Oseltamivir in seasonal, avian H5N1 and pandemic 2009 AH1N1 influenza: Pharmacokinetic and pharmacodynamic characteristics

Clinical Pharmacokinetics

Volumn 49, Issue 11, 2010, Pages 741-765

  Widmer, Nicolas ^a   Meylan, Pascal ^a   Ivanyuk, Anton ^a   Aouri, Manel ^a   Decosterd, Laurent A ^a   Buclin, Thierry ^a  

^a LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

Author keywords

Antivirals, pharmacodynamics; Antivirals, pharmacokinetics; Drug monitoring; Influenza A virus H1N1 subtype; Influenza A virus H5N1 subtype; Influenza virus infections; Neuraminidase inhibitors, pharmacodynamics; Neuraminidase inhibitors, pharmacokinetics; Oseltamivir, pharmacodynamics; Oseltamivir, pharmacokinetics

Indexed keywords

4 ACETAMIDO 5 AMINO 3 (1 ETHYLPROPOXY) 1 CYCLOHEXENE 1 CARBOXYLIC ACID; A 315675; ACETYLSALICYLIC ACID; AMANTADINE; ANTACID AGENT; ANTICOAGULANT AGENT; ANTIRETROVIRUS AGENT; CLOPIDOGREL; CYCLOSPORIN; LANINAMAVIR; METHOTREXATE; NONSTEROID ANTIINFLAMMATORY AGENT; OSELTAMIVIR; PERAMIVIR; PLACEBO; PROBENECID; RITONAVIR; SIALIDASE INHIBITOR; UNCLASSIFIED DRUG; WARFARIN; ZANAMIVIR;

ABDOMINAL PAIN; ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; AVIAN INFLUENZA; BEHAVIOR CHANGE; BLEEDING; BLOOD TOXICITY; BODY WEIGHT; BREAST FEEDING; CHILDHOOD DISEASE; CLINICAL TRIAL; CONVULSION; DELIRIUM; DEPRESSION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG SOLUBILITY; DRUG SURVEILLANCE PROGRAM; ENCEPHALITIS; FOOD DRUG INTERACTION; GASTROINTESTINAL TOXICITY; GLOMERULUS FILTRATION RATE; HEART RATE; HEMODIALYSIS; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE DEFICIENCY; IN VITRO STUDY; INFLUENZA A (H1N1); INFLUENZA A (H5N1); KIDNEY FUNCTION; LUNG TOXICITY; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NAUSEA; NONHUMAN; OBESITY; PANDEMIC INFLUENZA; PATIENT COMPLIANCE; PHARMACODYNAMICS; PHARMACOKINETICS; PREGNANT WOMAN; PRIORITY JOURNAL; QT PROLONGATION; REVIEW; SIDE EFFECT; SUDDEN DEATH; SUICIDAL IDEATION; THROMBOCYTOPENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; TOXIC EPIDERMAL NECROLYSIS; VOMITING;

ANTIVIRAL AGENTS; AREA UNDER CURVE; DISEASE OUTBREAKS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG MONITORING; HUMANS; INFLUENZA A VIRUS, H1N1 SUBTYPE; INFLUENZA A VIRUS, H5N1 SUBTYPE; INFLUENZA VACCINES; INFLUENZA, HUMAN; OSELTAMIVIR; PANDEMICS; PRODRUGS; UNITED STATES;

EID: 77957711113     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11534730-000000000-00000     Document Type: Review

References (186)

1. Zarocostas J. World Health Organization declares A (H1N1) influenza pan-demic. BMJ 2009 Jun 12; 338: b2425
2. Kmietowicz Z. WHO declares that H1N1 pandemic is officially over. BMJ 2010 Aug 11; 341: c4393
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]
4. Update: drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009. MMWR Morb Mortal Wkly Rep 2009 May 1; 58 (16): 433-5
5. Elliott M. Zanamivir: from drug design to the clinic. Philos Trans R Soc Lond B Biol Sci 2001 Dec 29; 356 (1416): 1885-93
6. Ruf BR, Szucs T. Reducing the burden of influenza-associated complications with antiviral therapy. Infection 2009 Jun; 37 (3): 186-96
7. von Itzstein M, Wu WY, Kok GB, et al. Rational design of potent sialidase-based inhibitors ofinfluenza virus replication. Nature 1993 Jun3; 363 (6428): 418-23
8. McNicholl IR, McNicholl JJ. Neuraminidase inhibitors: zanamivir and osel-tamivir. Ann Pharmacother 2001 Jan; 35 (1): 57-70
9. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005 Sep 29; 353 (13): 1363-73
10. Zhang H, Chen L. Possible origin of current influenza A H1N1 viruses. Lancet Infect Dis 2009 Aug; 9 (8): 456-7
11. Pinto LH, Lamb RA. The M2 proton channels of influenza A and B viruses. J Biol Chem 2006 Apr 7; 281 (14): 8997-9000
12. Shigeta S. Oseltamivir: a viewpoint by Shiro Shigeta. Drugs 1999 Nov; 58 (5): 861-2
13. Reddy D. Responding to pandemic (H1N1) 2009 influenza: the role of osel-tamivir. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii35-40
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): 1-60
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): D497-503
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): 1309-16
17. H1N1 vaccine for prevention of pandemic influenza. Med Lett Drugs Ther 2009 Oct 5; 51 (1322): 77-8
18. Rayner CR, Chanu P, Gieschke R, et al. Population pharmacokinetics of oseltamivir when coadministered with probenecid. J Clin Pharmacol 2008 Aug; 48 (8): 935-47
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): 1828-35
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): 996-7
21. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug osel-tamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999 Dec; 37 (6): 471-84
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): 399-418
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): 373-88
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): 1835-6
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): 852-7
26. Heinig K, Bucheli F. Sensitive determination of oseltamivir and oseltamivir carboxylate in plasma, urine, cerebrospinal fluid and brain by liquid chro-matography-tandem mass spectrometry. J Chromatogr A 2008 Dec 1; 876 (1): 129-36
27. Bahrami G, Mohammadi B, Kiani A. Determination of oseltamivir car-boxylic acid in human serum bysolid phase extraction and high performance liquid chromatography with UV detection. J Chromatogr A 2008 Mar 15; 864 (1-2): 38-42
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): 3197-9
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): 49-53
30. Massarella JW,He GZ, DorrA, etal. 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): 836-43
31. Abe M, Smith J, Urae A, et al. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann Pharmacother 2006 Oct; 40 (10): 1724-30
32. Snell P, Dave N, Wilson K, et al. Lack of effect of moderate hepatic impair-ment on the pharmacokinetics of oral oseltamivir and its metabolite osel-tamivir carboxylate. Br J Clin Pharmacol 2005 May; 59 (5): 598-601
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): 6660-3
34. Schentag JJ, Hill G, Chu T, et al. Similarity in pharmacokinetics of osel-tamivir and oseltamivir carboxylate in Japanese and Caucasian subjects. J Clin Pharmacol 2007 Jun; 47 (6): 689-96
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): 372-7
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): 3687-93
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): 654-62
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): 539-48
39. Dutkowski R, Smith JR, Davies BE. Safety and pharmacokinetics of osel-tamivir at standard and high dosages. Int J Antimicrob Agents 2010 May; 35 (5): 461-7
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): e1305
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): 1993-5
42. Holodniy M, Penzak SR, Straight TM, et al. Pharmacokinetics and toler-ability of oseltamivir combined with probenecid. Antimicrob Agents Chemo-ther 2008 Sep; 52 (9): 3013-21
43. Wattanagoon Y, Stepniewska K, Lindegardh N, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother 2009 Mar; 53 (3): 945-52
44. Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharm-acokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. Can Med Assoc J 2010 Mar 9; 182 (4): 357-63
