title: Pharmacokinetics of Oral and Intravenous Oseltamivir Treatment of Severe Influenza B Virus Infection Requiring Organ Replacement Therapy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Paediatrics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Karsch
authors.affiliation: Department of Paediatrics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Congenital Heart Disease, German Heart Institute Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Miera
authors.affiliation: Department of Congenital Heart Disease, German Heart Institute Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Peters
authors.affiliation: Department of Paediatrics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Obermeier
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Roland C
authors.initials: RC
authors.lastname: Francis
authors.affiliation: Department of Congenital Heart Disease, German Heart Institute Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Válerie
authors.initials: V
authors.lastname: Amann
authors.affiliation: Division of Influenza Viruses and Other Respiratory Viruses, Robert-Koch-Institute, National Reference Centre for Influenza, Seestraße 10, 13353, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Duwe
authors.affiliation: Department of Virology, ERASMUS University Rotterdam, Burgemeester Oudlaan 50, 3062 PA, Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Fraaij
authors.affiliation: Division of Influenza Viruses and Other Respiratory Viruses, Robert-Koch-Institute, National Reference Centre for Influenza, Seestraße 10, 13353, Berlin, Germany.
authors.forename: Alla
authors.initials: A
authors.lastname: Heider
authors.affiliation: PRA Health Sciences Bioanalytical Laboratory, Early Development Services, Westerbrink 3, 9405 BJ, Assen, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: de Zwart
authors.affiliation: Department of Congenital Heart Disease, German Heart Institute Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.affiliation: Department of Virology, ERASMUS University Rotterdam, Burgemeester Oudlaan 50, 3062 PA, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Osterhaus
authors.affiliation: Division of Influenza Viruses and Other Respiratory Viruses, Robert-Koch-Institute, National Reference Centre for Influenza, Seestraße 10, 13353, Berlin, Germany.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Schweiger
authors.affiliation: Department of Paediatrics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. Barbara.Rath@gmail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rath
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D005260:Female; D006801:Humans; D009981:Influenza B virus / Q000187:drug effects; D007251:Influenza, Human / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000601:surgery*; D009102:Multiple Organ Failure / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000601:surgery; D016377:Organ Transplantation / Q000379:methods*; D053139:Oseltamivir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir