535362
research-article2014
AOPXXX10.1177/1060028014535362Annals of PharmacotherapyFlannery and Bastin
Article
Oseltamivir Dosing in Critically Ill Patients With Severe Influenza
Annals of Pharmacotherapy 1–8 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014535362 aop.sagepub.com
Alexander H. Flannery, PharmD, BCPS1,2, and Melissa L. Thompson Bastin, PharmD, BCPS1,2
Abstract Objective: To evaluate the literature for published reports regarding the efficacy of standard versus higher dosing of oseltamivir in critically ill patients with severe influenza. Data Sources: An English-language literature search was conducted using MEDLINE (1966-February 2014) using the terms oseltamivir and influenza limited to humans and adults older than 19 years. Additional articles were identified through a manual search of the references obtained from the MEDLINE search. Study Selection and Data Extraction: Articles were manually screened for inclusion related to pharmacokinetic or clinical studies comparing varying doses of oseltamivir, particularly in the critically ill patient population. Studies investigating the pharmacokinetics of oseltamivir in continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) were also included. Data Synthesis: During the 2009 H1N1 influenza pandemic, the World Health Organization suggested 150 mg twice daily as a consideration in critically ill patients with severe influenza. The basis for the recommendation can be traced back to animal studies investigating the H5N1 virus. Three different studies in humans investigating higher doses in severe influenza have found no differences in clinical outcomes between standard and higher dosing. Pharmacokinetic studies suggest adequate absorption in critically ill patients. Although no dosage adjustment appears to be needed for ECMO patients, reduction may berequired for CRRT.. Conclusions:. Although additional data are needed for a definitive conclusion, the small body of literature available in humans does not support routine use of high-dose oseltamivir in critically ill patients.
Keywords oseltamivir, influenza, dosage, critical care
Question What is the optimal dose of oseltamivir for critically ill patients presenting with severe influenza?
Background In the years following the 2009 novel influenza A(H1N1) pandemic, there has been considerable interest in the efficacy, timing, and dosing of antiviral agents, specifically the neuraminidase inhibitors. The 2009 pandemic gave rise to the novel influenza A(H1N1) pdm09 virus. This replaced the seasonal influenza A(H1N1) virus, traditionally resistant to neuraminidase inhibitors, with a more susceptible subtype.1 Despite the lack of strong evidence to support the recommendation, the severity of the influenza pandemic of 2009 prompted the World Health Organization (WHO) to advise that use of higher doses of oseltamivir (150 mg twice daily) and longer treatment regimens (greater than 5 days) should be considered when treating severe or progressive illness.1 The majority of influenza cases in recent years
have been a result of influenza A (92%), of which (H1N1) pdm09 is the most prominent (>75%), making the 2009 pandemic influenza A(H1N1)pdm09 still the most commonly isolated strain.2 Oseltamivir phosphate (Tamiflu) is the only orally administered neuraminidase inhibitor for treatment of influenza infection. It is formulated as a lipophilic pro-drug, which undergoes ester hydrolysis by the liver, converting the parent drug to a highly hydrophilic active form—oseltamivir carboxylate. Oseltamivir phosphate is readily absorbed, and approximately 75% of each oral dose is converted to the active form.3 The therapeutic range of oseltamivir carboxylate required to inhibit neuraminidase-mediated viral replication has not been fully elucidated in human 1
University of Kentucky HealthCare, Lexington, KY, USA University of Kentucky College of Pharmacy, Lexington, KY, USA
2
Corresponding Author: Alexander H. Flannery, University of Kentucky HealthCare, 800 Rose Street, H110, Lexington, KY 40536, USA. Email: [email protected]
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studies. In vitro, the 50% maximal inhibitory concentration (IC50) for oseltamivir carboxylate has been reported to range from 0.090 µg/L to 0.186 µg/L for the influenza A(H1N1)pdm09 virus. In 2011, the WHO devised a working group to standardize laboratory assay testing of influenza virus susceptibility to neuraminidase inhibitors.4 Prior to this initiative, differences in testing modalities and assays prevented a standardized approach to susceptibility testing. Although the influenza A(H1N1)pdm09 is considered highly susceptible to oseltamivir, there have been reports of reduced inhibition of viral replication. Of the 449 isolates tested by the WHO working group, the median IC50 for influenza A(H1N1)pdm09 was 0.18 µg/L, noted as highly susceptible, with 1.8% of the isolates demonstrating reduced susceptibility to oseltamivir.4
Literature Review An English-language literature search was conducted using MEDLINE (1966-February 2014) using the terms oseltamivir and influenza limited to humans and adults older than 19 years. Article titles and abstracts were manually screened for inclusion related to pharmacokinetic or clinical studies comparing different doses of oseltamivir, particularly in the critically ill patient population. Additional articles were identified through a manual search of the references obtained from the MEDLINE search.