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 site-specific delivery capsules. Int J Pharm 2003 May 12; 257 (1-2): 297-9
46. Rigby JW, Scott AK, Hawksworth GM, et al. A comparison of the pharm-acokinetics of atenolol, metoprolol, oxprenolol and propranolol in elderly hypertensive and young healthy subjects. Br J Clin Pharmacol 1985 Oct; 20 (4): 327-31
47. Ogihara T,KanoT,Wagatsuma T, etal. Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos 2009 Aug; 37 (8): 1676-81
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]
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): 264-7
50. Bardsley-Elliot A, Noble S. Oseltamivir. Drugs 1999 Nov; 58 (5): 851-60; discussion 861-2
51. Davies BE. Pharmacokinetics of oseltamivir: an oral antiviral for the treat-ment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii5-10
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): 6-9
53. Ose A, Kusuhara H, Yamatsugu K, et al. P-glycoprotein restricts the pene-tration of oseltamivir across the blood-brain barrier. Drug Metab Dispos 2008 Feb; 36 (2): 427-34
54. Eisenberg EJ, Bidgood A, Cundy KC. Penetration of GS4071, a novel in-fluenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104. Antimicrob Agents Chemother 1997 Sep; 41 (9): 1949-52
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): 640-6
56. Woods JM, Bethell RC, Coates JA, et al. 4-Guanidino-2,4-dideoxy-2,3-de- hydro-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): 1473-9
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): 1974-6
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): 13-9
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 phos-phate (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): 315-21
60. El-Sheikh AA, Masereeuw R, Russel FG. Mechanisms of renal anionic drug transport. Eur J Pharmacol 2008 May 13; 585 (2-3): 245-55
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): 229-36
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): 411-5
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): 238-47
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): e10938
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)
66. European Medicines Agency [EMA]. CHMP assessment report on novel in-fluenza (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. 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. Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010 Aug 15; 202 (4): 563-6
69. Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase in-hibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. Can Med Assoc J 2009 Jul 7; 181 (1-2): 55-8
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): 631-42
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): 1925-34
72. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancyinthe USA. Lancet 2009 Aug8; 374 (9688): 451-8
73. Worley KC, Roberts SW, Bawdon RE. The metabolism and transplacental transfer of oseltamivir in the ex vivo human model. Infect Dis Obstet Gy-necol 2008; 2008: 927574
74. University of Pittsburgh. A study of the pharmacology of oseltamivir (Ta-miflu) 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. Wentges-van Holthe N, van Eijkeren M, van der Laan JW. Oseltamivir and breastfeeding. Int J Infect Dis 2008 Jul; 12 (4): 451
76. Cropp CD, Yee SW, Giacomini KM. Genetic variation in drug transporters in ethnic populations. Clin Pharmacol Ther 2008 Sep; 84 (3): 412-6
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): 2556-62
78. Karie S, Launay-Vacher V, Janus N, et al. Pharmacokinetics and dosage adjustment of oseltamivir and zanamivir in patients with renal failure. Ne-phrol Dial Transplant 2006 Dec; 21 (12): 3606-8
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): 1193-211
80. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002 Feb; 39 (2 Suppl. 1): S1-266
81. Gruber PC, Gomersall CD, Joynt GM. Avian influenza (H5N1): implications for intensive care. Intensive Care Med 2006 Jun; 32 (6): 823-9
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): 1427-8
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): 95-7
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): 493-504
85. IWK Health Centre. Oseltamivir pharmacokinetics in morbid obesity (OP-TIMO) [ClinicalTrials.gov identifier NCT01002729]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinical trials.gov/[Accessed 2010 Aug 12]
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): 1477-84
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 424-5
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): 1039-42
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): 5-36
90. Herxheimer A, Clarke M, EdwardsR, et al. A/H1N1 flu: time for case-control studies of NSAIDs and oseltamivir. BMJ 2009 Jul 28; 339: b3048
