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Pharmacokinetics of Oral and Intravenous Oseltamivir Treatment of Severe Influenza B Virus Infection Requiring Organ Replacement Therapy

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Abstract

Background and Objectives

Patients with severe influenza virus infection, multi-organ failure and organ replacement therapy may absorb and metabolize neuraminidase inhibitors differently. Systematic pharmacokinetic/pharmacodynamic clinical trials are currently lacking in this high-risk group. Inadequate dosing increases the risk of treatment failure and drug resistance, especially in severely ill patients with elevated virus loads. This study aims to explore the impact of organ replacement therapy on oseltamivir drug concentrations.

Methods

Serial pharmacokinetic/pharmacodynamic measurements and Sieving coefficients were assessed in two patients with severe influenza B infection requiring organ replacement therapy.

Results

Patient #1, a 9-year-old female with severe influenza B virus infection, biventricular assist device, and continuous veno-venous hemodiafiltration, received 75 mg oral oseltamivir twice-daily for 2 days, then intravenous oseltamivir with one-time renoprotective dosing (40 mg), followed by regular intravenous administration of 100 mg twice-daily. Plasma oseltamivir carboxylate concentrations were stable initially, but only regular administration of 100 mg resulted in virus load decline and clinical improvement. Patient #2, a 28-year-old female with influenza B virus infection requiring extracorporeal membrane oxygenation, received 75 mg oral oseltamivir twice-daily, resulting in erratic oseltamivir blood concentrations. In both patients, drug concentrations remained well within safety margins.

Conclusions

In severe cases with multi-organ failure, administration of 100 mg intravenous oseltamivir twice-daily provided reliable drug concentrations, as opposed to renoprotective and oral dosing, thereby minimizing the risk of treatment failure and drug resistance. Evidence-based pediatric dosing recommendations and effective intravenous antiviral treatment modalities are needed for intensive care patients with life-threatening influenza disease.

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References

  1. Ayscue P, Murray E, Uyeki T, Zipprich J, Harriman K, Salibay C, et al. Influenza-associated intensive-care unit admissions and deaths—California, September 29, 2013—January 18, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(7):143–7.

    PubMed  Google Scholar 

  2. Kumar K, Guirgis M, Zieroth S, Lo E, Menkis AH, Arora RC, et al. Influenza myocarditis and myositis: case presentation and review of the literature. Can J Cardiol. 2011;27:514–22.

    Article  PubMed  Google Scholar 

  3. WHO. Seasonal Influenza Fact sheet N°211. 2014. http://www.who.int/mediacentre/factsheets/fs211/en. Accessed 10 Mar 2014.

  4. Taylor G, Abdesselam K, Pelude L, Fernandes R, Mitchell R, McGEER A, et al. Epidemiological features of influenza in Canadian adult intensive care unit patients. Epidemiol Infect. 2016;144(4):741–50.

    Article  CAS  PubMed  Google Scholar 

  5. Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333–40.

    Article  CAS  PubMed  Google Scholar 

  6. Rello J, Rodríguez A, Ibañez P, Socias L, Cebrian J, Marques A, et al. Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain. Crit Care. 2009;13(5):R148.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kumar TC, Shivakumar NS, Deepak TS, Krishnappa R, Goutam MS, Ganigar V. H1N1- infected patients in ICU and their clinical outcome. N Am J Med Sci. 2012;4(9):394–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis. 2012;55:1198–204.

    Article  CAS  PubMed  Google Scholar 

  9. Lee N, Ison MG. Editorial commentary. “Late” treatment with neuraminidase inhibitors for severely ill patients with influenza: better late than never? Clin Infect Dis. 2012;55(9):1205–8.

    Article  PubMed  Google Scholar 

  10. Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2:395–404.

    Article  CAS  PubMed  Google Scholar 

  11. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60(1):1–24.

    PubMed  Google Scholar 

  12. Kohno S, Kida H, Mizuguchi M, Hirotsu N, Ishida T, Kadota J, et al. Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother. 2011;55:2803–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Leang S-K, Kwok S, Sullivan SG, Maurer-Stroh S, Kelso A, Barr IG, et al. Peramivir and laninamivir susceptibility of circulating influenza A and B viruses. Influenza Other Respir Viruses. 2014;8:135–9.

