Clinical Pharmacokinetics

, Volume 49, Issue 11, pp 741–765 | Cite as

Oseltamivir in Seasonal, Avian H5N1 and Pandemic 2009 A/H1N1 Influenza

Pharmacokinetic and Pharmacodynamic Characteristics
  • Nicolas Widmer
  • Pascal Meylan
  • Anton Ivanyuk
  • Manel Aouri
  • Laurent A. Decosterd
  • Thierry Buclin
Review Article

Abstract

Oseltamivir is the ester-type prodrug of the neuraminidase inhibitor oseltamivir carboxylate. It has been shown to be an effective treatment for both seasonal influenza and the recent pandemic 2009 A/H1N1 influenza, reducing both the duration and severity of the illness. It is also effective when used preventively. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of possible therapeutic drug monitoring.

According to the currently available literature, the pharmacokinetics of oseltamivir carboxylate after oral administration of oseltamivir are characterized by mean ± SD bioavailability of 79 ± 12%, apparent clearance of 25.3±7.0L/h, an elimination half-life of 7.4±2.5 hours and an apparent terminal volume of distribution of 267 ± 122 L. A maximum plasma concentration of 342±83 μg/L, a time to reach the maximum plasma concentration of 4.2 ± 1.1 hours, a trough plasma concentration of 168±32mg/L and an area under the plasma concentration-time curve from 0 to 24 hours of 6110 ± 1330 mg · h/L for a 75 mg twice-daily regimen were derived from literature data. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Interpatient variability is moderate (28% in apparent clearance and 46% in the apparent central volume of distribution); there is no indication of significant erratic or limited absorption in given patient subgroups.

The in vitro pharmacodynamics of oseltamivir carboxylate reveal wide variation in the concentration producing 50% inhibition of influenza A and B strains (range 0.17–44 μg/L). A formal correlation between systemic exposure to oseltamivir carboxylate and clinical antiviral activity or tolerance in influenza patients has not yet been demonstrated; thus no formal therapeutic or toxic range can be proposed.

The pharmacokinetic parameters of oseltamivir carboxylate after oseltamivir administration (bioavailability, apparent clearance and the volume of distribution) are fairly predictable in healthy subjects, with little interpatient variability outside the effect of renal function in all patients and bodyweight in children. Thus oseltamivir carboxylate exposure can probably be controlled with sufficient accuracy by thorough dosage adjustment according to patient characteristics. However, there is a lack of clinical study data on naturally infected patients. In addition, the therapeutic margin of oseltamivir carboxylate is poorly defined. The usefulness of systematic therapeutic drug monitoring in patients therefore appears to be questionable; however, studies are still needed to extend the knowledge to particular subgroups of patients or dosage regimens.

Notes

Acknowledgements

Support for this work was totally provided by internal funds. The authors have no conflicts of interest that are directly relevant to the content of this review. Marvin was used for drawing chemical structures and reactions (Marvin 5.3.7, 2010, Chemaxon [http://www.chemaxon.com]).

References

  1. 1.
    Zarocostas J. World Health Organization declares A (H1N1) influenza pandemic. BMJ 2009 Jun 12; 338: b2425PubMedCrossRefGoogle Scholar
  2. 2.
    Kmietowicz Z. WHO declares that H1N1 pandemic is officially over. BMJ 2010 Aug 11; 341: c4393PubMedCrossRefGoogle Scholar
  3. 3.
    World Health Organization [WHO]. Global alert and response (GAR): pandemic (H1N1) 2009 guidance documents. Geneva: WHO, 2010 [online]. Available from URL: http://www.who.int/csr/resources/publications/swineflu/en/ [Accessed 2010 Aug 21]Google Scholar
  4. 4.
    Update: drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009. MMWR Morb Mortal Wkly Rep 2009 May 1; 58 (16): 433–5Google Scholar
  5. 5.
    Elliott M. Zanamivir: from drug design to the clinic. Philos Trans R Soc Lond B Biol Sci 2001 Dec 29; 356(1416): 1885–93PubMedCrossRefGoogle Scholar
  6. 6.
    Ruf BR, Szucs T. Reducing the burden of influenza-associated complications with antiviral therapy. Infection 2009 Jun; 37(3): 186–96PubMedCrossRefGoogle Scholar
  7. 7.
    von Itzstein M, Wu WY, Kok GB, et al. Rational design of potent sialidasebased inhibitors ofinfluenza virus replication. Nature 1993 Jun3; 363(6428): 418–23CrossRefGoogle Scholar
  8. 8.
    McNicholl IR, McNicholl JJ. Neuraminidase inhibitors: zanamivir and oseltamivir. Ann Pharmacother 2001 Jan; 35(1): 57–70PubMedCrossRefGoogle Scholar
  9. 9.
    Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005 Sep 29; 353(13): 1363–73PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang H, Chen L. Possible origin of current influenza A H1N1 viruses. Lancet Infect Dis 2009 Aug; 9(8): 456–7PubMedCrossRefGoogle Scholar
  11. 11.
    Pinto LH, Lamb RA. The M2 proton channels of influenza A and B viruses. J Biol Chem 2006 Apr 7; 281(14): 8997–9000PubMedCrossRefGoogle Scholar
  12. 12.
    Shigeta S. Oseltamivir: a viewpoint by Shiro Shigeta. Drugs 1999 Nov; 58(5): 861–2CrossRefGoogle Scholar
  13. 13.
    Reddy D. Responding to pandemic (H1N1) 2009 influenza: the role of oseltamivir. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii35–40PubMedCrossRefGoogle Scholar
  14. 14.
    Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008 Aug 8; 57(RR-7): 1–60PubMedGoogle Scholar
  15. 15.
    Squires B, Macken C, Garcia-Sastre A, et al. BioHealthBase: informatics support in the elucidation of influenza virus host pathogen interactions and virulence. Nucleic Acids Res 2008 Jan; 36 (Database Issue): D497–503PubMedCrossRefGoogle Scholar
  16. 16.
    Keitel WA, Campbell JD, Treanor JJ, et al. Safety and immunogenicity of an inactivated influenza A/H5N1 vaccine given with or without aluminum hydroxide to healthy adults: results of a phase I-II randomized clinical trial. J Infect Dis 2008 Nov 1; 198(9): 1309–16PubMedCrossRefGoogle Scholar
  17. 17.
    H1N1 vaccine for prevention of pandemic influenza. Med Lett Drugs Ther 2009 Oct 5; 51 (1322): 77–8Google Scholar
  18. 18.
    Rayner CR, Chanu P, Gieschke R, et al. Population pharmacokinetics of oseltamivir when coadministered with probenecid. J Clin Pharmacol 2008 Aug; 48(8): 935–47PubMedCrossRefGoogle Scholar
  19. 19.
    Kawai N, Ikematsu H, Hirotsu N, et al. Clinical effectiveness of oseltamivir and zanamivir for treatment of influenza A virus subtype H1N1 with the H274Y mutation: a Japanese, multicenter study of the 2007–2008 and 2008–2009 influenza seasons. Clin Infect Dis 2009 Nov 13; 49(12): 1828–35PubMedCrossRefGoogle Scholar
  20. 20.
    Kawai N, Ikematsu H, Iwaki N, et al. Comparison of the effectiveness of zanamivir and oseltamivir against influenza A/H1N1, A/H3N2, and B. Clin Infect Dis 2009 Apr 1; 48(7): 996–7PubMedCrossRefGoogle Scholar
  21. 21.
    He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999 Dec; 37(6): 471–84PubMedCrossRefGoogle Scholar
  22. 22.
    Perrottet N, Decosterd LA, Meylan P, et al. Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements. Clin Pharmacokinet 2009 June 1; 48(6): 399–418PubMedCrossRefGoogle Scholar
  23. 23.
    Wiltshire H, Wiltshire B, Citron A, et al. Development of a high-performance liquid chromatographic-mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma and urine. J Chromatogr B Biomed Sci App 2000 Aug 18; 745(2): 373–88CrossRefGoogle Scholar
  24. 24.
    Lindegardh N, Davies GR, Hien TT, et al. Importance of collection tube during clinical studies of oseltamivir. Antimicrob Agents Chemother 2007 May; 51(5): 1835–6PubMedCrossRefGoogle Scholar
  25. 25.
    Chang Q, Chow MS, Zuo Z. Studies on the influence of esterase inhibitor to the pharmacokinetic profiles of oseltamivir and oseltamivir carboxylate in rats using an improved LC/MS/MS method. Biomed Chromatogr 2009 Aug; 23(8): 852–7PubMedCrossRefGoogle Scholar
  26. 26.
    Heinig K, Bucheli F. Sensitive determination of oseltamivir and oseltamivir carboxylate in plasma, urine, cerebrospinal fluid and brain by liquid chromatography-tandem mass spectrometry. J Chromatogr A 2008 Dec 1; 876(1): 129–36Google Scholar
  27. 27.
    Bahrami G, Mohammadi B, Kiani A. Determination of oseltamivir carboxylic acid in human serum bysolid phase extraction and high performance liquid chromatography with UV detection. J Chromatogr A 2008 Mar 15; 864(1–2): 38–42Google Scholar
  28. 28.
    Lindegardh N, Davies GR, Tran TH, et al. Rapid degradation of oseltamivir phosphate in clinical samples by plasma esterases. Antimicrob Agents Chemother 2006 Sep; 50(9): 3197–9PubMedCrossRefGoogle Scholar
  29. 29.
    Kurowski M, Oo C, Wiltshire H, et al. Oseltamivir distributes to influenza virus replication sites in the middle ear and sinuses. Clin Drug Investig 2004; 24(1): 49–53PubMedCrossRefGoogle Scholar
  30. 30.
    Massarella JW, He GZ, Dorr A, et al. The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers. J Clin Pharmacol 2000 Aug; 40(8): 836–43PubMedCrossRefGoogle Scholar
  31. 31.
    Abe M, Smith J, Urae A, et al. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann Pharmacother 2006 Oct; 40(10): 1724–30PubMedCrossRefGoogle Scholar
  32. 32.
    Snell P, Dave N, Wilson K, et al. Lack of effect of moderate hepatic impairment on the pharmacokinetics of oral oseltamivir and its metabolite oseltamivir carboxylate. Br J Clin Pharmacol 2005 May; 59(5): 598–601PubMedCrossRefGoogle Scholar
  33. 33.
    Brewster M, Smith JR, Dutkowski R, et al. Active metabolite from Tamiflu solution is bioequivalent to that from capsule delivery in healthy volunteers: a cross-over, randomised, open-label study. Vaccine 2006 Nov 10; 24(44–46): 6660–3PubMedCrossRefGoogle Scholar
  34. 34.
    Schentag JJ, Hill G, Chu T, et al. Similarity in pharmacokinetics of oseltamivir and oseltamivir carboxylate in Japanese and Caucasian subjects. J Clin Pharmacol 2007 Jun; 47(6): 689–96PubMedCrossRefGoogle Scholar
  35. 35.
    Snell P, Oo C, Dorr A, et al. Lack of pharmacokinetic interaction between the oral anti-influenza neuraminidase inhibitor prodrug oseltamivir and antacids. Br J Clin Pharmacol 2002 Oct; 54(4): 372–7PubMedCrossRefGoogle Scholar
  36. 36.
    Jhee SS, Yen M, Ereshefsky L, et al. Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers. Antimicrob Agents Chemother 2008 Oct; 52(10): 3687–93PubMedCrossRefGoogle Scholar
  37. 37.
    Kongpatanakul S, Chatsiricharoenkul S, Panich U, et al. A randomized, open-label, 2-period, crossover bioequivalence study of two oral formulations of 75 mg oseltamivir in healthy Thai volunteers. Int J Clin Pharmacol Ther 2008 Dec; 46(12): 654–62PubMedGoogle Scholar
  38. 38.
    Lennon S, Barrett J, Kirkpatrick C, et al. Oseltamivir oral suspension and capsules are bioequivalent for the active metabolite in healthy adult volunteers. Int J Clin Pharmacol Ther 2009 Aug; 47(8): 539–48PubMedGoogle Scholar
  39. 39.
    Dutkowski R, Smith JR, Davies BE. Safety and pharmacokinetics of oseltamivir at standard and high dosages. Int J Antimicrob Agents 2010 May; 35(5): 461–7PubMedCrossRefGoogle Scholar
  40. 40.
    Morrison D, Roy S, Rayner C, et al. A randomized, crossover study to evaluate the pharmacokinetics of amantadine and oseltamivir administered alone and in combination. PLoS One 2007 Dec; 2(12): e1305PubMedCrossRefGoogle Scholar
  41. 41.
    Oo C, Barrett J, Dorr A, et al. Lack of pharmacokinetic interaction between the oral anti-influenza prodrug oseltamivir and aspirin. Antimicrob Agents Chemother 2002 Jun; 46(6): 1993–5PubMedCrossRefGoogle Scholar
  42. 42.
    Holodniy M, Penzak SR, Straight TM, et al. Pharmacokinetics and tolerability of oseltamivir combined with probenecid. Antimicrob Agents Chemother 2008 Sep; 52(9): 3013–21PubMedCrossRefGoogle Scholar
  43. 43.
    Wattanagoon Y, Stepniewska K, Lindegardh N, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother 2009 Mar; 53(3): 945–52PubMedCrossRefGoogle Scholar
  44. 44.
    Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. Can Med Assoc J 2010 Mar 9; 182(4): 357–63CrossRefGoogle Scholar
  45. 45.
    Oo C, Snell P, Barrett J, et al. Pharmacokinetics and delivery of the anti-influenza prodrug oseltamivir to the small intestine and colon using sitespecific delivery capsules. Int J Pharm 2003 May 12; 257(1–2): 297–9PubMedCrossRefGoogle Scholar
  46. 46.
    Rigby JW, Scott AK, Hawksworth GM, et al. A comparison of the pharmacokinetics of atenolol, metoprolol, oxprenolol and propranolol in elderly hypertensive and young healthy subjects. Br J Clin Pharmacol 1985 Oct; 20(4): 327–31PubMedCrossRefGoogle Scholar
  47. 47.
    Ogihara T, Kano T, Wagatsuma T, et al. Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos 2009 Aug; 37(8): 1676–81PubMedCrossRefGoogle Scholar
  48. 48.
    European Medicines Agency [EMA]. Tamiflu: European public assessment report. Geneva: EMA; 2010 Aug 10 [online]. Available from URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000402/human_med_001075.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124 [Accessed 2010 Aug 23]Google Scholar
  49. 49.
    Zhu HJ, Markowitz JS. Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab Dispos 2009 Feb; 37(2): 264–7PubMedCrossRefGoogle Scholar
  50. 50.
    Bardsley-Elliot A, Noble S. Oseltamivir. Drugs 1999 Nov; 58(5): 851–60; discussion 861–2PubMedCrossRefGoogle Scholar
  51. 51.
    Davies BE. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii5–10PubMedCrossRefGoogle Scholar
  52. 52.
    Morimoto K, Nakakariya M, Shirasaka Y, et al. Oseltamivir (Tamiflu) efflux transport at the blood-brain barrier via P-glycoprotein. Drug Metab Dispos 2008 Jan; 36(1): 6–9PubMedCrossRefGoogle Scholar
  53. 53.
    Ose A, Kusuhara H, Yamatsugu K, et al. P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier. Drug Metab Dispos 2008 Feb; 36(2): 427–34PubMedCrossRefGoogle Scholar
  54. 54.
    Eisenberg EJ, Bidgood A, Cundy KC. Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104. Antimicrob Agents Chemother 1997 Sep; 41(9): 1949–52PubMedGoogle Scholar
  55. 55.
    Mendel DB, Tai CY, Escarpe PA, et al. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets againstinfluenza infection. Antimicrob Agents Chemother 1998 Mar; 42(3): 640–6PubMedGoogle Scholar
  56. 56.
    Woods JM, Bethell RC, Coates JA, et al. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide rangeof influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993 Jul; 37(7): 1473–9PubMedCrossRefGoogle Scholar
  57. 57.
    Peng AW, Milleri S, Stein DS. Direct measurement of the anti-influenza agent zanamivir in the respiratory tract following inhalation. Antimicrob Agents Chemother 2000 Jul; 44(7): 1974–6PubMedCrossRefGoogle Scholar
  58. 58.
    Hill G, Cihlar T, Oo C, et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos 2002 Jan; 30(1): 13–9PubMedCrossRefGoogle Scholar
  59. 59.
    Ose A, Ito M, Kusuhara H, et al. Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos 2009 Feb; 37(2): 315–21PubMedCrossRefGoogle Scholar
  60. 60.
