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Characterizing the Pharmacokinetic Interaction Between Simeprevir and Odalasvir in Healthy Volunteers Using a Population Modeling Approach

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Abstract

The aim of this study was to characterize the pharmacokinetic drug–drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach. Previous pharmacokinetic models developed to characterize the pharmacokinetics for each drug were used as starting point. The dual effect of simeprevir and odalasvir on their pharmacokinetic parameters was explored. Simulations were performed to assess the impact of the DDI on exposure parameters. In presence of odalasvir, the relative bioavailability of simeprevir increased by 26% and the apparent clearance was reduced following competitive inhibition depending on odalasvir plasma concentrations, with an inhibitory constant (Ki) estimated to be 1610 ng/mL. The apparent odalasvir clearance was reduced by simeprevir plasma concentrations following an Imax model, characterized by a maximum inhibitory effect of 46.7% and an IC50 of 257 ng/mL. Model-based simulations indicated that both Cmax and AUC24h increased for both drugs, when co-administered. The pharmacokinetic model adequately describes the time course of plasma concentrations and their variability when simeprevir and/or odalasvir were orally administered. This model can be used as a first step to predict the exposures of concomitant administration of simeprevir and odalasvir in HCV-infected subjects. Data from study AL355-602 (NCT02512562) were used for this analysis.

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References

  1. Lanini S, Easterbrook PJ, Zumla A, Ippolito G. Hepatitis C: global epidemiology and strategies for control. Clin Microbiol Infect. 2016;22(10):833–8. https://doi.org/10.1016/j.cmi.2016.07.035.

    Article  CAS  PubMed  Google Scholar 

  2. Pawlotsky J-M, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007;132(5):1979–98. https://doi.org/10.1053/j.gastro.2007.03.116.

    Article  CAS  PubMed  Google Scholar 

  3. EASL Recommendations on Treatment of Hepatitis C. European Association for the Study of the Liver. J Hepatol. 2018. https://doi.org/10.1016/j.jhep.2018.03.026.

    Article  Google Scholar 

  4. Jacobson IM, Dore GJ, Foster GR, Fried MW, Radu M, Rafalshy VV, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384(9941):403–113. https://doi.org/10.1016/S0140-6736(14)60494-3.

    Article  CAS  PubMed  Google Scholar 

  5. Ouwerkerk-Mahadevan S, Simion A, Mortier S, Peeters M, Beumont-Mauviel M. The effect of food and different meal types on the bioavailability of simeprevir (TMC435), an HCV protease inhibitor in clinical development. 8th international workshop on clinical pharmacology of hepatitis therapy. Cambridge, MA, USA, June 26–27, 2013.

  6. Ouwerkerk-Mahadevan S, Snoeys J, Peeters M, Beumont-Mauviel M, Simion A. Drug–drug interactions with the NS3/4A protease inhibitor simeprevir. Clin Pharmacokinet. 2016;55(2):197–208. https://doi.org/10.1007/s40262-015-0314-y.

    Article  CAS  PubMed  Google Scholar 

  7. OLYSIO (simeprevir) capsules: prescribing information. Titusville: Janssen Pharmaceuticals, Inc; 2017. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/OLYSIO-pi.pdf. Published Nov 2017. Accessed 27 Jun 2018.

  8. Reesink HW, Fanning GC, Farha KA, Weegink C, Van Vliet A, Van’t Klooster G, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138(3):913–21. https://doi.org/10.1053/j.gastro.2009.10.033.

    Article  CAS  PubMed  Google Scholar 

  9. Viberg A, Petersson K, Hoeben E, Brochot A. A population PK model for simperevir in healthy volunteers and patients. 24th population approach Group in Europe meeting, June 2015; Crete, Greece http://www.page-meeting.org/?abstract=3368.

  10. Yang G, Wiles J, Patel D, Zhao Y, Fabrycki J, Weinheimer S, et al. Preclinical characteristics of ACH-3102; a novel NS5A inhibitor with improved potency against genotype-1A virus and variants resistant to 1st generation NS5A inhibitors. J Hepatol. 2012;56(2):S330. https://doi.org/10.1016/S0168-8278(12)60857-5.

    Article  Google Scholar 

  11. Gane E, Schwabe C, Mader M, Suri V, Donohue M, Huang M, et al. Sustained virologic response after ACH-3102 and sofosbuvir treatment for 8 or 6 weeks: a phase 2 “proxy” study. European Association for the Study of the Liver, The International Liver Congress™. Vienna, Austria, April 22–26, 2015. Abstract P017.