Animal Data A thorough literature search tracking the origins of higher oseltamivir dosing leads back to 2 animal studies performed by the same research group.5,6 Yen et al5 studied varying doses and durations of oseltamivir prophylaxis in mice inoculated with the avian H5N1 virus. Mice were given placebo, 0.1 mg/kg/d, 1 mg/kg/d, or 10 mg/kg/d for 5 or 8 days, with the first dose given 4 hours prior to inoculation. A dose-dependent survival was observed across the 5- and 8-day treatment groups. The highest survival rate (80%) occurred in the mice (n = 10) receiving 10 mg/kg/d for 8 days (death hazard ratio = 0.04; P < 0.01). The 10-mg/kg/d dosing (n = 10) was associated with the highest survival in the 5-day treatment group as well (death hazard ratio = 0.03; P < 0.01). This dose (10 mg/kg/d) in mice has been reported to achieve comparable plasma concentrations in humans as the 75-mg twice daily regimen.5 An increase in lung virus titers at day 9 was noted in the 5-day treatment group receiving the 1 and 10 mg/kg/d dosing, indicating replication of the residual virus following the 5-day regimen. This fact, coupled with improved survival across all dosing regimens in the 8-day group, led to the suggestion that longer courses of treatment may be necessary.5 The same research group subsequently studied oseltamivir therapy in ferrets exposed to the H5N1 influenza virus.6
In a delayed treatment arm of the experiment, investigators waited 24 hours following inoculation prior to starting treatment with 10 versus 25 mg/kg/d of oseltamivir or placebo. The 10-mg/kg/d dose is reported to be equivalent to the 75-mg twice daily dose in humans. Treatment with the higher dose of oseltamivir resulted in 100% survival as compared with 0% survival in the 10-mg/kg/d and placebo groups. Of note, these data only included 9 test subjects.6 These animal studies were the first suggestion that inoculum of influenza virus may influence the dose of oseltamivir needed to treat, particularly if delayed treatment is sought.
Human Studies In the largest study to date of critically ill patients with (H1N1)pdm09, an analysis of 1859 severe influenza cases in California admitted to an ICU from April 2009 to August 2010, patients who received neuraminidase inhibitors were compared with those who did not. Neuraminidase inhibitor administration in critically ill patients was associated with a survival benefit (75% vs 58%; P < 0.0001). Of patients receiving treatment, 17% (n = 278) received the double dosing of oseltamivir.7 Despite a letter to the editor questioning if the higher dose and/or prolonged treatment was associated with improved outcomes in the data set, that particular analysis has unfortunately not been published.8,9 Recently, the South East Asia Infectious Disease Clinical Research Network conducted a multicenter, double-blind, dose-comparison study of patients with severe influenza.10 Severe influenza was defined as hospital admission plus one of the following predefined clinical characteristics: new infiltrate on chest X ray, tachypnea, dyspnea, or hypoxia. Patients testing positive for H5N1 were also included in the study along with those with severe influenza. A total of 326 patients of all age groups were randomized to either standard dose oseltamivir (75 mg twice daily) or double-dose oseltamivir (150 mg twice daily) or their pediatric equivalents. The primary outcome, virological clearance of the virus as assessed by polymerase chain reaction (PCR) from nasal and throat swabs, was similar between the 2 dosing groups on day 5. Using the higher dose of oseltamivir failed to show improvement in any of the secondary outcomes, including clinical failure, duration of mechanical ventilation, duration of ICU stay, and mortality. Despite a number of post hoc exploratory analyses, the authors were unable to find any significant differences in clinical or virological outcomes between the 2 dosing regimens among a variety of subgroups. This study has a number of considerations that limit its applicability to the drug information question proposed. First, the majority of participants were children (75.5%). Only 18.7% needed admission to the intensive care unit at enrollment, and only 10.4% required mechanical ventilation; thus, only a small proportion of patients can be classified as critically ill.10 Additionally, there was a
