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NDT Advance Access originally published online on June 24, 2006
Nephrology Dialysis Transplantation 2006 21(9):2556-2562; doi:10.1093/ndt/gfl267
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis

Richard Robson1, Adrian Buttimore2, Kelvin Lynn2, Mike Brewster3 and Penelope Ward3

1 Christchurch Clinical Studies Trust, 2 Department of Nephrology, Christchurch Hospital, Christchurch, New Zealand and 3 Roche Products Ltd, Welwyn Garden City, Hertfordshire, UK

Correspondence and offprint requests to: Richard Robson, Christchurch Clinical Studies Trust, Christchurch, New Zealand. Email: richard.robson{at}cdhb.govt.nz



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Oseltamivir dose reduction is recommended for patients with end-stage renal disease (ESRD). However, dosing recommendations are not available for treatment or prophylaxis of influenza in these patients. This study assessed the pharmacokinetics and tolerability of oseltamivir in ESRD patients undergoing maintenance haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD).

Methods. In this open-label, multiple-dose study, patients received 30 mg oral oseltamivir suspension over 6.5 weeks. This dose was predicted to be suitable for ESRD patients based on a 2-compartment model. HD patients received 9 doses given 1 h after the completion of alternate HD sessions (three times a week). CAPD patients received 6 doses given once weekly after a dialysate exchange. The primary parameters were peak plasma concentration (Cmax) and the area under the curve (AUC) for oseltamivir and oseltamivir carboxylate.

Results. In HD patients, the Cmax for oseltamivir carboxylate after single and repeated dosing were 943 and 1120 ng/ml, respectively. The mean AUC0–42 was 31 600 ng h/ml for days 1–5 and 38 200 ng h/ml for days 38–43. Similarly, in CAPD patients, mean Cmax after the first and sixth doses were 885 and 849 ng/ml, respectively. The mean AUC0–48 values for days 1–6 and days 36–43 were 33 400 and 32 400 ng h/ml, respectively. Oseltamivir was well-tolerated in both the patient groups.

Conclusions. A 30 mg dose of oseltamivir given once weekly in CAPD or after alternate sessions in HD patients provides sufficient exposure to oseltamivir carboxylate to allow safe and effective anti-influenza treatment and prophylaxis.

Keywords: dialysis; dosing recommendations; ESRD; oseltamivir; pharmacokinetics; safety



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Oseltamivir (Tamiflu®) is the prodrug of oseltamivir carboxylate, a potent inhibitor of influenza virus neuraminidase. It is effective and well-tolerated when used for the treatment or prophylaxis of influenza A and B in adults and children alike [1–8] as well as in high-risk populations such as the elderly, who are more susceptible to influenza-associated complications and can experience significant morbidity and mortality [5, 9,10].

Patients with renal dysfunction are also more susceptible to influenza virus infections, and are at an increased risk of complications from influenza [11]. As the excretion of oseltamivir carboxylate is primarily via the kidneys, patients with impaired renal function experience decreased renal clearance and increased systemic exposure to oseltamivir carboxylate as the severity of their renal impairment increases [12]. Thus, oseltamivir dose reduction is recommended [13] for patients with a creatinine clearance (CLcr) between 10 and 30 ml/min [pre-end-stage renal disease (ESRD)]. However, dosing recommendations are not available for either the treatment or prophylaxis of influenza for ESRD patients on maintenance dialysis treatment.

The purpose of this study was to determine a dosing strategy for oseltamivir in patients with ESRD, undergoing dialysis, and to investigate the safety of the proposed dosing regimen.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
This was an open-label, multiple-dose study of the pharmacokinetics and tolerability of oseltamivir oral suspension (30 mg dose) at repeated dosing intervals to ESRD patients on maintenance haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). The study was conducted at a single centre in New Zealand, approved by The Canterbury Ethics Committee and in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice. All patients provided written informed consent.

Patients
Male and female patients with ESRD on CAPD or HD were eligible for this study if they were aged ≥18 years, had a body mass index (BMI) of 18–34 kg/m2 and a stable CLcr of <10 ml/min. Subjects were excluded if they had severe and/or unstable comorbidity, known HIV or hepatitis virus infection, a history of hypersensitivity to oseltamivir or related compounds, a history of drug or alcohol abuse within the previous year, were pregnant or lactating, or were currently participating or had recently participated in another investigational study.