  12. Ackaert O, Valade E, Ouwerkerk-Mahadevan S, Kakuda T, Perez-Ruixo J, Hoeben E. Dose-selection of odalasvir for use in combination with AL-335 and simeprevir in a phase 2A study using a population pharmacokinetic modelling and simulation approach. 18th international workshop on clinical pharmacology of antiviral therapy, June 2017; Chicago, USA. http://www.natap.org/2017/Pharm/Pharm_44.htm. Accessed 18 Dec 2017.

  13. Kakuda TN, McClure MW, Westland C, Vuong J, Homery M-C, Poizat G, et al. Pharmacokinetics, safety and tolerability of the 2- and 3-direct-acting antiviral combination of AL-335, odalasvir and simeprevir in healthy subjects. Pharmacol Res Perspect. 2018;6(3):e00395. https://doi.org/10.1002/prp2.395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lehr T, Staab A, Trommeshauser D, Schaefer HG, Kloft C. Semi-mechanistic population pharmacokinetic drug–drug interaction modelling of a long half-life substrate and itraconazole. Clin Pharmacokinet. 2010;49(1):53–66. https://doi.org/10.2165/11317210-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  15. Beal S, Boeckman A, Scheiner L. NONMEM user’s guides. San Francisco: University of California at San Francisco; 1988.

    Google Scholar 

  16. R Development Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2007. ISBN 3-900051-07-0, URL http://www.R-project.org

    Google Scholar 

  17. Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Prog Biomed. 2004;75(2):85–94. https://doi.org/10.1016/j.cmpb.2003.11.003.

    Article  Google Scholar 

  18. Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34(5):711–26. https://doi.org/10.1007/s10928-007-9066-0.

    Article  CAS  PubMed  Google Scholar 

  19. Wilkins JJ, Savic RM, Karlsson MO, Langdon G, McIlleron H, Pillai G, et al. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Antimicrob Agents Chemother. 2008;52(6):2138–48. https://doi.org/10.1128/AAC.00461-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Akaike H. A new look at the statistical model identification. IEEE Trans Autom Control. 1974;19:716–23.

    Article  Google Scholar 

  21. Nguyen TH, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, et al. Model evaluation of continuous data pharmacometric models: metrics and graphics. CPT Pharmacometrics Syst Pharmacol. 2017;6(2):87–109. https://doi.org/10.1002/psp4.12161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yano Y, Beal SL, Sheiner LB. Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn. 2001;28:171–92.

    Article  CAS  PubMed  Google Scholar 

  23. Thakkar N, Slizgi JR, Brouwer KLR. Effect of liver disease on hepatic transporter expression and function. J Pharm Sci. 2017;106(9):2282–94. https://doi.org/10.1016/j.xphs.2017.04.053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gane E, Stedman C, Schwabe C, et al. Short duration AL-335, odalasvir, with/without simeprevir, in patients with HCV GT1 or 3 infection without cirrhosis. Hepatology. 2018. https://doi.org/10.1002/hep.30126.

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Acknowledgements

The authors thank Eef Hoeben for her comments and support during the analysis. In addition, the authors would like to thank the healthy volunteers, investigators, and their medical, nursing, and laboratory staff who participated in the clinical trials included in the present study.

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Author notes

  1. Matthew W. McClure

    Present address: Second Genome, South San Francisco, California, USA

Authors and Affiliations

  1. Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium

    Elodie Valade, Sivi Ouwerkerk-Mahadevan, Juan José Perez-Ruixo & Oliver Ackaert

  2. SGS Exprimo NV, Mechelen, Belgium

    Belén Valenzuela

  3. Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, California, USA

    Thomas N. Kakuda, Christopher Westland & Matthew W. McClure

Authors
  1. Elodie Valade
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  2. Belén Valenzuela
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  3. Thomas N. Kakuda
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  4. Christopher Westland
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  5. Matthew W. McClure
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  6. Sivi Ouwerkerk-Mahadevan
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  7. Juan José Perez-Ruixo
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  8. Oliver Ackaert
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Corresponding author

Correspondence to Oliver Ackaert.

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Disclosure Section

M.W.M. was an employee of Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies at the time this study was conducted.

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Valade, E., Valenzuela, B., Kakuda, T.N. et al. Characterizing the Pharmacokinetic Interaction Between Simeprevir and Odalasvir in Healthy Volunteers Using a Population Modeling Approach. AAPS J 20, 111 (2018). https://doi.org/10.1208/s12248-018-0271-0

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  • DOI: https://doi.org/10.1208/s12248-018-0271-0

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