    Article  CAS  PubMed  Google Scholar 

  14. McLaughlin MM, Skoglund EW, Ison MG. Peramivir: an intravenous neuraminidase inhibitor. Expert Opin Pharmacother. 2015;8:1–12.

    Google Scholar 

  15. EMA. Summary on Compassionate Use for Tamiflu IV. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/05/WC500090250.pdf. Accessed 10 Mar 2014.

  16. EMA. Summary on Compassionate Use for IV Zanamivir. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/03/WC500104028.pdf. Accessed 10 Mar 2014.

  17. Davies BE. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother. 2010;65(Suppl 2):ii5–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Widmer N, Meylan P, Ivanyuk A, Aouri M, Decosterd LA, Buclin T. Oseltamivir in seasonal, avian H5N1 and pandemic 2009 A/H1N1 influenza: pharmacokinetic and pharmacodynamic characteristics. Clin Pharmacokinet. 2010;49(11):741–65.

    Article  CAS  PubMed  Google Scholar 

  19. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999;37(6):471–84.

    Article  CAS  PubMed  Google Scholar 

  20. Gibiansky L, Giraudon M, Rayner CR, Brennan BJ, Subramoney V, Robson R, et al. Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment. J Pharmacokinet Pharmacodyn. 2015;42(3):225–36.

    Article  CAS  PubMed  Google Scholar 

  21. Scheetz MH, Griffith MM, Ghossein C, Hollister AS, Ison MG. Pharmacokinetic assessment of peramivir in a hospitalized adult undergoing continuous venovenous hemofiltration. Ann Pharmacother. 2011;45:e64.

    Article  PubMed  Google Scholar 

  22. Eyler RF, Heung M, Pleva M, Sowinski KM, Park PK, Napolitano LM, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy. 2012;32(12):1061–9.

    Article  CAS  PubMed  Google Scholar 

  23. Vincent HH, Vos MC, Akcahuseyin E, Goessens WH, van Duyl WA, Schalekamp MA. Drug clearance by continuous haemodiafiltration. Analysis of sieving coefficients and mass transfer coefficients of diffusion. Blood Purif. 1993;11(2):99.

    Article  CAS  PubMed  Google Scholar 

  24. Gruber PC, Tian Q, Gomersall CD, Joynt GM, Choi GY. An in vitro study of the elimination of oseltamivir carboxylate by haemofiltration. Int J Antimicrob Agents. 2007;30:95–7.

    Article  CAS  PubMed  Google Scholar 

  25. Wildschut ED, de Hoog M, Ahsman MJ, Tibboel D, Osterhaus AD, Fraaij PL. Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support. PLoS One. 2010;5:e10938.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Flannery AH, Bastin MLT. Oseltamivir dosing in critically ill patients with severe influenza. Ann Pharmacother. 2014;48:1011–8.

    Article  PubMed  Google Scholar 

  27. Lemaitre F, Luyt CE, Roullet-Renoleau F, Nieszkowska A, Zahr N, Corvol E, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit. 2012;34:171–5.

    Article  CAS  PubMed  Google Scholar 

  28. Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. Anaesth Intensive Care. 2013;41(1):66–73.

    CAS  PubMed  Google Scholar 

  29. Kromdijk W, Sikma MA, van den Broek MP, Beijnen JH, Huitema AD, de Lange DW. Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique. Intensive Care Med. 2013;39(5):977–8.

    Article  CAS  PubMed  Google Scholar 

  30. Eyler RF, Klein KC, Mueller BA. The pharmacokinetics of oseltamivir and oseltamivir carboxylate in a critically ill pediatric patient receiving extracorporeal membrane oxygenation and continuous venovenous hemodialysis. J Pediatr Pharmacol Ther. 2012;17:173–6.

    PubMed  PubMed Central  Google Scholar 

  31. Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005;55(Suppl 1):i5–21.

    Article  CAS  PubMed  Google Scholar 

  32. Oo C, Barrett J, Hill G, Mann J, Dorr A, Dutkowski R, et al. Pharmacokinetics and dosage recommendations for an oseltamivir oral suspension for the treatment of influenza in children. Paediatr Drugs. 2001;3(3):229–36.