Study design
Rationale for dosage selection
In a previous study, a single oral dose of 75 mg oseltamivir in ESRD patients on HD and CAPD produced plasma levels of oseltamivir carboxylate ~10 times higher than those associated with clinical efficacy [14]. Based on these data, a single dose of 75 mg oseltamivir should deliver effective neuraminidase inhibition adequate for the treatment of influenza illness in ESRD patients who receive routine HD or CAPD. No dose recommendation could be made for prophylaxis of influenza in these patients as repeat dose exposures were not explored. A 2-compartment model was used to predict repeat dose regimens which could be suitable for either treatment or prophylaxis of influenza in these patients. The model predicted that a 30 mg dose given weekly to patients undergoing CAPD, or after alternate HD treatments in patients undergoing HD three times a week, would deliver effective neuraminidase inhibition for the short-term (5 day) treatment of influenza and the prophylaxis of influenza over a 6 week influenza season. These dose regimens were chosen for this study.

As the study was also intended to provide information regarding suitable doses for the prophylaxis of influenza, the total dosing period in both the groups was 6.5 weeks. All HD patients had 19 HD sessions [three times a week (Monday, Wednesday and Friday) for 5 h each] during the 6.5 week study period. HD patients received 30 mg of oseltamivir oral suspension (12 mg/ml) given 1 h after the completion of alternate HD sessions (9 doses in total). The following HD sessions occurred between 42 and 47 h post-dose. CAPD patients also received 30 mg of oseltamivir oral suspension, but on a once a week schedule (Monday), immediately after a dialysate exchange. All CAPD patients received usual CAPD treatment (four exchanges per 24 h) during the 6.5 week study period and received 6 doses in total.

All the patients consumed a standard meal 30 min before each oseltamivir dose. Giving oseltamivir with food has been shown to minimize the frequency of gastrointestinal (GI) adverse effects [15].

Assessments
Pharmacokinetic parameters
The primary study parameters were peak plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) for oseltamivir and oseltamivir carboxylate. Other computed parameters were considered secondary.

The following pharmacokinetic parameters were calculated: Cmax; terminal elimination half-life (t1/2) computed as natural logarithm 2 = 0.693147181/elimination rate constant (Kel); AUC extrapolated to infinity, calculated as AUClast + CLQCT/Kel, where CLQCT is the last measurable concentration; dialysis clearance (CLd); renal clearance (CLr) and oral plasma clearance (CL/F; where F is the bioavailability).

For HD patients, CLd = Qb (Cin–Cout)/Cin; where Cin = dialyser plasma concentration before dialyser from a 5 h arterial sample, Cout = filter plasma concentration after dialyser from 5 h venous sample and Qb = blood flow rate through HD filter. For CAPD patients, CLd = amount of drug recovered in dialysis fluid divided by the AUC during dialysis procedure. CLr was computed as the ratio of the amount of drug excreted over a given time interval to the AUC over the same time interval.

Schedule of assessments
Evaluations were performed at screening (2–28 days prior to the first dose) and post-study (7–14 days after the final pharmacokinetic assessment). Evaluation of vital signs, ECG, laboratory safety tests and pregnancy testing were performed at screening, pre-dose (day 1) and at follow-up.

HD patients
Serial blood sampling for pharmacokinetic analysis was conducted after the first and the 17th HD sessions (days 1 and 38) immediately before dosing, then at 1, 2, 4, 8, 12, 20, 32 and 42 h after dosing. HD patients were hospitalized for the whole of the pharmacokinetic assessment period. Arterial and venous dialyser blood samples were collected during the 2nd and 18th HD sessions at 1, 2, 4 and 5 h after the start of HD. Two additional blood samples were collected 1 and 2 h after the completion of the 2nd and 18th HD sessions (~48 and 49 h post-dose) and one additional blood sample just before the initiation of the 3rd and the 19th HD sessions. Blood samples for urea reduction rate (URR) were collected immediately before and 30 min after the 2nd and 18th HD sessions. Blood samples for the determination of trough oseltamivir carboxylate concentrations were collected within 1 h of the completion of the 5th, 9th and 13th HD sessions but before drug dosing. Urine samples were collected over the following periods: 0–12, 12–24 and 24–42 h after the first dose.

