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Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects.

Methods

This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18–45 years). In Period 1 (Days 1–12), siponimod was up-titrated from 0.25 to 2 mg over 5 days (Days 1–6) followed by 2 mg once daily on days 7–12. In Period 2, siponimod 2 mg qd was co-administered with rifampin 600 mg qd (Days 13–24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC).

Results

Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3 years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6 ng/mL) was achieved in 4 h (median Tmax,ss; range, 1.58–8.00) and the geometric mean AUCtau,ss was 546 h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h × ng/mL, respectively; median Tmax remained unchanged (4 h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L.

Conclusions

The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.

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References

  1. Fitzner D, Simons M (2010) Chronic progressive multiple sclerosis - pathogenesis of neurodegeneration and therapeutic strategies. Curr Neuropharmacol 8(3):305–315. https://doi.org/10.2174/157015910792246218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M, Ebers GC (2010) The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 133(Pt 7):1914–1929. https://doi.org/10.1093/brain/awq118

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, Pan S, Gray NS, Hinterding K, Cooke NG, Groenewegen A, Vitaliti A, Sing T, Luttringer O, Yang J, Gardin A, Wang N, Crumb WJ Jr, Saltzman M, Rosenberg M, Wallstrom E (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 167(5):1035–1047. https://doi.org/10.1111/j.1476-5381.2012.02061.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T, Wolf C, Wallstrom E, Dahlke F, Investigators EC (2018) Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391(10127):1263–1273. https://doi.org/10.1016/S0140-6736(18)30475-6

    Article  CAS  PubMed  Google Scholar 

  5. Brinkmann V (2007) Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 115(1):84–105. https://doi.org/10.1016/j.pharmthera.2007.04.006

    Article  CAS  PubMed  Google Scholar 

  6. Seabrook T SP SA, Wallström E, Nuesslein-Hildesheim B (2010) Efficacy of the selective S1P1/5 modulator, BAF312 in established EAE and redistribution of S1P1 and S1P5 in the inflamed human CNS tissue. Mult Scler 16(10 Suppl):S301. Abstract P858. In: ed

  7. Amit Bar-Or TD, Vermersch P, Gold R, Tomic D, Cheviet S, Rouyrre N, Scherz T, Hillenbrand R, Kappos L (2017) Longitudinal changes in lymphocyte subsets of siponimod treated patients with secondary progressive multiple sclerosis. Mult Scler 23:P1238 In: ECTRIMSed

    Google Scholar 

  8. Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, Teo ST, Yung YC, Lu M, Kennedy G, Chun J (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 108(2):751–756. https://doi.org/10.1073/pnas.1014154108

    Article  PubMed  Google Scholar 

  9. Mullershausen F, Craveiro LM, Shin Y, Cortes-Cros M, Bassilana F, Osinde M, Wishart WL, Guerini D, Thallmair M, Schwab ME, Sivasankaran R, Seuwen K, Dev KK (2007) Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 102(4):1151–1161. https://doi.org/10.1111/j.1471-4159.2007.4629.x

    Article  CAS  PubMed  Google Scholar 

  10. Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, Piras E, Gargano F, Borsellino G, Battistini L, Schubart A, Mandolesi G, Centonze D (2016) Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation 13(1):207. https://doi.org/10.1186/s12974-016-0686-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jin Y, Borell H, Gardin A, Ufer M, Huth F, Camenisch G (2018) In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics. Eur J Clin Pharmacol 74(4):455–464. https://doi.org/10.1007/s00228-017-2404-2

    Article  CAS  PubMed  Google Scholar 

  12. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A (2018) Metabolism and disposition of siponimod, a novel selective S1P1/S1P5 agonist, in healthy volunteers and in vitro identification of human cytochrome P450 enzymes involved in its oxidative metabolism. Drug Metab Dispos 46(7):1001–1013. https://doi.org/10.1124/dmd.117.079574

    Article  CAS  PubMed  Google Scholar 

  13. Cheng J, Ma X, Krausz KW, Idle JR, Gonzalez FJ (2009) Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab Dispos 37(8):1611–1621. https://doi.org/10.1124/dmd.109.027565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT (2003) Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet 42(9):819–850. https://doi.org/10.2165/00003088-200342090-00003

    Article  CAS  PubMed  Google Scholar 

  15. Richter WF, Bhansali SG, Morris ME (2012) Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 14(3):559–570. https://doi.org/10.1208/s12248-012-9367-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Turner-Stokes T, Lu TY, Ehrenstein MR, Giles I, Rahman A, Isenberg DA (2011) The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation. Rheumatology (Oxford) 50(8):1401–1408. https://doi.org/10.1093/rheumatology/ker018

    Article  CAS  Google Scholar 

  17. Shakeri-Nejad K, Aslanis V, Veldandi UK, Gardin A, Zaehringer A, Dodman A, Su Z, Legangneux E (2017) Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther 55(1):41–53. https://doi.org/10.5414/CP202588