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Flannery and Bastin significant delay (median of 5 days) in this study from onset of illness to treatment with oseltamivir, which may further limit the generalizability.10 In a second dose-comparison study published in 2013, investigators in Hong Kong conducted a prospective, openlabel study in adults hospitalized with influenza, comparing standard dose (75 mg twice daily) versus higher dose (150 mg twice daily) in 157 patients.11 Similar to the previous study, no difference in viral RNA negativity or clinical outcomes, including duration of hospitalization, was demonstrated between the 2 dosing regimens. Although the higher dose trended toward significance being associated with faster rate of viral RNA decline for influenza B, this association was not observed with any of the influenza A subtypes. With only 2 patients in the study requiring ICU admission, this study population best represents non–critically ill patients, which limits its applicability to the drug information question at hand.11 Most recently, a dose-comparison study was presented in abstract form at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).12 The ROSII study investigators performed a double-blind, randomized controlled study across 25 Canadian ICUs, randomizing patients to either standard (75 mg twice daily) or triple (225 mg twice daily) therapy. The primary end point was complete viral clearance on the fifth day of therapy among patients with a positive PCR nasal swab or tracheal aspirate. Because of the difficulty in timing a randomized controlled trial during a seasonal pandemic as well as the fact that inclusion criteria included suspected versus confirmed influenza, recruiting enough patients who were H1N1 positive was likely a challenge. Although 59 patients were randomized, only 18 patients were pandemic H1N1 PCR positive on study entry. The study population had a fairly high severity of illness with Acute Physiology and Chronic Health Evaluation II scores of approximately 20 in both groups. Of those treated with triple-dose therapy, 7/9 (78%) cases were PCR negative (nasal and tracheal aspirate testing) on day 5 compared with 1/9 (11%) cases in the standard therapy group. Despite the difference observed in viral clearance, no differences were found in secondary end points, including survival, duration of mechanical ventilation, and Sequential Organ Failure Assessment scores, although the study was not sufficiently powered to do so. The authors claim the study provides a rationale for higher dose therapy “insofar as more rapid clearance of pathogens has been associated with improved clinical outcomes in other infectious syndromes.”12
Characterization of Oseltamivir Carboxylate Levels in Critically Ill Patients Pharmacokinetic studies in healthy volunteers support the excellent absorption and easily obtainable therapeutic levels
of oseltamivir carboxylate; however, numerous concerns exist in the critically ill patient population that may interfere with absorption of medications.3,13 A study of enteric absorption in critically ill patients determined the area under the curve (AUC) of oseltamivir carboxylate at standard doses (75 mg twice daily) far exceeds the IC50 required for viral replication.14 The ability to achieve this pharmacokinetic goal was not affected by the presence of vasopressors or enteral feeding in any of the patients assessed. Although there was a small delay in gastrointestinal absorption after nasogastric or nasojejunal administration, the average oseltamivir carboxylate concentration in this evaluation of critically ill patients exceeded the IC50 by a factor of 2000- to 4000-fold. These authors also found no correlation between trough or AUC values and clinical outcomes, including length of hospital stay and survival, suggesting that levels obtained with standard dosing are already in excess of any pharmacodynamic threshold.14
Safety Despite higher concentrations of oseltamivir and its metabolites, serious adverse effects have not emerged from studies looking at higher doses.10,11 Reported adverse effects with higher doses have been similar to those observed in ambulatory patients and include nausea, vomiting, and dizziness.10,11 Dosages of up to 450 mg twice daily have been studied in healthy volunteers without serious side effects; nausea and vomiting are the most commonly reported side effects associated with higher dose.13 Although higher doses have not appeared harmful to date in the critically ill population, a limited amount of adult patient data are available, and actual safety remains largely unknown at this time.
Dosing Strategies in Altered Organ Function Critically ill patients commonly have impairments in renal function, leading to renal failure, and may be placed on continuous renal replacement therapy (CRRT). Additionally, patients with severe cases of influenza may be supported with extracorporeal membrane oxygenation (ECMO). Because of potential alterations in circuit binding, alterations in volume of distribution, effluent rates, and other factors, optimal dosing of oseltamivir with concurrent CRRT or ECMO therapy must be given consideration. The enteral absorption study previously discussed had 12% of patients on CRRT and recommended a dose of 30 mg daily or 75 mg every 48 hours based on clearance of the oseltamivir carboxylate metabolite during the study.14 However, the mode of CRRT and effluent rates used were not reported, making this recommendation difficult to apply to individual patient cases across different institutions with differing modalities of CRRT. Although scarce, the literature for oseltamivir
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dosing in different modalities of CRRT and ECMO deserves mention. These studies are summarized in Table 1.