    Article  CAS  PubMed  Google Scholar 

  33. Monto AS. Implications of antiviral resistance of influenza viruses. Clin Infect Dis. 2009;48(4):397–9.

    Article  CAS  PubMed  Google Scholar 

  34. Tief F, Hoppe C, Seeber L, Obermeier P, Chen X, Karsch K, et al. An inception cohort study assessing the role of pneumococcal and other bacterial pathogens in children with influenza and ILI and a clinical decision model for stringent antibiotic use. Antivir Ther. 2016;. doi:10.3851/IMP3034 [Epub ahead of print].

    PubMed  Google Scholar 

  35. Rath B, Conrad T, Karsch K, Tief F, Obermeier P, Chen X, et al. The ChILD-score: a standardized clinical outcome parameter for infants and children with influenza-like illness (ILI). In: Oral presentation, ISIRV antiviral group conference influenza and other respiratory virus infections: advances in clinical management, Tokyo, Japan, June 4–6, 2014.

  36. WHO. Clinical management of human infection with pandemic (H1N1) 2009: revised guidance. 2009. http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdf. Accessed 06 Jul 2014.

  37. Rath B, von Kleist M, Tief F, Karsch K, Tuerk E, Muehlhans S, et al. Virus load kinetics and resistance development during oseltamivir treatment in infants and children infected with Influenza A(H1N1) 2009 and Influenza B viruses. Pediatr Infect Dis J. 2012;31:899–905.

    Article  PubMed  Google Scholar 

  38. Biere B, Bauer B, Schweiger B. Differentiation of influenza B virus lineages Yamagata and Victoria by real-time PCR. J Clin Microbiol. 2010;48(4):1425–7.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Duwe SC, Wedde M, Birkner P, Schweiger B. Genotypic and phenotypic resistance of pandemic A/H1N1 influenza viruses circulating in Germany. Antiviral Res. 2011;89:115–8.

    Article  CAS  PubMed  Google Scholar 

  40. Kamal MA, Acosta EP, Kimberlin DW, Gibiansky L, Jester P, Niranjan V, et al. The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach. Clin Pharmacol Ther. 2014;96:380–9.

    Article  CAS  PubMed  Google Scholar 

  41. Patel K, Rayner CR, Giraudon M, Kamal MA, Morcos PN, Robson R, et al. Pharmacokinetics and safety of oseltamivir in patients with end-stage renal disease treated with automated peritoneal dialysis. Br J Clin Pharmacol. 2015;79:624–35.

    Article  CAS  PubMed  Google Scholar 

  42. Wattanagoon Y, Stepniewska K, Lindegardh N, Pukrittayakamee S, Silachamroon U, Piyaphanee W, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009;53:945–52.

    Article  CAS  PubMed  Google Scholar 

  43. Lemaitre F, Luyt CE, Roullet-Renoleau F, Nieszkowska A, Zahr N, Fernandez C, et al. Oseltamivir carboxylate accumulation in a patient treated by haemodiafiltration and extracorporeal membrane oxygenation. Intensive Care Med. 2010;36:1273–4.

    Article  PubMed  Google Scholar 

  44. Chan-Tack KM, Kim C, Moruf A, Birnkrant DB. Clinical experience with intravenous zanamivir under an Emergency IND program in the United States (2011–2014). Antivir Ther. 2015;. doi:10.3851/IMP2944.

    PubMed  Google Scholar 

  45. Ariano RE, Sitar DS, Zelenitsky SA, Zarychanski R, Pisipati A, Ahern S, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ. 2010;182(4):357–63.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dutkowski R, Smith JR, Davies BE. Safety and pharmacokinetics of oseltamivir at standard and high dosages. Int J Antimicrob Agents. 2010;35:461–7.

    Article  CAS  PubMed  Google Scholar 

  47. Munoz FM, Anderson EJ, Deville JG, Clinch B, Kamal MA. Pharmacokinetics and safety of intravenous oseltamivir in infants and children in openlabel studies. Int J Clin Pharmacol Ther. 2015;53:531–40.

    Article  CAS  PubMed  Google Scholar 

  48. Rath BA, Blumentals WA, Miller MK, Starzyk K, Tetiurka B, Wollenhaupt M. A prospective observational study of oseltamivir safety and tolerability in infants and young children ≤24 months. Pharmacoepidemiol Drug Saf. 2015;24(3):286–96.