    El-Sheikh AA, Masereeuw R, Russel FG. Mechanisms of renal anionic drug transport. Eur J Pharmacol 2008 May 13; 585(2–3): 245–55PubMedCrossRefGoogle Scholar
  61. 61.
    Oo C, Barrett J, Hill G, et al. Pharmacokinetics and dosage recommendations for an oseltamivir oral suspension for the treatment of influenza in children. Paediatr Drugs 2001; 3(3): 229–36PubMedCrossRefGoogle Scholar
  62. 62.
    Oo C, Hill G, Dorr A, et al. Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1–5 years. Eur J Clin Pharmacol 2003 Sep; 59(5–6): 411–5PubMedCrossRefGoogle Scholar
  63. 63.
    Yang D, Pearce RE, Wang X, et al. Human carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol 2009 Jan 15; 77(2): 238–47PubMedCrossRefGoogle Scholar
  64. 64.
    Wildschut ED, de Hoog M, Ahsman MJ, et al. Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extra-corporeal membrane oxygenation support. PloS One 2010 Jun; 5(6): e10938PubMedCrossRefGoogle Scholar
  65. 65.
    Kimberlin DW, Acosta E, Sanchez P, et al. Oseltamivir (OST) and OST carboxylate (CBX) pharmacokinetics (PK) in infants: interim results from a multicenter trial [abstract no. 804]. 47th Annual Meeting, Infectious Diseases Society of America; 2009 Oct 29–Nov 1; Philadelphia (PA)sGoogle Scholar
  66. 66.
    European Medicines Agency [EMA]. CHMP assessment report on novel influenza (H1N1) outbreak: Tamiflu (oseltamivir); Relenza (zanamivir) [document reference EMEA/CHMP/287662/2009]. London: EMA, 2009 May 7 [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/28766209en.pdf [Accessed 2010 Aug 23]
  67. 67.
    Hoffmann-La Roche. A study of intravenous oseltamivir [Tamiflu] in infants with influenza [ClinicalTrials.gov identifier NCT01053663]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT01053663?id=NCT01053663&rank=1 [Accessed 2010 Aug 23]
  68. 68.
    Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010 Aug 15; 202(4): 563–6PubMedCrossRefGoogle Scholar
  69. 69.
    Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. Can Med Assoc J 2009 Jul 7; 181(1–2): 55–8CrossRefGoogle Scholar
  70. 70.
    Donner B, Niranjan V, Hoffmann G. Safety of oseltamivir in pregnancy: a review of preclinical and clinical data. Drug Saf 2010 Aug 1; 33(8): 631–42PubMedCrossRefGoogle Scholar
  71. 71.
    Webb SA, Pettila V, Seppelt I, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009 Nov 12; 361(20): 1925–34PubMedCrossRefGoogle Scholar
  72. 72.
    Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancyinthe USA. Lancet 2009 Aug8; 374(9688): 451–8PubMedCrossRefGoogle Scholar
  73. 73.
    Worley KC, Roberts SW, Bawdon RE. The metabolism and transplacental transfer of oseltamivir in the ex vivo human model. Infect Dis Obstet Gynecol 2008; 2008: 927574PubMedCrossRefGoogle Scholar
  74. 74.
    University of Pittsburgh. A study of the pharmacology of oseltamivir (Tamiflu) in pregnancy [ClinicalTrials.gov identifier NCT00873886]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00873886?id=nct00873886&rank=1 [Accessed 2010 Aug 23]
  75. 75.
    Wentges-van Holthe N, van Eijkeren M, van der Laan JW. Oseltamivir and breastfeeding. Int J Infect Dis 2008 Jul; 12(4): 451PubMedCrossRefGoogle Scholar
  76. 76.
    Cropp CD, Yee SW, Giacomini KM. Genetic variation in drug transporters in ethnic populations. Clin Pharmacol Ther 2008 Sep; 84(3): 412–6PubMedCrossRefGoogle Scholar
  77. 77.
    Robson R, Buttimore A, Lynn K, et al. The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2006 Sep; 21(9): 2556–62PubMedCrossRefGoogle Scholar
  78. 78.
    Karie S, Launay-Vacher V, Janus N, et al. Pharmacokinetics and dosage adjustment of oseltamivir and zanamivir in patients with renal failure. Nephrol Dial Transplant 2006 Dec; 21(12): 3606–8PubMedCrossRefGoogle Scholar
  79. 79.
    Tett SE, Kirkpatrick CM, Gross AS, et al. Principles and clinical application of assessing alterations in renal elimination pathways. Clin Pharmacokinet 2003; 42(14): 1193–211PubMedCrossRefGoogle Scholar
  80. 80.
    K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002 Feb; 39 (2 Suppl. 1): S1-266Google Scholar
  81. 81.
    Gruber PC, Gomersall CD, Joynt GM. Avian influenza (H5N1): implications for intensive care. Intensive Care Med 2006 Jun; 32(6): 823–9PubMedCrossRefGoogle Scholar
  82. 82.
    Schreuder MF, van der Flier M, Knops NB, et al. Oseltamivir dosing in children undergoing hemodialysis. Clin Infect Dis 2010 May 15; 50(10): 1427–8PubMedCrossRefGoogle Scholar
  83. 83.
    Gruber PC, Tian Q, Gomersall CD, et al. An in vitro study of the elimination of oseltamivir carboxylate by haemofiltration. Int J Antimicrob Agents 2007 Jul; 30(1): 95–7PubMedCrossRefGoogle Scholar
  84. 84.
    Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis 2009 Aug; 9(8): 493–504PubMedCrossRefGoogle Scholar
  85. 85.
