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A Phase I Open-Label Study to Evaluate the Effects of Rifampin on the Pharmacokinetics of Olanzapine and Samidorphan Administered in Combination in Healthy Human Subjects

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Abstract

Background

A combination of the atypical antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of schizophrenia. The goal of OLZ/SAM is to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain and many associated long-term metabolic consequences. The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5′-diphospho-glucuronosyltransferase (UGT)1A4 and cytochrome P450 (CYP)-mediated oxidation, mainly by CYP1A2. In contrast, the samidorphan metabolic pathway is mediated predominantly by CYP3A4.

Objective

The aim of this study was to evaluate the effects of CYP3A4 induction on the single-dose pharmacokinetics of OLZ/SAM in healthy subjects.

Methods

In this phase I, single-center, open-label, two-period study, 24 healthy volunteers received a single oral dose of OLZ/SAM 10/10 (10 mg olanzapine/10 mg samidorphan) on day 1. After a 14-day washout, 600 mg of rifampin (rifampicin), a strong CYP3A4 inducer, as well as an inducer of UGT enzymes and a weak inducer of CYP1A2, was administered once daily on days 15‒21. A single oral dose of OLZ/SAM 10/10 was coadministered with rifampin 600 mg on day 22. Olanzapine and samidorphan pharmacokinetic parameters were determined after OLZ/SAM dosing on days 1 and 22. The geometric mean ratio of maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from zero to infinity (AUC∞) for olanzapine and samidorphan in the presence and absence of rifampin, along with its two-sided 90% confidence interval, were derived from a linear mixed-effects model. Safety was monitored throughout the study.

Results

Compared with OLZ/SAM alone, coadministration of OLZ/SAM with rifampin decreased the Cmax and AUC∞ of olanzapine by 11% and 48%, and that of samidorphan by 44% and 73%, respectively. OLZ/SAM 10/10 was generally well tolerated in this study.

Conclusion

Coadministration with rifampin decreased total systemic exposure (based on AUC∞) of olanzapine and samidorphan by 48% and 73%, respectively.

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References

  1. Wentland MP, Lou R, Lu Q, et al. Syntheses of novel high affinity ligands for opioid receptors. Bioorg Med Chem Lett. 2009;19:2289–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bidlack JM, Knapp BI, Deaver DR, et al. In vitro pharmacological characterization of buprenorphine, samidorphan, and combinations being developed as an adjunctive treatment of major depressive disorder. J Pharmacol Exp Ther. 2018;367:267–81.

    Article  CAS  PubMed  Google Scholar 

  3. Shram MJ, Silverman B, Ehrich E, Sellers EM, Turncliff R. Use of remifentanil in a novel clinical paradigm to characterize onset and duration of opioid blockade by samidorphan, a potent mu-receptor antagonist. J Clin Psychopharmacol. 2015;35:242–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Silverman BL, Martin W, Memisoglu A, et al. A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers. Schizophr Res. 2018;195:245–51.

    Article  PubMed  Google Scholar 

  5. Martin W, Correll C, Weiden P, et al. Mitigation of olanzapine-induced weight gain with samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. Am J Psychiatry. 2019. https://doi.org/10.1176/appi.ajp.2018.18030280.

    Article  PubMed  Google Scholar 

  6. Sun L, McDonnell D, von Moltke L. Pharmacokinetics and short-term safety of ALKS 3831, a fixed-dose combination of olanzapine and samidorphan, in adult subjects with schizophrenia. Clin Ther. 2018;40:1845–54.

    Article  CAS  PubMed  Google Scholar 

  7. Kassahun K, Mattiuz E, Nyhart E Jr, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos. 1997;25:81–93.

    CAS  PubMed  Google Scholar 

  8. Korprasertthaworn P, Polasek TM, Sorich MJ, et al. In vitro characterization of the human liver microsomal kinetics and reaction phenotyping of olanzapine metabolism. Drug Metab Dispos. 2015;43:1806–14.

    Article  CAS  PubMed  Google Scholar 

  9. Turncliff R, DiPetrillo L, Silverman B, Ehrich E. Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers. Clin Ther. 2015;37:338–48.

    Article  CAS  PubMed  Google Scholar 

  10. Lee SY, Lee JY, Kim YM, Kim SK, Oh SJ. Expression of hepatic cytochrome P450 s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin. Toxicol Lett. 2015;235:107–15.

    Article  CAS  PubMed  Google Scholar 

  11. Srinivas NR. Pharmacokinetic interaction of rifampicin with oral versus intravenous anticancer drugs: challenges, dilemmas and paradoxical effects due to multiple mechanisms. Drugs R&D. 2016;16:141–8.