    Article  CAS  PubMed  Google Scholar 

  49. Farrukee R, Mosse J, Hurt AC. Review of the clinical effectiveness of the neuraminidase inhibitors against influenza B viruses. Expert Rev Anti Infect Ther. 2013;11:1135–45.

    Article  CAS  PubMed  Google Scholar 

  50. Hurt AC, Barr IG. Influenza viruses with reduced sensitivity to neuraminidase inhibitor drugs in untreated young children. Commun Dis Intell. 2008;32:57–62.

    Google Scholar 

  51. Chen X, Pouran Yousef K, Duwe S, Karsch K, Grover S, Wählisch S, et al. Quantitative influenza follow-up testing (QIFT)—a novel biomarker for the monitoring of disease activity at the point-of-care. PLoS One. 2014;9:e92500.

    Article  PubMed  PubMed Central  Google Scholar 

  52. WHO-EURO. Seasonal influenza: Key issues for case management of severe disease. 2011. http://www.euro.who.int/__data/assets/pdf_file/0020/153380/flu_case_management.pdf?ua=1. Accessed 10 Mar 2014.

  53. Nicholson KG, Wood JM, Zambon M. Influenza. Lancet. 2003;362:1733–45.

    Article  CAS  PubMed  Google Scholar 

  54. Esposito S, Daleno C, Baldanti F, Scala A, Campanini G, Taroni F, et al. Viral shedding in children infected by pandemic A/H1N1/2009 influenza virus. Virol J. 2011;8:349.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank the quality management team and the clinical teams in the respective intensive care units for their assistance with sample and data collection and their excellent clinical care. We are most grateful to the laboratory team at the National Reference Centre for Influenza, at Erasmus University Rotterdam and at PRA International Bioanalytical Laboratories for timely processing and detailed analysis of patient samples. We also thank Hoffmann-La Roche Inc. in Basel for kindly providing intravenous oseltamivir through the compassionate-use program. We would also like to express our sincere condolences to the deceased patient’s families.

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    Authors and Affiliations

    1. Department of Paediatrics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

      Katharina Karsch, Xi Chen, Patrick Obermeier & Barbara Rath

    2. Department of Congenital Heart Disease, German Heart Institute Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

      Oliver Miera, Björn Peters, Válerie Amann & Felix Berger

    3. Department of Anaesthesiology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

      Roland C. Francis

    4. Division of Influenza Viruses and Other Respiratory Viruses, Robert-Koch-Institute, National Reference Centre for Influenza, Seestraße 10, 13353, Berlin, Germany

      Susanne Duwe, Alla Heider & Brunhilde Schweiger

    5. Department of Virology, ERASMUS University Rotterdam, Burgemeester Oudlaan 50, 3062 PA, Rotterdam, The Netherlands

      Pieter Fraaij & Albert Osterhaus

    6. PRA Health Sciences Bioanalytical Laboratory, Early Development Services, Westerbrink 3, 9405 BJ, Assen, The Netherlands

      Marcel de Zwart

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    1. Katharina Karsch
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    Correspondence to Barbara Rath.

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    Funding

    No specific funding was received.

    Conflict of interest

    Hoffmann-La Roche kindly provided intravenous oseltamivir through the compassionate-use program and the option for pharmacokinetic analysis at the PRA Health Sciences Bioanalytical Laboratory, Early Development Services, Assen, The Netherlands. PF participates in the IRIS trial, sponsored by Hoffmann-La Roche. AO is a former employee of Erasmus MC that receives IRIS grant from Roche for oseltamivir resistance monitoring. Roche had no influence on pharmacokinetic and data analysis or writing of the manuscript. AO is director of ESWI and MUGAS, two non-profit foundations that receive financial support from Pharma Industry. The authors have no additional conflicts of interest to declare with respect to the presented work.

    Ethical 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 the deceased patients’ proxies.

    Additional information

    K. Karsch and X. Chen contributed equally to this project and should be considered co-first authors.

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    Karsch, K., Chen, X., Miera, O. et al. Pharmacokinetics of Oral and Intravenous Oseltamivir Treatment of Severe Influenza B Virus Infection Requiring Organ Replacement Therapy. Eur J Drug Metab Pharmacokinet 42, 155–164 (2017). https://doi.org/10.1007/s13318-016-0330-9

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