Continuous Veno-Venous Hemodialysis In 13 patients receiving 150 mg oseltamivir twice daily and receiving continuous veno-venous hemodialysis (CVVHD) and/or ECMO, the median 12-hour oseltamivir carboxylate concentration was greater than 9000-fold higher than a previously reported IC50 for the 2009 H1N1 influenza pandemic, suggesting that 150 mg twice daily is a supratherapeutic dose for these patients.15 The authors recommended a dose of 75 mg once daily for patients on CVVHD.
Continuous Veno-Venous Hemofiltration In 3 patients treated with oseltamivir 150 mg twice daily receiving continuous veno-venous hemofiltration (CVVH), oseltamivir carboxylate exhibited marked variability.16 The 3 patients had oseltamivir carboxylate concentrations ranging from 1.3 to 9 times and AUCs that were 1.2 to 7 times higher than that of normal, healthy volunteers. Based on the finding that the oseltamivir carboxylate removal was minimal at the ultrafiltration rates used, the authors concluded that a compensatory dose increase is not warranted. Based on the variability and data from 3 individuals, optimal dosing in CVVH cannot be concluded, but as previous studies in CRRT suggest, 150 mg twice daily is likely supratherapeutic in these patients.
Continuous Veno-Venous Hemodiafiltration In 3 patients on ECMO and continuous veno-venous hemodiafiltration (CVVHDF) receiving oseltamivir 150 mg twice daily, the mean Cmax was >7 times higher and the mean AUC >8 times higher than that observed in healthy volunteers.17 Although not recommending a specific dose for patients on CVVHDF, the authors concluded that CVVHDF had little impact on oseltamivir carboxylate concentrations.17 As always, when considering dosing in CRRT, effluent rates, filter types, and other settings may dictate additional dosing considerations on an individual basis.
Extracorporeal Membrane Oxygenation In the largest series evaluating pharmacokinetic parameters of oseltamivir in ECMO, 14 adult patients on 75 mg
oseltamivir twice daily receiving ECMO, with varying degrees of renal function and requirement for CRRT, were studied.18 When compared with pharmacokinetic parameters in ambulatory adults, the ECMO group was found to exhibit a significantly larger volume of distribution of oseltamivir carboxylate (179 vs 26 L). Despite this, and likely as a result of variations in renal function, the mean systemic exposure of oseltamivir carboxylate in patients on 75 mg twice daily on ECMO were in excess of levels obtained in healthy volunteers receiving the same dose. The authors concluded that dosage adjustment for ECMO, particularly if there is any degree of renal insufficiency, is not necessary, despite theoretical concerns of reduced levels secondary to increased volume of distribution and binding to the circuit components.18 Smaller studies prior to publication of this study suggested similar conclusions regarding the lack of dosage adjustment required for ECMO.15,17
Discussion Although higher doses of oseltamivir do not appear to be harmful, based on limited published data, the evidence reviewed above does not support routine use of higher doses of oseltamivir in critically ill patients infected with influenza A(H1N1)pdm09. These data are mostly consistent with previous studies in outpatients demonstrating no significant difference in virological or clinical outcomes between the 2 dosing regimens.19,20 The exception to this of course is the Canadian study presented in abstract form at ICAAC, suggesting more rapid virological clearance at 5 days with triple dose therapy.12 Whereas faster virological clearance of influenza may affect isolation time and resources for an ICU, the relationship between virological clearance and clinical outcomes is less well described, particularly in the critically ill. As evidenced by the review of the literature, oseltamivir levels are highly variable during critical illness and are commonly well in excess of IC50 values. Of all ICU patients, pregnant patients may require higher doses because of their larger volume of distribution. Based on animal data with H5N1, those patients seeking delayed treatment for this specific viral infection may potentially benefit from higher dosing because of its increased virulence relative to H1N1. If severe diarrhea is present, or other gastrointestinal disorder that may affect absorption, consideration may be given to the higher doses. Unfortunately, the question of which patients would benefit from higher doses remains largely expert opinion at the current time. Based on our literature review, there is no evidence that higher oseltamivir dosing in the critically ill affects clinical outcomes. In an era of unpredictable drug shortages and pandemics, the dosing strategy used by institutions during the flu season for hospitalized and critically ill patients, many of whom are treated empirically for influenza, may have far-reaching effects on supply of
