrott N, Hainzl D, Alberati D, Hofmann C, Robson R, Boutouyrie B, et al. Physiologically based pharmacokinetic modelling to predict single- and multiple-dose human pharmacokinetics of bitopertin. Clin Pharmacokinet. 2013;52(8):673–83. doi:10.1007/s40262-013-0061-x.

    Article  CAS  PubMed  Google Scholar 

  8. Janssen-Cilag. Ketoconazole 200 mg tablets: summary of product characteristics. Available from: www.ema.europa.eu. Accessed Nov 2014.

  9. Ragueneau-Majlessi I, Boulenc X, Rauch C, Hachad H, Levy RH. Quantitative correlations among CYP3A sensitive substrates and inhibitors: literature analysis. Curr Drug Metab. 2007;8(8):810–4.

    Article  CAS  PubMed  Google Scholar 

  10. Periti P, Mazzei T, Mini E, Novelli A. Adverse effects of macrolide antibacterials. Drug Saf. 1993;9(5):346–64.

    Article  CAS  PubMed  Google Scholar 

  11. World Medical Association. Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA. 1997;277(11):925–6.

    Article  Google Scholar 

  12. International Conference on Harmonisation Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline. Guideline for good clinical practice E6 (R1). Geneva: International Conference on Harmonisation Steering Committee; 1996.

  13. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “pie”. Drug Metab Dispos. 2006;34(5):880–6. doi:10.1124/dmd.105.008672.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tjia JF, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. Aids. 1997;11(4):F29–33.

    Article  CAS  PubMed  Google Scholar 

  15. Chien JY, Lucksiri A, Ernest CS 2nd, Gorski JC, Wrighton SA, Hall SD. Stochastic prediction of CYP3A-mediated inhibition of midazolam clearance by ketoconazole. Drug Metab Dispos. 2006;34(7):1208–19. doi:10.1124/dmd.105.008730.

    Article  CAS  PubMed  Google Scholar 

  16. Okudaira T, Kotegawa T, Imai H, Tsutsumi K, Nakano S, Ohashi K. Effect of the treatment period with erythromycin on cytochrome P450 3A activity in humans. J Clin Pharmacol. 2007;47(7):871–6. doi:10.1177/0091270007302562.

    Article  CAS  PubMed  Google Scholar 

  17. Fan Y, Rodriguez-Proteau R. Ketoconazole and the modulation of multidrug resistance-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models. Xenobiotica. 2008;38(2):107–29. doi:10.1080/00498250701744625.

    Article  CAS  PubMed  Google Scholar 

  18. Kanazawa S, Ohkubo T, Sugawara K. The effects of grapefruit juice on the pharmacokinetics of erythromycin. Eur J Clin Pharmacol. 2001;56(11):799–803.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang X, Jones DR, Hall SD. Prediction of the effect of erythromycin, diltiazem, and their metabolites, alone and in combination, on CYP3A4 inhibition. Drug Metab Dispos. 2009;37(1):150–60. doi:10.1124/dmd.108.022178.

    Article  CAS  PubMed  Google Scholar 

  20. Franke RM, Baker SD, Mathijssen RH, Schuetz EG, Sparreboom A. Influence of solute carriers on the pharmacokinetics of CYP3A4 probes. Clin Pharmacol Ther. 2008;84(6):704–9. doi:10.1038/clpt.2008.94.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang L, Strong JM, Qiu W, Lesko LJ, Huang SM. Scientific perspectives on drug transporters and their role in drug interactions. Mol Pharm. 2006;3(1):62–9.

    Article  CAS  PubMed  Google Scholar 

  22. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36. doi:10.1038/nrd3028.

    Article  CAS  PubMed  Google Scholar 

  23. Poirier A, Funk C, Lave T, Noe J. New strategies to address drug–drug interactions involving OATPs. Curr Opin Drug Discov Devel. 2007;10(1):74–83.

    CAS  PubMed  Google Scholar 

  24. Schuetz EG, Yasuda K, Arimori K, Schuetz JD. Human MDR1 and mouse mdr1a P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene. Arch Biochem Biophys. 1998;350(2):340–7. doi:10.1006/abbi.1997.0537.

    Article  CAS  PubMed  Google Scholar 

  25. Wacher VJ, Silverman JA, Zhang Y, Benet LZ. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci. 1998;87(11):1322–30. doi:10.1021/js980082d.

    Article  CAS  PubMed  Google Scholar 

  26. Somogyi AA, Bochner F, Hetzel D, Williams DB. Evaluation of the intestinal absorption of erythromycin in man: absolute bioavailability and comparison with enteric coated erythromycin. Pharm Res. 1995;12(1):149–54.

    Article  CAS  PubMed  Google Scholar 

  27. Poirier A, Cascais AC, Bader U, Portmann R, Brun ME, Walter I, Hillebrecht A, Ullah M, Funk C. Calibration of in vitro multidrug resistance protein 1 substrate and inhibition assays as a basis to support the prediction of clinically relevant interactions in vivo. Drug Metab Dispos. 2014;42(9):1411–22. doi:10.1124/dmd.114.057943.

    Article  PubMed  Google Scholar 

  28. Parrott N, Hainzl D, Scheubel E, Krimmer S, Boetsch C, Guerini E, Martin-Facklam M. Physiologically based absorption modelling to predict the impact of drug properties on pharmacokinetics of bitopertin. AAPS J. 2014;16(5):1077–84. doi:10.1208/s12248-014-9639-y.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

All authors were employees of F. Hoffmann-La Roche when this work was carried out. The authors would like to thank Thomas Ramp for in vitro study execution.

Author contributions

Participated in research design: Boetsch, Hofmann, Fowler, Martin-Facklam, Poirier, Hainzl.

Conducted experiments: Boetsch, Fowler, Hofmann, Poirier.

Performed data analysis: Banken, Boetsch, Fowler, Hofmann, Parrott, Poirier.

Wrote or contributed to writing the manuscript: Boetsch, Fowler, Hofmann, Martin-Facklam, Parrott.

Reviewed manuscript drafts and approved final version for submission: Banken, Boetsch, Fowler, Hainzl, Hofmann, Martin-Facklam, Parrott, Poirier.

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Correspondence to Meret Martin-Facklam.

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Boetsch, C., Parrott, N., Fowler, S. et al. Effects of Cytochrome P450 3A4 Inhibitors—Ketoconazole and Erythromycin—on Bitopertin Pharmacokinetics and Comparison with Physiologically Based Modelling Predictions. Clin Pharmacokinet 55, 237–247 (2016). https://doi.org/10.1007/s40262-015-0312-0

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