CAPD patients
In CAPD patients, two series of blood samples for pharmacokinetic analysis were collected before and after the 1st and 6th study doses (days 1 and 36) immediately before dosing, then at 1, 2, 4, 8, 12, 24, 48, 72, 120 and 168 h after dosing. In addition, three trough blood samples were collected just before the 3rd, 4th and 5th study doses. Urine samples were collected over the following periods: 0–12, 12–24 and 24–48 h after the first dose. Dialysate bag volumes (by weight) and samples were collected at 0–4, 4–8, 8–12, 12–24, 24–28, 28–32, 32–36 and 36–48 h after the first study dose. The dialysate was changed four times every 24 h.

Sample collection and storage
Venous blood samples for drug assay (4 ml) were collected into monovettes or vacutainers containing ethylenediaminetetraacetic acid (EDTA) as an anticoagulant. Each blood sample was kept frozen after collection. Plasma was separated by centrifugation within 30 min of collection if collected in the unit, and within 90 min if collected at the patient's home. Plasma samples were analysed for oseltamivir and oseltamivir carboxylate by BAS Analytics, Kenilworth, UK.

Urine was collected and stored at ~4°C until the end of the collection interval; the pH and volume of all specimens were measured. Approximately 10 ml of each sample was transferred to polyethylene tubes for analysis. The dialysate bag for CAPD patients was well-shaken before the collection of the dialysate pharmacokinetic samples (10 ml). The syringe was filled and emptied twice with the dialysate from the dialysate bag before drawing up the actual sample for analysis. Plasma, urine and dialysate samples were stored as soon as possible after the collection at ~–20°C until analysis.

Safety assessments
Adverse events were monitored throughout the study period. Vital signs (blood pressure and pulse rate) were monitored pre-dose and 8 h post-dose on the serial sampling days. Venous blood samples (10 ml) were collected for haematology and biochemistry analysis, and urine samples for urinalysis, at screening, pre-dose, after the last pharmacokinetic sample had been taken and at follow-up. Three venous blood samples (5 ml) were collected from HD patients for biochemistry tests within 1 h of completion of the 5th, 9th and 13th HD sessions.

Statistical analyses
Oseltamivir and oseltamivir carboxylate plasma concentrations and computed pharmacokinetic parameters were listed and summarized by treatment regimens (mean, SD, coefficient of variation, geometric means, median, minimum, maximum and number of observations). Individual and mean plasma concentrations were plotted against time. All the patients who received at least one dose of study drug and a safety follow-up were included in the safety analysis.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Patient
A total of 24 patients with ESRD (HD, n = 12; CAPD, n = 12) took part in this study. One patient was switched from HD to CAPD in mid-study at his own request. Thus, his data were only included in the first dose analysis of the HD group (days 1–5) and excluded from the second dose analysis (days 38–43). All screened patients were assigned to and completed treatment, and all of their pharmacokinetic and safety data were analysed. No patients were prematurely withdrawn from the study.

The demographic data and baseline characteristics of the HD and CAPD study populations are shown in Table 1. HD and CAPD groups differed with regard to sex and race.


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  		Table 1. Demographic data and baseline characteristics of HD and CAPD patients

 
Pharmacokinetic results
HD patients
The mean plasma concentration–time profiles for oseltamivir carboxylate on days 1–5 and 38–43 are shown in Figure 1.


Figure 1
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  		Fig. 1. Mean (±SD) plasma concentration–time profile for oseltamivir carboxylate on days 1–5 (A) and 38–43 (B) in HD patients.

 
Mean values of the main pharmacokinetic parameters for oseltamivir and oseltamivir carboxylate in HD patients are summarized in Table 2. The Cmax for oseltamivir was reached within 1–2 h in most patients, and plasma concentration declined rapidly thereafter due to the metabolism to the carboxylate; in most patients, the trough plasma concentrations of oseltamivir occurred at 8 h and concentrations were below the lower quantification limit at 12 h. Peak concentrations of oseltamivir carboxylate are substantially delayed in HD patients following single and repeated dosing [time to Cmax (Tmax) of 29.7 and 29.2 h, respectively]. Plasma concentrations of oseltamivir carboxylate were higher after repeated dosing than after the first dose, as shown by increases in Cmax, AUC and AUClast. HD contributed substantially to the total body clearance; as expected with these type of patients, renal clearance was negligible (Table 2).