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Eyler et al,15 2012 12; *1 patient received ECMO only which is not reviewed here
Mulla et al,18 2013
14
7
Lemaitre et al,17 2012
20
Number of Patients
Product information oseltamivir 2008
Study
CRRT Settings/ Filter
Dose of Oseltamivir Notable PK Findings
Conclusion
(continued)
75 mg twice daily Oseltamivir Pharmacokinetics of oseltamivir and OC in •• Cmax: 65 (26) ng/mL; AUC0-12h: normal healthy volunteers for comparison. 112 (25) ng·h/mL Oseltamivir carboxylate •• Cmax: 348 (18) ng/mL; AUC0: 2719 (20) ng·h/mL 12h Vd in 24 patients 23-26 L; **mean (coefficient of variation) ECMO + Dialysate flow rate: 150mg twice daily Oseltamivir carboxylate ECMO had no effect on OC pharmacokinetics. CVVHDF (3) 1500 mL/h; UF (all) •• Cmax: 4173 (3944-4551) ng/mL High dose (150mg twice daily) is unnecessary •• AUC0-12: 42 730 (39 200-49 flow rate: 1500 for patients on CVVHDF and should be 400) ng h/mL mL/h; Prismaflex reserved for patients with normal renal **mean (range) ST 150 with AN function. One patient in the ECMO group 69ST filter was pregnant and had significantly lower Cmax and AUC concentrations. ECMO alone (4); 150 mg twice Oseltamivir carboxylate CrCl 86 ± 46 daily (2); 75 mg •• Cmax: 1029 (349-1470) ng/mL mL/min twice daily (2) •• AUC0-12: 9000 (2200-14 500) ng h/mL **mean ± SD **mean (range) ECMO only Dose adjustments are unnecessary in ECMO. Not stated 75 mg twice daily Oseltamivir carboxylate (10); ECMO Doses should be reduced in patients •• Cmax: 509 (54-1277) ng/mL •• AUC0-12: 4346 (644-13 660) + CVVH (4); with reduced renal function. All OC ng h/mL CrCl 146 ± 75 concentrations exceeded the IC50 of H1N1 virus. Vd was significantly greater in these Vd: 179 (61-436) L; **median mL/min ECMO patients than ambulatory patients but (range) **mean ± SD comparable to previously measured Vd in critically ill patients. Preoxygenation and postoxygenation filter OC CVVHD only (8) Dialysate flow 150 mg twice Oseltamivir carboxylate rate: 2420 ± 764 daily •• Cmax: 2670 (1710–3580) ng/mL concentrations did not differ, suggesting that •• AUC0-12: 29 500 (17 600-35 drug binding to oxygenator filter in ECMO mL/h; effluent 800) ng h/mL is not a significant source of clearance. For flow rate: 3300 ± **median (interquartile range) the patients who received CVVHD, the mean 919 mL/h; dose: saturation coefficient for oseltamivir was 0.62 30.8 ± 3.57 mL/ ± 0.11 and for oseltamivir carboxylate was kg/h; Prismaflex 0.94 ± 0.11. Thus, the authors concluded machine with that oseltamivir carboxylate is freely dialyzed HF1000 or through the CVVHD membrane. All OC HF1400 filters; concentrations exceeded the IC50 of H1N1. A **mean ± SD dose decrease of 75mg daily may be indicated in patients receiving CVVHD.
Healthy volunteers
Mode of CRRT or ECMO ± CrCl
Table 1. Summary of Pharmacokinetic Studies
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Dose of Oseltamivir Notable PK Findings
Conclusion
Oseltamivir carboxylate •• Cmax: 981 (553-1670) ng/mL •• AUC0-12: 9390 (5000-17 600) ng h/mL **median (interquartile range) •• UF rate Patient 150mg twice daily Oseltamivir carboxylate Oseltamivir carboxylate concentrations directly A: 2750 mL/h correlated to the UF rates on the CVVH •• Patient A: •• Patient B: 2200 setting. Authors concluded that patient C Cmax: 591 ng/mL AUC0-12: 5932 ng h/mL mL/h could have been treated with a reduced dose •• Patient B: •• Patient C: 2000 of oseltamivir and experienced the same Cmax: 1210 ng/mL mL/h virological clearance. AUC0-12:10 951 ng h/mL AN69 •• Patient C: Hemofilter dose: Cmax: 1270 ng/mL 45 mL/kg/h AUC0-12: 34 670 ng h/mL
CRRT Settings/ Filter
Abbreviations: CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; AUC, area under the curve; Vd, volume of distribution; CrCl, creatinine clearance; PK, pharmacokinetic; OC, oseltamivir carboxylate; CVVHDF, continuous veno-venous hemodiafiltration; UF, ultrafiltration; CVVHD, continuous veno-venous hemodialysis; CVVH, continuous veno-venous hemofiltration.