91. Starko KM. Salicylates and pandemic influenza mortality, 1918-1919 phar-macology, pathology, and historic evidence. Clin Infect Dis 2009 Nov 1; 49 (9): 1405-10
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, DC
93. Khazeni N, Bravata DM, Holty JE, et al. Systematic review: safety and effi-cacy of extended-duration antiviral chemoprophylaxis against pandemic and seasonal influenza. Ann Intern Med 2009 Oct 6; 151 (7): 464-73
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): e3410
95. Parker RM, Wolf MS, Jacobson KL, et al. Risk of confusion in dosing Ta-miflu oral suspension inchildren. N Engl J Med 2009 Nov 5; 361 (19): 1912-3
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): 19287
97. Yoshimura M, Kimura T, Ishii M, et al. Functional polymorphisms in car-boxylesterase1A2 (CES1A2) gene involves specific protein 1 (Sp1) binding sites. Biochem Biophys Res Commun 2008 May 9; 369 (3): 939-42
98. Fujita T, Brown C, Carlson EJ,et al. Functional analysisof polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet Geno-mics 2005 Apr; 15 (4): 201-9
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): 102-6
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): 215-25
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): 1625-34
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): e986
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): A285-6
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): 103-7
105. Tillett T. A measure of resistance: detecting tamiflu metabolite in sewage discharge and river water. Environ Health Perspect 2010 Jan; 118 (1): A34
106. Hilleman MR. Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine 2002 Aug 19; 20 (25-26): 3068-87
107. Wagner R, Feldmann A, Wolff T, et al. Hemagglutinin and neuraminidase as determinants of influenza virus pathogenicity. Int Congr Ser 2001 Oct; 1219: 533-43
108. Schirmer P, Holodniy M. Oseltamivir for treatment and prophylaxis of in-fluenza infection. Expert Opin Drug Saf 2009 May; 8 (3): 357-71
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\USA 2007 May 1; 104 (18): 7711-6
110. Potter CW. A history of influenza. J Appl Microbiol 2001 Oct; 91 (4): 572-9
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: i5-21
112. Poland GA, Jacobson RM, Ovsyannikova IG. Influenza virus resistance to anti-viral agents: a plea for rational use. Clin Infect Dis 2009 May 1; 48 (9): 1254-6
113. Von Itzstein M. The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 2007 Dec; 6 (12): 967-74
114. Varghese JN, Laver WG, Colman PM. Structure of the influenza virus gly-coprotein antigen neuraminidase at 2.9 A resolution. Nature 1983 May 5-11; 303 (5912): 35-40
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): 41-4
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): 681-90
117. Nguyen-Van-Tam JS. Foreword: oseltamivir for seasonal, avian and pan-demic influenza: 10 years of clinical experience. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii3-4
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): 123-9
119. Sidwell RW, Smee DF. Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza. Expert Opin Investig Drugs 2002 Jun; 11 (6): 859-69
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. Birnkrant D, Cox E. The emergency use authorization of peramivir for treat-ment of 2009 H1N1 influenza. N Engl J Med 2009 Dec 3; 361 (23): 2204-7
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): 186-92
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): 163-6
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): 107-20
125. Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intra-venous zanamivir. Lancet 2009 Sep 19; 374 (9694): 1036
126. Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med 2010 Jan 7; 362 (1): 88-9
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): 1249-51
128. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase in-hibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA 1999 Oct 6; 282 (13): 1240-6
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): 1025-31
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): 748-54
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): 440-9
132. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neura-minidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999 Oct 28; 341 (18): 1336-43
133. Dutkowski R. Oseltamivir in seasonal influenza: cumulative experience in low-and high-risk patients. J Antimicrob Chemother 2010 Apr; 65 (Suppl. 2): ii11-24
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): 21-31
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): 3403-8
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): 537-45
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): CD001265
138. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-ana-lysis. BMJ 2009 Dec 8; 339: b5106