    IWK Health Centre. Oseltamivir pharmacokinetics in morbid obesity (OPTIMO) [ClinicalTrials.gov identifier NCT01002729]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ [Accessed 2010 Aug 12]
  86. 86.
    Shi D, Yang J, Yang D, et al. Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation isinhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther 2006 Dec; 319(3): 1477–84PubMedCrossRefGoogle Scholar
  87. 87.
    Fowler S, Lennon SM, Hoffmann G, et al. Comments on “Anti-influenza prodrug oseltamiviris activatedby carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel”. J Pharmacol Exp Ther 2007 Jul; 322(1): 422-3; author reply 424–5CrossRefGoogle Scholar
  88. 88.
    Masuda S, Saito H, Inui KI. Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1. J Pharmacol Exp Ther 1997 Dec; 283(3): 1039–42PubMedGoogle Scholar
  89. 89.
    Hama R. Fatal neuropsychiatric adverse reactions to oseltamivir: case series and overview of causal relationships. Int J Risk Saf Med 2008 Apr; 20(1–2): 5–36Google Scholar
  90. 90.
    Herxheimer A, Clarke M, Edwards R, et al. A/H1N1 flu: time for case-control studies of NSAIDs and oseltamivir. BMJ 2009 Jul 28; 339: b3048PubMedCrossRefGoogle Scholar
  91. 91.
    Starko KM. Salicylates and pandemic influenza mortality, 1918–1919 pharmacology, pathology, and historic evidence. Clin Infect Dis 2009 Nov 1; 49(9): 1405–10PubMedCrossRefGoogle Scholar
  92. 92.
    Davies BE, Aceves Baldo P, Brewster M. Effect of oseltamivir on anti-coagulation: a crossover study inpatients stabilized onwarfarin [abstract no. A1-596]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2009 Sep 12–15; Washington, DCGoogle Scholar
  93. 93.
    Khazeni N, Bravata DM, Holty JE, et al. Systematic review: safety and efficacy of extended-duration antiviral chemoprophylaxis against pandemic and seasonal influenza. Ann Intern Med 2009 Oct 6; 151(7): 464–73PubMedGoogle Scholar
  94. 94.
    Taylor WR, Thinh BN, Anh GT, et al. Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. PLoS One 2008 Oct; 3(10): e3410PubMedCrossRefGoogle Scholar
  95. 95.
    Parker RM, Wolf MS, Jacobson KL, et al. Risk of confusion in dosing Tamiflu oral suspension inchildren. N Engl J Med 2009 Nov 5; 361(19): 1912–3PubMedCrossRefGoogle Scholar
  96. 96.
    Kitching A, Roche A, Balasegaram S, et al. Oseltamivir adherence and side effects among children in three London schools affected by influenza A(H1N1)v, May 2009 — an internet-based cross-sectional survey. Euro Surveill 2009 Jul 30; 14(30): 19287PubMedGoogle Scholar
  97. 97.
    Yoshimura M, Kimura T, Ishii M, et al. Functional polymorphisms in carboxylesterase1A2 (CES1A2) gene involves specific protein 1 (Sp1) binding sites. Biochem Biophys Res Commun 2008 May 9; 369(3): 939–42PubMedCrossRefGoogle Scholar
  98. 98.
    Fujita T, Brown C, Carlson EJ, et al. Functional analysisof polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet Genomics 2005 Apr; 15(4): 201–9PubMedCrossRefGoogle Scholar
  99. 99.
    Singer AC, Nunn MA, Gould EA, et al. Potential risks associated with the proposed widespread use of Tamiflu. Environ Health Perspect 2007 Jan; 115(1): 102–6PubMedCrossRefGoogle Scholar
  100. 100.
    Bartels P, von Tumpling Jr W. The environmental fate of the antiviral drug oseltamivir carboxylate in different waters. Sci Total Environ 2008 Nov 1; 405(1–3): 215–25PubMedCrossRefGoogle Scholar
  101. 101.
    Straub JO. An environmental risk assessment for oseltamivir (Tamiflu) for sewage works and surface waters under seasonal-influenza- and pandemic-use conditions. Ecotoxicol Environ Saf 2009 Sep; 72(6): 1625–34PubMedCrossRefGoogle Scholar
  102. 102.
    Fick J, Lindberg RH, Tysklind M, et al. Antiviral oseltamivir is not removed or degraded in normal sewage water treatment: implications for development of resistance by influenza A virus. PLoS One 2007 Oct; 2(10): e986PubMedCrossRefGoogle Scholar
  103. 103.
    Singer AC, Johnson AC, Anderson PD, et al. Reassessing the risks of Tamiflu use during a pandemic to the Lower Colorado River. Environ Health Per-spect 2008 Jul; 116(7): A285–6CrossRefGoogle Scholar
  104. 104.
    Ghosh GC, Nakada N, Yamashita N, et al. Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (tamiflu), detected in sewage discharge and river water in Japan. Environ Health Perspect 2010 Jan; 118(1): 103–7PubMedGoogle Scholar
  105. 105.
    Tillett T. A measure of resistance: detecting tamiflu metabolite in sewage discharge and river water. Environ Health Perspect 2010 Jan; 118(1): A34PubMedCrossRefGoogle Scholar
  106. 106.
    Hilleman MR. Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine 2002 Aug 19; 20(25–26): 3068–87PubMedCrossRefGoogle Scholar
  107. 107.
    Wagner R, Feldmann A, Wolff T, et al. Hemagglutinin and neuraminidase as determinants of influenza virus pathogenicity. Int Congr Ser 2001 Oct; 1219: 533–43CrossRefGoogle Scholar
  108. 108.