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  		Table 2. Mean values (SD) of the main pharmacokinetic variables for oseltamivir and oseltamivir carboxylate in HD patients

 
Plasma concentrations of oseltamivir carboxylate decreased by ~70% (to 171 ng/ml) during the 5 h dialysis session on day 3 (Table 3; Figure 1) but rebounded to 240 ng/ml at 90 h post-dose. Similarly on day 40, oseltamivir carboxylate concentrations decreased by 67% (to 218 ng/ml) but then rebounded to 283 ng/ml at 114 h post-dose. The minimum mean plasma concentrations of oseltamivir carboxylate were 240 ng/ml on day 5 and 283 ng/ml on day 43.


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  		Table 3. Mean plasma concentrations (SD) of oseltamivir carboxylate during the 5 h HD session from 42–47 h for dialyser inflow (‘arterial’) and outflow (‘venous’) on days 3 and 40

 
CAPD patients
The mean plasma concentration–time profiles of oseltamivir carboxylate on days 1–6 and 36–43 are shown in Figure 2.


Figure 2
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  		Fig. 2. Mean (±SD) plasma concentration–time profile for oseltamivir carboxylate on days 1–6 (A) and 36–43 (B) in CAPD patients.

 
Mean values of the main pharmacokinetic parameters for oseltamivir and oseltamivir carboxylate in CAPD patients are summarized in Table 4. The pharmacokinetic profile for oseltamivir carboxylate in CAPD patients was similar to that in HD patients. Following dosing on day 1 and day 36, the Cmax of oseltamivir occurred within 1–2 h in most CAPD patients, followed by a rapid decline because of metabolism to the active moiety. Trough plasma concentrations of oseltamivir occurred at 8 h in most patients and were below the lower quantification limit at 12 h. The mean AUC0–48 of oseltamivir carboxylate on days 1–6 in CAPD patients was similar to the mean AUC0–42 in HD patients (31 600 ng h/ml); doses given on days 36 or 38 produced an AUC0–42 of 38 200 ng h/ml in HD patients compared with an AUC0–48 of 32 400 ng h/ml in CAPD patients. Mean Cmax values in CAPD patients after the first and the sixth doses were similar to those in HD patients. Mean Tmax was achieved earlier in CAPD than in HD patients because of the continuous dialysis. CAPD constituted 32.6% of the total body clearance of oseltamivir carboxylate as CLr was low or negligible in these patients (Table 4). At the time of the last two sample collections at 120 and 168 h, plasma concentrations of oseltamivir carboxylate were 147 and 63 ng/ml, respectively.


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  		Table 4. Mean values (SD) of the main pharmacokinetic variables for oseltamivir and oseltamivir carboxylate in CAPD patients

 
Safety analysis
Oseltamivir was generally well-tolerated in this study, adverse events reported being generally minor. In the HD group, eight of the 12 patients experienced 22 adverse events and in the CAPD group, 10 of 12 patients experienced 39 adverse events. GI events, including nausea and vomiting were reported by 50% (n = 6) of the HD patients and 50% (n = 6) of the CAPD patients. There was a low frequency of GI events occurring on day 1 of dosing (n = 1, HD group). In two patients in the HD group, the adverse events were judged by the investigator to be probably related to treatment (diarrhoea and mouth ulceration) and in four patients, remotely related. In the CAPD group, none of the adverse events were probably related to treatment, one was possibly related and 11 in six patients were remotely related. Serious adverse events occurred in three patients (HD group: n = 1 unstable angina; CAPD group: n = 1 peritonitis, n = 1 coccydynia and pericarditis), none of which were considered to be treatment related and all recovered without sequelae. No deaths or withdrawals due to adverse events were reported. There were no apparent effects of any dosing regimen on the clinical laboratory parameters or vital signs.



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
This study shows that Tamiflu® (30 mg oral suspension), in ESRD patients who are undergoing HD or CAPD, provides an exposure to oseltamivir carboxylate that has been shown to be clinically effective in other patient groups.