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): 469-80
140. Smith J. Point-by-point response from Roche to BMJ questions. BMJ 2009 Dec 8; 339: b5374
141. Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir? BMJ 2009 Dec 8; 339: b5351
142. Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003 Jul 28; 163 (14): 1667-72
143. Fleming DM, Elliot AJ, MeijerA,etal. Influenza virus resistancetooseltamivir: what are the implications? Eur J Public Health 2009 Jun; 19 (3): 238-9
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): 101-15
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): 2723-32
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): 1414-24
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, DC
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): 1221-4
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): 1935-44
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): 2264-72
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): 8026
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): 552-60
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]
154. Weinstock DM, Zuccotti G. The evolution of influenza resistance and treat-ment. JAMA 2009 Mar 11; 301 (10): 1066-9
155. Stephenson I, Democratis J, Lackenby A, et al. Neuraminidase inhibitor re-sistance after oseltamivir treatment of acute influenza A and B in children. Clin Infect Dis 2009 Feb 15; 48 (4): 389-96
156. Ferraris O, Lina B. Mutations of neuraminidase implicated in neuraminidase inhibitors resistance. J Clin Virol 2008 Jan; 41 (1): 13-9
157. White NJ, Webster RG, Govorkova EA, etal. What isthe optimal therapy for patients with H5N1 influenza? PLoS Medicine 2009 Jun 23; 6 (6): e1000091
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): 2667-72
159. Smith JR. Oseltamivir in human avian influenza infection. J Antimicrob Chemother 2010 Apr; 65 Suppl. 2: ii25-33
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): 969-72
161. Baz M, Abed Y, Papenburg J, et al. Emergence of oseltamivir-resistant pan-demic H1N1 virus during prophylaxis. N Engl J Med 2009 Dec 3; 361 (23): 2296-7
162. Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec 2009 Oct 30; 84 (44): 453-9
163. Dutkowski R, Thakrar B, Froehlich E, et al. Safety and pharmacology of oseltamivir in clinical use. Drug Saf 2003; 26 (11): 787-801
164. Strong M, Burrows J, Redgrave P. A/H1N1 pandemic. Oseltamivir's adverse events. BMJ 2009 Aug 11; 339: b3249
165. Fuyuno I. Tamiflu side effects come under scrutiny. Nature 2007 Mar 22; 446 (7134): 358-9
166. Maxwell SR. Tamiflu and neuropsychiatric disturbance in adolescents. BMJ 2007 Jun 16; 334 (7606): 1232-3
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): 911-7
168. Long M. Side effects of Tamiflu: clues from an Asian single nucleotide
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): 357-62
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): 6-10
171. OkamotoS,KamiyaI, KishidaK, etal. Experience with oseltamivir for infants younger than 1 year old in Japan. Pediatr Infect Dis J 2005 Jun; 24 (6): 575-6
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): 1097-114
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): 647-8
174. Enger C, Nordstrom BL, Thakrar B, et al. Health outcomes among patients receiving oseltamivir. Pharmacoepidemiol Drug Saf 2004 Apr; 13 (4): 227-37
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): 108-15
176. Lewis JA. Post-marketing surveillance: how many patients? Trends Phar-macol Sci 1981; 2: 93-4
177. Oseltamivir: cutaneous and neurological adverse effects in children. Prescrire Int 2006 Oct; 15 (85): 182-3
178. Raisch DW, Straight TM, Holodniy M. Thrombocytopenia from combina-tion treatment with oseltamivir and probenecid: case report, MedWatch data summary, and review of the literature. Pharmacotherapy 2009 Aug; 29 (8): 988-92
179. McSharry JJ, Weng Q, Brown A, et al. Prediction of the pharmacodynami-cally linked variable ofoseltamivir carboxylate for influenzaA virus using an in vitro hollow-fiber infection model system. Antimicrob Agents Chemother 2009 Jun; 53 (6): 2375-81
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 Che-mother 2001 Jul; 45 (7): 2115-8
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): 3393-9
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): 265-79
183. Eisenberg EJ, Cundy KC. High-performance liquid chromatographic de-termination of GS4071, a potent inhibitor of influenza neuraminidase, in plasma by precolumn fluorescence derivatization with naphthalenedialde-hyde. J Chromatogr B Biomed Sci App 1998 Sep 25; 716 (1-2): 267-73
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): 74-83
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): 25S
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): 262-8