CVVH (3)
3
Taylor et al,16 2008
Mode of CRRT or ECMO ± CrCl ECMO + CVVHD (4)
Number of Patients
Study
Table 1. (continued)
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Flannery and Bastin the medication during difficult times. Additional data and adequately powered studies to detect the impact of higher doses on duration of mechanical ventilation and survival as well as provide additional scrutiny of safety with higher doses in the critically ill are needed to definitively answer this question. The challenge to optimal dosing of oseltamivir lies in a number of factors. First, the response of the virus to oseltamivir may very well depend on the viral characteristics. Different influenza virus strains demonstrate different in vivo susceptibilities to neuraminidase inhibitors.5 The dosecomparison studies in humans discussed previously had a mix of viral strains, including influenza A—A(H3N2), A(H1N1)pdm09, seasonal A(H1N1), and A(H5N1) or avian flu—and B, which differ in their pathogenicity.10,11 For example, H5N1 is associated with higher viral levels and more sustained viral replication than seasonal influenza.21 The wide variability observed in the pharmacokinetics of oseltamivir in the critically ill has led some to propose monitoring levels to optimize area under the concentrationtime curve.22 A case report published has questioned whether the 75 mg twice-daily dose would achieve the oseltamivir carboxylate AUC target in critically ill pregnant patients because of their increased volume of distribution and increased clearance. However, the pharmacokineticpharmacodynamic relationship of oseltamivir in influenza remains poorly understood. Although much of the available data focus on plasma concentrations of oseltamivir carboxylate, the drug levels in the respiratory mucosa and pulmonary parenchyma, where the virus may be actively replicating, remain poorly understood.23 The use of PCR as an outcome measure in many of these trials may be called into question as well. Even if not replicating, PCR will detect viable virus. PCR samples from the lower respiratory tract would be more desirable as an outcome measure as compared with nasal and throat swabs. Whereas microbiological clearance of the pathogen is generally considered to be correlated well with outcome, this issue with regard to clearance of influenza remains inconclusive and widely debated. Proponents of using higher doses have suggested that development of resistance be one rationale for use of higher dosing. Sporadic reports of resistance emerged in 2009 from immunosuppressed patients on prolonged treatment or in those receiving prophylaxis.21 Although the development of resistance involving the H275Y mutation was noted with the seasonal H1N1 virus in the South East Asia study, emergence of oseltamivir resistance in the A(H1N1)pdm09 strain was not documented in either of the 2 largest human studies published to date comparing higher versus lower dosing strategies.10,11 Of note, intravenous zanamivir is currently undergoing phase III studies for adult and adolescent patients hospitalized with influenza.24 In addition to being available intravenously and minimizing the variability of
oral absorption, zanamivir remains stable to many of the mutations resulting in oseltamivir resistance, including H274Y and H275Y.25 One hypothesis supporting the failure of higher doses of oseltamivir to provide benefit is that the inhibition of neuraminidase by oseltamivir may be a saturable process.10 A trial of intravenous peramivir, which has peak active metabolite concentrations well in excess of oseltamivir, showed similar decreases in titers of influenza A when compared with oral oseltamivir.26 The possibility that standard doses of oseltamivir saturate this process may explain why no strong clinical benefit for higher dosing has emerged from the literature. A compromising solution, and one that deserves further investigation, includes the use of a loading dose to reduce the time to reach steady-state drug levels.23 Future trials would benefit from a randomized, dose-blinded design and risk stratification at enrollment.27 Guidance on clinical trials in severe influenza recommend that virological end points be considered as the primary outcome measure while acknowledging that more data are needed to characterize the relationship between virological and clinical outcomes in patients with severe influenza.27 Evidence suggests that administration of neuraminidase inhibitors up to 5 days from symptom onset is associated with a statistically significant survival benefit (P < 0.05 for each day, 0 to 5) in critically ill patients.7 The timing of initiation of oseltamivir treatment in critically ill patients appears far more critical than the actual dose itself.7