Previous treatment studies in subjects with normal renal function showed that oseltamivir dosages of 75 mg twice daily result in oseltamivir carboxylate plasma levels sufficient to inhibit neuraminidase enzyme activity from all the tested influenza virus strains [12]. Other studies have shown that oseltamivir 75 mg, given once daily for prophylaxis, effectively prevents influenza illness [1,5,6,8]. However, exposure to oseltamivir carboxylate increases with decreasing renal function, and dose reduction is recommended for patients with severe renal impairment (CLcr of >10 and ≤30 ml/min). Furthermore, single doses of 75 mg oseltamivir produce a Cmax substantively above that observed in subjects with normal renal function; although these have not been associated with adverse events, the number of subjects studied is small [12].

The pharmacokinetics of oseltamivir carboxylate in HD and CAPD patients observed in the present study differ from those of patients with normal renal function (CLcr of >90 ml/min), given single or repeated doses of 75 mg oseltamivir [16]. Tmax was longer in ESRD patients than in patients with normal renal function (3 h at a steady state) [16], as expected, given the reduced excretory capacity in dialysis patients. Cmax was approximately four times higher in ESRD patients after a single 30 mg dose of oseltamivir than in patients with normal renal function after a single 75 mg dose (225 ng/ml) [16]. Cmax values after repeated dosing in ESRD patients were also higher than in patients with normal renal function (348 ng/ml) [16]. The AUC0–last of oseltamivir carboxylate in HD and CAPD patients after repeated 30 mg doses was approximately three times higher than the AUC0–last at steady state in patients with normal renal function, receiving repeated doses of 75 mg twice daily (21 752 ng h/ml) [16]. In addition, a high degree of inter-individual variability was noted in all the pharmacokinetic parameters of oseltamivir carboxylate taken from both HD and CAPD patients, the variability exceeding that observed in healthy volunteers with normal renal function following oral dosing with oseltamivir [12]. Possible reasons for this disparity include either more variable absorption of the drug or altered protein binding of the drug. However, this needs to be studied further. Nevertheless, the increased pharmacokinetic variability observed will have little clinical impact on these populations. Oseltamivir carboxylate has been shown to be well-tolerated at levels above the extremes of Cmax and AUC observed in the present study [12]. Furthermore, the minimum oseltamivir carboxylate concentrations measured in the present study are still sufficient to inhibit replication of different influenza virus subtypes [17]. Thus, the current dosing regimen in dialysis patients can be considered to be effective and well-tolerated.

Oseltamivir is not currently recommended for use by patients with ESRD (CLcr of ≤10 ml/min) because a suitable dose regimen has not been established [18,19]. As subjects with ESRD are at a particular risk of influenza complications [11], most authorities recommend pre-season vaccination [11,20]. However, in circumstances where vaccination is likely to be ineffective (seasons in which the vaccine is a poor match to the circulating strain) or in the early stage of a pandemic, before vaccination is possible, there may be a need for chemoprophylaxis in this high-risk patient group. Model predictions suggested that 30 mg oseltamivir, given weekly to CAPD patients, or following alternate HD cycles in patients undergoing HD three times a week, would deliver anti-viral drug levels suitable for effective prophylaxis of influenza over a 6 week influenza season [14]. Additionally, the model predicted that the plasma concentrations would be above the minimum inhibitory concentration known to be associated with effective treatment of influenza over the first 5 days of use. In the current study, the regimens employed produced plasma concentrations of oseltamivir carboxylate that were greater than the concentration required for 50% inhibition values (i.e. drug concentration reducing viral activity by 50%) for oseltamivir carboxylate reported for various influenza A and B laboratory and clinical isolates [8,21]. The data from this study, therefore, provide useful information from which to provide guidance for the use of oseltamivir in patients with ESRD receiving CAPD or HD for either the treatment, or prophylaxis, of influenza in situations where vaccination is not effective.

As expected, treatment with oseltamivir over a 6.5 week period did not lead to increases in adverse event rates or abnormal laboratory findings in the ESRD patient population, compared with the data reported from studies in the otherwise healthy patients [18]. The present study was conducted over 6.5 weeks, and intermittent episodes of nausea and vomiting are not unusual even in a healthy population over that time period [1]. Nausea and vomiting have previously been reported to occur more often when oseltamivir was administered in a fasting state and at doses of 200 mg once or twice daily [2]. In the present study, oseltamivir was administered 30 min after a standard meal, and this may account for the low frequency of GI events occurring on day 1. No drug-related serious effects were observed in this study.