    Schirmer P, Holodniy M. Oseltamivir for treatment and prophylaxis of influenza infection. Expert Opin Drug Saf 2009 May; 8(3): 357–71PubMedCrossRefGoogle Scholar
  109. 109.
    Recker M, Pybus OG, Nee S, et al. The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types. Proc Natl Acad Sci U S A 2007 May 1; 104(18): 7711–6PubMedCrossRefGoogle Scholar
  110. 110.
    Potter CW. A history of influenza. J Appl Microbiol 2001 Oct; 91(4): 572–9PubMedCrossRefGoogle Scholar
  111. 111.
    Ward P, Small I, Smith J, et al. Oseltamivir (Tamiflu) and its potential for use in the eventof an influenza pandemic. J Antimicrob Chemother 2005 Feb; 55 Suppl. 1: i5–21PubMedCrossRefGoogle Scholar
  112. 112.
    Poland GA, Jacobson RM, Ovsyannikova IG. Influenza virus resistance to antiviral agents: a plea for rational use. Clin Infect Dis 2009 May 1; 48(9): 1254–6PubMedCrossRefGoogle Scholar
  113. 113.
    von Itzstein M. The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 2007 Dec; 6(12): 967–74CrossRefGoogle Scholar
  114. 114.
    Varghese JN, Laver WG, Colman PM. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature 1983 May 5–11; 303(5912): 35–40PubMedCrossRefGoogle Scholar
  115. 115.
    Colman PM, Varghese JN, Laver WG. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983 May 5–11; 303(5912): 41–4PubMedCrossRefGoogle Scholar
  116. 116.
    Kim CU, Lew W, Williams MA, et al. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 1997 Jan 29; 119(4): 681–90PubMedCrossRefGoogle Scholar
  117. 117.
    Nguyen-Van-Tam JS. Foreword: oseltamivir for seasonal, avian and pandemic influenza: 10 years of clinical experience. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii3–4PubMedCrossRefGoogle Scholar
  118. 118.
    Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003 Jan; 51(1): 123–9PubMedCrossRefGoogle Scholar
  119. 119.
    Sidwell RW, Smee DF. Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza. Expert Opin Investig Drugs 2002 Jun; 11(6): 859–69PubMedCrossRefGoogle Scholar
  120. 120.
    US Department of Health and Human Services. HHS pursues advance development of new influenza antiviral drug [media release]. 2007 Jan 4 [online]. Available from URL: http://www.hhs.gov/news/press/2007pres/20070104.html
  121. 121.
    Birnkrant D, Cox E. The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza. N Engl J Med 2009 Dec 3; 361(23): 2204–7PubMedCrossRefGoogle Scholar
  122. 122.
    Yamashita M, Tomozawa T, Kakuta M, et al. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity. Antimicrob Agents Chemother 2009 Jan; 53(1): 186–92PubMedCrossRefGoogle Scholar
  123. 123.
    Abed Y, Nehme B, Baz M, et al. Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res 2008 Feb; 77(2): 163–6PubMedCrossRefGoogle Scholar
  124. 124.
    Sidwell RW, Huffman JH, Barnard DL, et al. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neura-minidase inhibitor. Antiviral Res 1998 Feb; 37(2): 107–20PubMedCrossRefGoogle Scholar
  125. 125.
    Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet 2009 Sep 19; 374(9694): 1036PubMedCrossRefGoogle Scholar
  126. 126.
    Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivirresistant 2009 H1N1 influenza. N Engl J Med 2010 Jan 7; 362(1): 88–9PubMedCrossRefGoogle Scholar
  127. 127.
    Harter G, Zimmermann O, Maier L, et al. Intravenous zanamivir for patients with pneumonitis due to pandemic (H1N1) 2009 influenza virus. Clin Infect Dis 2010 May 1; 50(9): 1249–51PubMedCrossRefGoogle Scholar
  128. 128.
    Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA 1999 Oct 6; 282(13): 1240–6PubMedCrossRefGoogle Scholar
  129. 129.
    Peters Jr PH, Gravenstein S, Norwood P, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 2001 Aug; 49(8): 1025–31PubMedCrossRefGoogle Scholar
  130. 130.
    Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001 Feb 14; 285(6): 748–54PubMedCrossRefGoogle Scholar
  131. 131.
    Hayden FG, Belshe R, Villanueva C, et al. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004 Feb 1; 189(3): 440–9PubMedCrossRefGoogle Scholar
  132. 132.
    Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999 Oct 28; 341(18): 1336–43PubMedCrossRefGoogle Scholar
  133. 133.
    Dutkowski R. Oseltamivir in seasonal influenza: cumulative experience in low- and high-risk patients. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii11–24PubMedCrossRefGoogle Scholar
  134. 134.
    Schunemann HJ, Hill SR, Kakad M, et al. WHO rapid advice guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. Lancet Infect Dis 2007 Jan; 7(1): 21–31PubMedCrossRefGoogle Scholar
  135. 135.
    Gubareva LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother 2001 Dec; 45(12): 3403–8PubMedCrossRefGoogle Scholar
  136. 136.
    Burch J, Corbett M, Stock C, et al. Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis. Lancet Infect Dis 2009 Sep; 9(9): 537–45PubMedCrossRefGoogle Scholar
  137. 137.
    Jefferson T, Demicheli V, Di Pietrantonj C, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev 2006 Jul 19; (3): CD001265PubMedGoogle Scholar
  138. 138.
    Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 2009 Dec 8; 339: b5106PubMedCrossRefGoogle Scholar
  139. 139.
    Talbird SE, Brogan AJ, Winiarski AP, et al. Cost-effectiveness of treating influenzalike illness with oseltamivir in the United States. Am J Health Syst Pharm 2009 Mar 1; 66(5): 469–80PubMedCrossRefGoogle Scholar
  140. 140.