    Article  CAS  PubMed  Google Scholar 

  18. Biswal S, Polus F, Pal P, Veldandi UK, Marbury TC, Perry R, Legangneux E (2015) Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects. Int J Clin Pharmacol Ther 53(10):855–865. https://doi.org/10.5414/CP202369

    Article  CAS  PubMed  Google Scholar 

  19. Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, Freedman MS, Stuve O, Rieckmann P, Montalban X, Ziemssen T, Auberson LZ, Pohlmann H, Mercier F, Dahlke F, Wallstrom E (2013) Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 12(8):756–767. https://doi.org/10.1016/S1474-4422(13)70102-9

    Article  CAS  PubMed  Google Scholar 

  20. Legangneux E, Gardin A, Johns D (2013) Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. Br J Clin Pharmacol 75(3):831–841. https://doi.org/10.1111/j.1365-2125.2012.04400.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gardin A, Dodman A, Kalluri S, Neelakantham S, Tan X, Legangneux E, Shakeri-Nejad K (2017) Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: a single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther 55(1):54–65. https://doi.org/10.5414/CP202608

    Article  CAS  PubMed  Google Scholar 

  22. Naesens M, Kuypers DR, Streit F, Armstrong VW, Oellerich M, Verbeke K, Vanrenterghem Y (2006) Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients. Clin Pharmacol Ther 80(5):509–521. https://doi.org/10.1016/j.clpt.2006.08.002

    Article  CAS  PubMed  Google Scholar 

  23. Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum M, Siegmund W, Schrenk D (2000) The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol 157(5):1575–1580. https://doi.org/10.1016/S0002-9440(10)64794-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gardin A, Ufer M, Legangneux E, Rossato G, Jin Y, Su Z, Pal P, Li W, Shakeri-Nejad K (2018) Effect of fluconazole co-administration and CYP2C9 genetic polymorphism on siponimod pharmacokinetics in healthy subjects. Clin Pharmacol. https://doi.org/10.1007/s40262-018-0700-3

  25. Jigorel E, Le Vee M, Boursier-Neyret C, Parmentier Y, Fardel O (2006) Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos 34(10):1756–1763. https://doi.org/10.1124/dmd.106.010033

    Article  CAS  PubMed  Google Scholar 

  26. Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ (2010) Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics 11(6):781–791. https://doi.org/10.2217/pgs.10.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kirchheiner J, Brockmoller J (2005) Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 77(1):1–16. https://doi.org/10.1016/j.clpt.2004.08.009

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank subjects and participating centres involved in study. The authors would also like to acknowledge Sivaram Vedantam and Anuja Shah of Novartis Healthcare Pvt. Ltd. Hyderabad, India, for providing medical writing support, which encompassed preparing the manuscript, formatting, referencing, preparing tables and figures, incorporating authors’ revisions, finalising, and submission, all under the direction of the authors. In keeping with the guidelines of the International Committee of Medical Journal Editors, all authors have contributed significantly to the study and were thoroughly involved in the critical review of the manuscript for important intellectual content. All authors have reviewed and approved the final draft for submission.

Funding

The study was funded by Novartis Pharma AG, Basel, Switzerland.

Author information

Authors and Affiliations

  1. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Anne Gardin, Felix Huth, Swati Dumitras, Eric Legangneux & Kasra Shakeri-Nejad

  2. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Cathy Gray

  3. Novartis Healthcare Pvt. Ltd., Hyderabad, India

    Srikanth Neelakantham

  4. PPD, Austin, TX, USA

    Antonia M. Davidson

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  1. Anne Gardin
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Contributions

Anne Gardin and Kasra Shakeri-Nejad conceptualised and designed the studies, analysed and interpreted the study data. Cathy Gray was involved in study design and study execution. Srikanth Neelakantham conceptualised and designed the studies, analysed and interpreted the study data, and conducted statistical analysis of the data. Felix Huth, Antonia M. Davidson, and Eric Legangneux were involved in conceptualising and designing of studies, and acquisition and analysis of data. All authors made significant contribution to data interpretation and review of the manuscript.

Corresponding author

Correspondence to Anne Gardin.

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Conflicts of interest

Antonia M. Davidson is a principal investigator at the PPD Phase 1 Clinic, Austin, TX, USA.

Anne Gardin, Cathy Gray, Srikanth Neelakantham, Felix Huth, Swati Dumitras, Eric Legangneux, and Kasra Shakeri-Nejad are employees of Novartis.

Research involving human participants

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Gardin, A., Gray, C., Neelakantham, S. et al. Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects. Eur J Clin Pharmacol 74, 1593–1604 (2018). https://doi.org/10.1007/s00228-018-2533-2

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  • DOI: https://doi.org/10.1007/s00228-018-2533-2

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