The results of the present study suggest that 30 mg oseltamivir in suspension can be given weekly (to CAPD patients) or after alternate HDs (to HD patients), to provide effective treatment for, or prophylaxis against, influenza illness. HD patients should take 30 mg after alternate HD sessions over a 5 day period. For prophylaxis, our results indicate that administration of 30 mg oseltamivir once a week after CAPD and 30 mg after each alternate HD session are well-tolerated when administered over a 6 week period, and further dose reductions need not be made in either of these patient populations. Administration over a 6 week period would normally be sufficient to provide protection for the duration of a local influenza outbreak.

In conclusion, novel dosing regimens of 30 mg oseltamivir, once a week in CAPD or after alternate sessions in patients undergoing HD, provide sufficient exposure to the active metabolite to allow well-tolerated and effective anti-influenza treatment and prophylaxis in patients with ESRD undergoing CAPD or HD. These findings warrant the studies of the efficacy of this dose regimen against influenza in a clinical scenario, such as during an influenza outbreak in a renal unit.



   Acknowledgments
 
The authors would like to thank the dialysis staff, Department of Nephrology, Christchurch Hospital. Editorial assistance was provided by Annete Njue-Doswell. Funding for this study was provided by F. Hoffmann La-Roche Ltd.

Conflict of interest statement. R.R. has received funding from various pharmaceutical companies for attending meetings, advisory work and research. M.B. and P.W. are currently employed by Roche Products Ltd. K.L. and A.B. have no conflict of interest.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Hayden FG, Atmar RL, Schilling M et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999; 341: 1336–1343[Abstract/Free Full Text]
  2. 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; 282: 1240–1246[Abstract/Free Full Text]
  3. Nicholson KG, Aoki FY, Osterhaus A et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 2000; 355: 1845–1850[CrossRef][ISI][Medline]
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  5. Peters PH Jr, 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; 49: 1025–1031[CrossRef][ISI][Medline]
  6. Welliver R, Monto AS, Carewicz O et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001; 285: 748–754[Abstract/Free Full Text]
  7. Whitley RJ, Hayden FG, Reisinger KS et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20: 127–133[ISI][Medline]
  8. 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; 189: 440–449[CrossRef][ISI][Medline]
  9. Barker WH, Borisute H, Cox C. A study of the impact of influenza on the functional status of frail older people. Arch Intern Med 1998; 158: 645–650[Abstract/Free Full Text]
  10. McGeer A. Oseltamivir was safe and effective for prophylaxis of influenza in the frail elderly. ACP J Club 2002; 136: 24[Medline]
  11. ACIP (Advisory Committee on Immunization Practices 2004) May 28. Prevention and control of influenza. MMWR. 53 (RR06): 1–40. Available online at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5306a1.htm
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  13. He G. The pharmacokinetics and tolerability of the oral neuraminidase inhibitor Ro 64-0796 in subjects with renal impairment [poster P0246]. 9th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 21–24 March 1999, Berlin.
  14. Roche (data on file, 2000) Clinical Study Report PP15974. A single oral dose, multi-center study of the PK, safety and tolerability of Oseltamivir/GS4104 in ESRD patients on HD and peritoneal dialysis. Research Report No W–144167.
  15. Aoki FY, Macleod MD, Paggiaro P et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51: 123–129[Abstract/Free Full Text]
  16. Roche (data on file, 1999) Clinical Study Report – Protocol NP15717. Study of the pharmacodynamics and pharmacokinetics of the neuraminidase inhibitor Oseltamivir (GS4104) in the treatment of volunteers experimentally infected with human influenza B virus. Research Report No. W–144105.
  17. Roberts NA, Wiltshire HR, Mendel DB et al. Oseltamivir carboxylate is effective against all subtypes of influenza neuraminidase.ASM Biodefense Research Meeting, 9–12 March 2003, Baltimore, Maryland, USA.
  18. Dutkowski R, Thakrar B, Froehlich E, Suter P, Oo C, Ward P. Safety and pharmacology of oseltamivir in clinical use. Drug Saf 2003; 26: 787–801[CrossRef][ISI][Medline]
  19. Roche TamifluTM (oseltamivir phosphate) capsules and oral suspension product information. Nutley, NJ: Roche Laboratories, Inc., 2004. Available online at: http://www.rocheusa.com/products/tamiflu/pi.pdf
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Received for publication: 30.11.05
Accepted in revised form: 18. 4.06


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