    Smith J. Point-by-point response from Roche to BMJ questions. BMJ 2009 Dec 8; 339: b5374CrossRefGoogle Scholar
  141. 141.
    Godlee F, Clarke M. Why don’t we have all the evidence on oseltamivir? BMJ 2009 Dec 8; 339: b5351PubMedCrossRefGoogle Scholar
  142. 142.
    Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treatment on influenzarelated lower respiratory tract complications and hospitalizations. Arch Intern Med 2003 Jul 28; 163(14): 1667–72PubMedCrossRefGoogle Scholar
  143. 143.
    Fleming DM, Elliot AJ, Meijer A, et al. Influenza virus resistancetooseltamivir: what are the implications? Eur J Public Health 2009 Jun; 19(3): 238–9PubMedCrossRefGoogle Scholar
  144. 144.
    Leneva IA, Roberts N, Govorkova EA, et al. The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. Antiviral Res 2000 Nov; 48(2): 101–15PubMedCrossRefGoogle Scholar
  145. 145.
    Govorkova EA, Leneva IA, Goloubeva OG, et al. Comparisonof efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother 2001 Oct; 45(10): 2723–32PubMedCrossRefGoogle Scholar
  146. 146.
    Govorkova EA, Ilyushina NA, Boltz DA, et al. Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob Agents Chemother 2007 Apr; 51(4): 1414–24PubMedCrossRefGoogle Scholar
  147. 147.
    Toovey S, Avex Avian Influenza Expert Group. First results from an avian influenza case registry [abstract no. V-533]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2009 Sep 12–15; Washington, DCGoogle Scholar
  148. 148.
    Yu K, Luo C, Qin G, et al. Why are oseltamivir and zanamivir effective against the newly emerged influenza A virus (A/H1N1)? Cell Res 2009 Oct; 19(10): 1221–4PubMedCrossRefGoogle Scholar
  149. 149.
    Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009. N Engl J Med 2009 Nov 12; 361(20): 1935–44PubMedCrossRefGoogle Scholar
  150. 150.
    McKimm-Breschkin J, Trivedi T, Hampson A, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother 2003 Jul; 47(7): 2264–72PubMedCrossRefGoogle Scholar
  151. 151.
    Lackenby A, Hungnes O, Dudman SG, et al. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill 2008 Jan 31; 13(5): 8026PubMedGoogle Scholar
  152. 152.
    Meijer A, Lackenby A, Hungnes O, et al. Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007–08 season. Emerg Infect Dis 2009 Apr; 15(4): 552–60PubMedCrossRefGoogle Scholar
  153. 153.
    World Health Organization [WHO]. Global alert and response (GAR): weekly virological update on 12 August 2010. Geneva: WHO, 2010 Aug 12 [online]. Available from URL: http://www.who.int/csr/disease/swineflu/laboratory13_08_2010/en/index.html [Accessed 2010 Sep 13]Google Scholar
  154. 154.
    Weinstock DM, Zuccotti G. The evolution of influenza resistance and treatment. JAMA 2009 Mar 11; 301(10): 1066–9PubMedCrossRefGoogle Scholar
  155. 155.
    Stephenson I, Democratis J, Lackenby A, et al. Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children. Clin Infect Dis 2009 Feb 15; 48(4): 389–96PubMedCrossRefGoogle Scholar
  156. 156.
    Ferraris O, Lina B. Mutations of neuraminidase implicated in neuraminidase inhibitors resistance. J Clin Virol 2008 Jan; 41(1): 13–9PubMedCrossRefGoogle Scholar
  157. 157.
    White NJ, Webster RG, Govorkova EA, et al. What isthe optimal therapy for patients with H5N1 influenza? PLoS Medicine 2009 Jun 23; 6(6): e1000091PubMedCrossRefGoogle Scholar
  158. 158.
    de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005 Dec 22; 353(25): 2667–72PubMedCrossRefGoogle Scholar
  159. 159.
    Smith JR. Oseltamivir in human avian influenza infection. J Antimicrob Chemother 2010 Apr; 65 Suppl. 2: ii25–33PubMedCrossRefGoogle Scholar
  160. 160.
    Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis — North Carolina, 2009. MMWR Morb Mortal Wkly Rep 2009 Sep 11; 58 (35): 969–72Google Scholar
  161. 161.
    Baz M, Abed Y, Papenburg J, et al. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. N Engl J Med 2009 Dec 3; 361(23): 2296–7PubMedCrossRefGoogle Scholar
  162. 162.
    Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec 2009 Oct 30; 84 (44): 453–9Google Scholar
  163. 163.
    Dutkowski R, Thakrar B, Froehlich E, et al. Safety and pharmacology of oseltamivir in clinical use. Drug Saf 2003; 26(11): 787–801PubMedCrossRefGoogle Scholar
  164. 164.
    Strong M, Burrows J, Redgrave P. A/H1N1 pandemic. Oseltamivir’s adverse events. BMJ 2009 Aug 11; 339: b3249PubMedCrossRefGoogle Scholar
  165. 165.
    Fuyuno I. Tamiflu side effects come under scrutiny. Nature 2007 Mar 22; 446(7134): 358–9PubMedCrossRefGoogle Scholar
  166. 166.
    Maxwell SR. Tamiflu and neuropsychiatric disturbance in adolescents. BMJ 2007 Jun 16; 334(7606): 1232–3PubMedCrossRefGoogle Scholar
  167. 167.
    Izumi Y, Tokuda K, O’Dell K, et al. Synaptic and behavioral interactions of oseltamivir (Tamiflu) with neurostimulants. Hum Exp Toxicol 2008 Dec; 27(12): 911–7PubMedCrossRefGoogle Scholar
  168. 168.