Conclusion Based on limited published evidence, higher doses of oseltamivir in the critically ill do not appear to be associated with significant side effects. Although additional data are needed to make a definitive conclusion, the small body of literature available in humans does not support routine use of high-dose oseltamivir in critically ill patients. Limiting the use of higher doses in the critically ill during pandemic seasons in an era of drug shortages may help conserve supply. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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A(H1N1) 2009 and Other Influenza Viruses. Geneva, Switzerland: WHO; 2010. http://www.ncbi.nlm.nih.gov/ books/NBK138515/. Accessed February 27, 2014. 2. World Health Organization. FluNet Summary. Geneva, Switzerland: WHO; 2014. http://www.who.int/influenza/gisrs_laboratory/updates/summaryreport/en/. Accessed February 25, 2014. 3. Tamiflu (oseltamivir) [product information]. Foster City, CA: Roche Pharmaceuticals; 2008. 4. Okomo-Adhiambo M, Nguyen HT, Abd Elal A, Sleeman K, Fry AM, Gubareva LV. Drug susceptibility surveillance of influenza viruses circulating in the United States in 20112012: application of the WHO antiviral working group criteria. Influenza Other Respir Viruses. 2014;8:258-265. 5. Yen HL, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis. 2005;192:665-672. 6. Govorkova EA, Ilyushina NA, Boltz DA, Douglas A, Yilmaz N, Webster RG. Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob Agents Chemother. 2007;51:1414-1424. 7. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis. 2012;55:1198-1204. 8. Kadhiravan T. Did oseltamivir really improve survival in critically ill patients with influenza A (H1N1) pdm09? Clin Infect Dis. 2013;56:1062. 9. Louie J, Yang S, Schechter R. Reply to Kadhiravan. Clin Infect Dis. 2013;56:1063. 10. South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ. 2013;346:f3039. 11. Lee N, Hui DS, Zuo Z, et al. A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza A and B infections. Clin Infect Dis. 2013;57:1511-1519. 12. Kumar A; ROSII Study Investigators. Viral clearance with standard or triple dose oseltamivir therapy in critically ill patients with pandemic (H1N1) 2009 influenza. Paper presented at: 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 10-13, 2013; Denver, CO. 13. Dutkowski R, Smith JR, Davies BE. Safety and pharmacokinetics of oseltamivir at standard and high dosages. Int J Antimicrob Agents. 2010;35:461-467. 14. Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ. 2010;182:357-363. 15. Eyler RF, Heung M, Pleva M, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients
receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharma-cotherapy. 2012;32:1061-1069. 16. 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;3:e3410. 17. Lemaitre F, Luyt CE, Roullet-Renoleau F, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit. 2012;34:171-175. 18. Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. Anaesth Intensive Care. 2013;41:66-73. 19. Nicholson KG, Aoki FY, Osterhaus AD, 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. 20. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000;283: 1016-1024. 21. Bautista E, Chotpitayasunondh T, Gao Z, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010;362:1708-1719. 22. Kromdijk W, Sikma MA, van den Broek MP, Beijnen JH, Huitema AD, de Lange DW. Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique. Intensive Care Med. 2013;39:977-978. 23. Wattanagoon Y, Stepniewska K, Lindegardh N, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009;53:945-952. 24. GlaxoSmithKline. A study of intravenous zanamivir versus oral oseltamivir in adults and adolescents hospitalized with influenza (ZORO). http://www.clinicaltrials.gov/ct2/show/ NCT01231620. Accessed April 28, 2014. 25. Hurt AC, Holien JK, Parker MW, Barr IG. Oseltamivir resistance and the H274Y neuraminidase mutation in seasonal, pandemic and highly pathogenic influenza viruses. Drugs. 2009;69:2523-2531. 26. Ison MG, Hui DS, Clezy K, et al. A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther. 2013;18:651-661. 27. Ison MG, de Jong MD, Gilligan KJ, et al. End points for testing influenza antiviral treatments for patients at high risk of severe and life-threatening disease. J Infect Dis. 2010;201:1654-1662.