    Article  CAS  Google Scholar 

  12. Rae JM, Johnson MD, Lippman ME, Flockhart DA. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther. 2001;299:849–57.

    CAS  PubMed  Google Scholar 

  13. Backman JT, Granfors MT, Neuvonen PJ. Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol. 2006;62:451–61.

    Article  CAS  PubMed  Google Scholar 

  14. Rifadin [package insert]. Bridgewater: Sanofi-Aventis; 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/050420s073,050627s012lbl.pdf. Accessed 18 Jan 2019.

  15. Komura H, Iwaki M. In vitro and in vivo small intestinal metabolism of CYP3A and UGT substrates in preclinical animals species and humans: species differences. Drug Metab Rev. 2011;43:476–98.

    Article  CAS  PubMed  Google Scholar 

  16. Kolars JC, Lown KS, Schmiedlin-Ren P, et al. CYP3A gene expression in human gut epithelium. Pharmacogenetics. 1994;4:247–59.

    Article  CAS  PubMed  Google Scholar 

  17. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest. 1992;90:1871–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther. 1992;52:453–7.

    Article  CAS  PubMed  Google Scholar 

  19. Yamanaka H, Nakajima M, Katoh M, Yokoi T. Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes. Drug Metab Dispos. 2007;35:1642–8.

    Article  CAS  PubMed  Google Scholar 

  20. Nakamura A, Nakajima M, Yamanaka H, Fujiwara R, Yokoi T. Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines. Drug Metab Dispos. 2008;36:1461–4.

    Article  CAS  PubMed  Google Scholar 

  21. Ohno S, Nakajin S. Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos. 2009;37:32–40.

    Article  CAS  PubMed  Google Scholar 

  22. de Waziers I, Cugnenc PH, Yang CS, Leroux JP, Beaune PH. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther. 1990;253:387–94.

    PubMed  Google Scholar 

  23. McDonnell WM, Scheiman JM, Traber PG. Induction of cytochrome P450IA genes (CYP1A) by omeprazole in the human alimentary tract. Gastroenterology. 1992;103:1509–16.

    Article  CAS  PubMed  Google Scholar 

  24. Duan JZ. Drug-drug interaction pattern recognition. Drugs R&D. 2010;10:9–24.

    Article  Google Scholar 

  25. Markowitz JS, DeVane CL, Boulton DW, Liston HL, Risch SC. Hypotension and bradycardia in a healthy volunteer following a single 5 mg dose of olanzapine. J Clin Pharmacol. 2002;42:104–6.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all the patients and investigators who participated in, and contributed to, this study. The authors also thank Mark S. Todtenkopf, PhD, who assisted in the preparation and proofreading of the manuscript. Medical writing and editorial support was provided by Tabasum Mughal, PhD (ApotheCom, London, UK) and Bina J. Patel, PharmD (Peloton Advantage, Parsippany, NJ, USA), and was funded by Alkermes, Inc.

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Authors and Affiliations

  1. Clinical Pharmacology and Translational Medicine, Alkermes, Inc., 852 Winter Street, Waltham, MA, 02451, USA

    Lei Sun

  2. Biostatistics, Alkermes, Inc., Waltham, MA, USA

    Miao Yu

  3. DMPK and Bioanalysis, Alkermes, Inc., Waltham, MA, USA

    Vipul Kumar

  4. Clinical Research, Alkermes, Inc., Waltham, MA, USA

    Lisa von Moltke

  5. Clinical Science, Alkermes Pharma Ireland Limited, Dublin, Ireland

    David McDonnell

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  1. Lei Sun
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  2. David McDonnell
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  3. Miao Yu
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  4. Vipul Kumar
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  5. Lisa von Moltke
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Corresponding author

Correspondence to Lei Sun.

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Funding

This study was funded by Alkermes, Inc.

Conflict of interest

Lei Sun, David McDonnell, Miao Yu, Vipul Kumar, and Lisa von Moltke are employees and shareholders of Alkermes Inc.

Ethics approval

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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Sun, L., McDonnell, D., Yu, M. et al. A Phase I Open-Label Study to Evaluate the Effects of Rifampin on the Pharmacokinetics of Olanzapine and Samidorphan Administered in Combination in Healthy Human Subjects. Clin Drug Investig 39, 477–484 (2019). https://doi.org/10.1007/s40261-019-00775-8

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  • DOI: https://doi.org/10.1007/s40261-019-00775-8

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