    Long M. Side effects of Tamiflu: clues from an Asian single nucleotide polymorphism. Cell Res 2007 Apr; 17(4): 309–10PubMedCrossRefGoogle Scholar
  169. 169.
    Li CY, Yu Q, Ye ZQ, et al. A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir. Cell Res 2007 Apr; 17(4): 357–62PubMedCrossRefGoogle Scholar
  170. 170.
    Lindemann L, Jacobsen H, Schuhbauer D, et al. In vitro pharmacological selectivity profile of oseltamivir prodrug (Tamiflu®) and active metabolite. Eur J Pharmacol 2010 Feb 25; 628(1–3): 6–10PubMedCrossRefGoogle Scholar
  171. 171.
    Okamoto S, Kamiya I, Kishida K, et al. Experience with oseltamivir for infants younger than 1 year old in Japan. Pediatr Infect Dis J 2005 Jun; 24(6): 575–6PubMedCrossRefGoogle Scholar
  172. 172.
    Toovey S, Rayner C, Prinssen E, et al. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf 2008 Dec 1; 31(12): 1097–114PubMedGoogle Scholar
  173. 173.
    Huang YC, Li WC, Tsao KC, et al. Influenza-associated central nervous system dysfunction in Taiwanese children: clinical characteristics and outcomes with and without administration of oseltamivir. Pediatr Infect Dis J 2009 Jul; 28(7): 647–8PubMedCrossRefGoogle Scholar
  174. 174.
    Enger C, Nordstrom BL, Thakrar B, et al. Health outcomes among patients receiving oseltamivir. Pharmacoepidemiol Drug Saf 2004 Apr; 13(4): 227–37PubMedCrossRefGoogle Scholar
  175. 175.
    Casscells SW, Granger E, Kress AM, et al. Use of oseltamivir after influenza infection is associated with reduced incidence of recurrent adverse cardiovascular outcomes among military health system beneficiaries with prior cardiovascular diseases. Circ Cardiovasc Qual Outcomes 2009 Mar; 2(2): 108–15PubMedCrossRefGoogle Scholar
  176. 176.
    Lewis JA. Post-marketing surveillance: how many patients? Trends Pharmacol Sci 1981; 2: 93–4CrossRefGoogle Scholar
  177. 177.
    Oseltamivir: cutaneous and neurological adverse effects in children. Prescrire Int 2006 Oct; 15 (85): 182–3Google Scholar
  178. 178.
    Raisch DW, Straight TM, Holodniy M. Thrombocytopenia from combination treatment with oseltamivir and probenecid: case report, MedWatch data summary, and review of the literature. Pharmacotherapy 2009 Aug; 29(8): 988–92PubMedCrossRefGoogle Scholar
  179. 179.
    McSharry JJ, Weng Q, Brown A, et al. Prediction of the pharmacodynamically linked variable ofoseltamivir carboxylate for influenzaA virus using an in vitro hollow-fiber infection model system. Antimicrob Agents Chemother 2009 Jun; 53(6): 2375–81PubMedCrossRefGoogle Scholar
  180. 180.
    Drusano GL, Preston SL, Smee D, et al. Pharmacodynamic evaluation of RWJ-270201, a novel neuraminidase inhibitor, in a lethal murine model of influenza predicts efficacy for once-daily dosing. Antimicrob Agents Chemother 2001 Jul; 45(7): 2115–8PubMedCrossRefGoogle Scholar
  181. 181.
    Preston SL, Piliero PJ, Bilello JA, et al. In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours. Antimicrob Agents Chemother 2003 Nov; 47(11): 3393–9PubMedCrossRefGoogle Scholar
  182. 182.
    Ensom MH, Davis GA, Cropp CD, et al. Clinical pharmacokinetics in the 21st century: does the evidence support definitive outcomes? Clin Pharma-cokinet 1998; 34(4): 265–79CrossRefGoogle Scholar
  183. 183.
    Eisenberg EJ, Cundy KC. High-performance liquid chromatographic determination of GS4071, a potent inhibitor of influenza neuraminidase, in plasma by precolumn fluorescence derivatization with naphthalenedialdehyde. J Chromatogr B Biomed Sci App 1998 Sep 25; 716(1–2): 267–73CrossRefGoogle Scholar
  184. 184.
    Lindegardh N, Hanpithakpong W, Wattanagoon Y, et al. Development and validation of a liquid chromatographic-tandem mass spectrometric method for determination of oseltamivir and its metabolite oseltamivir carboxylate in plasma, saliva and urine. J Chromatogr A 2007 Nov 1; 859(1): 74–83Google Scholar
  185. 185.
    Aouri M, Zanolari B, Meylan P, et al. Determination of oseltamivir and oseltamivir carboxylate inhuman plasma byliquid chromatography-tandem mass spectrometry [abstract no. P52]. Schweiz Med Forum 2010 Aug 18; 10 (Suppl. 52): 25SGoogle Scholar
  186. 186.
    Kaiser L, Fritz RS, Straus SE, et al. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol 2001 Jul; 64(3): 262–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Nicolas Widmer
    • 1
  • Pascal Meylan
    • 2
  • Anton Ivanyuk
    • 1
  • Manel Aouri
    • 1
  • Laurent A. Decosterd
    • 1
  • Thierry Buclin
    • 1
  1. 1.Division of Clinical Pharmacology and ToxicologyUniversity Hospital Center and University of LausanneLausanneSwitzerland
  2. 2.Microbiology InstituteUniversity Hospital Center and University of LausanneLausanneSwitzerland

Personalised recommendations