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research-article2014
AOPXXX10.1177/1060028014535362Annals of PharmacotherapyFlannery and Bastin
Article
Oseltamivir Dosing in Critically Ill Patients With Severe Influenza
Annals of Pharmacotherapy 1–8 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014535362 aop.sagepub.com
Alexander H. Flannery, PharmD, BCPS1,2, and Melissa L. Thompson Bastin, PharmD, BCPS1,2
Abstract Objective: To evaluate the literature for published reports regarding the efficacy of standard versus higher dosing of oseltamivir in critically ill patients with severe influenza. Data Sources: An English-language literature search was conducted using MEDLINE (1966-February 2014) using the terms oseltamivir and influenza limited to humans and adults older than 19 years. Additional articles were identified through a manual search of the references obtained from the MEDLINE search. Study Selection and Data Extraction: Articles were manually screened for inclusion related to pharmacokinetic or clinical studies comparing varying doses of oseltamivir, particularly in the critically ill patient population. Studies investigating the pharmacokinetics of oseltamivir in continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) were also included. Data Synthesis: During the 2009 H1N1 influenza pandemic, the World Health Organization suggested 150 mg twice daily as a consideration in critically ill patients with severe influenza. The basis for the recommendation can be traced back to animal studies investigating the H5N1 virus. Three different studies in humans investigating higher doses in severe influenza have found no differences in clinical outcomes between standard and higher dosing. Pharmacokinetic studies suggest adequate absorption in critically ill patients. Although no dosage adjustment appears to be needed for ECMO patients, reduction may berequired for CRRT.. Conclusions:. Although additional data are needed for a definitive conclusion, the small body of literature available in humans does not support routine use of high-dose oseltamivir in critically ill patients.
Keywords oseltamivir, influenza, dosage, critical care
Question What is the optimal dose of oseltamivir for critically ill patients presenting with severe influenza?
Background In the years following the 2009 novel influenza A(H1N1) pandemic, there has been considerable interest in the efficacy, timing, and dosing of antiviral agents, specifically the neuraminidase inhibitors. The 2009 pandemic gave rise to the novel influenza A(H1N1) pdm09 virus. This replaced the seasonal influenza A(H1N1) virus, traditionally resistant to neuraminidase inhibitors, with a more susceptible subtype.1 Despite the lack of strong evidence to support the recommendation, the severity of the influenza pandemic of 2009 prompted the World Health Organization (WHO) to advise that use of higher doses of oseltamivir (150 mg twice daily) and longer treatment regimens (greater than 5 days) should be considered when treating severe or progressive illness.1 The majority of influenza cases in recent years
have been a result of influenza A (92%), of which (H1N1) pdm09 is the most prominent (>75%), making the 2009 pandemic influenza A(H1N1)pdm09 still the most commonly isolated strain.2 Oseltamivir phosphate (Tamiflu) is the only orally administered neuraminidase inhibitor for treatment of influenza infection. It is formulated as a lipophilic pro-drug, which undergoes ester hydrolysis by the liver, converting the parent drug to a highly hydrophilic active form—oseltamivir carboxylate. Oseltamivir phosphate is readily absorbed, and approximately 75% of each oral dose is converted to the active form.3 The therapeutic range of oseltamivir carboxylate required to inhibit neuraminidase-mediated viral replication has not been fully elucidated in human 1
University of Kentucky HealthCare, Lexington, KY, USA University of Kentucky College of Pharmacy, Lexington, KY, USA
2
Corresponding Author: Alexander H. Flannery, University of Kentucky HealthCare, 800 Rose Street, H110, Lexington, KY 40536, USA. Email: [email protected]
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studies. In vitro, the 50% maximal inhibitory concentration (IC50) for oseltamivir carboxylate has been reported to range from 0.090 µg/L to 0.186 µg/L for the influenza A(H1N1)pdm09 virus. In 2011, the WHO devised a working group to standardize laboratory assay testing of influenza virus susceptibility to neuraminidase inhibitors.4 Prior to this initiative, differences in testing modalities and assays prevented a standardized approach to susceptibility testing. Although the influenza A(H1N1)pdm09 is considered highly susceptible to oseltamivir, there have been reports of reduced inhibition of viral replication. Of the 449 isolates tested by the WHO working group, the median IC50 for influenza A(H1N1)pdm09 was 0.18 µg/L, noted as highly susceptible, with 1.8% of the isolates demonstrating reduced susceptibility to oseltamivir.4
Literature Review An English-language literature search was conducted using MEDLINE (1966-February 2014) using the terms oseltamivir and influenza limited to humans and adults older than 19 years. Article titles and abstracts were manually screened for inclusion related to pharmacokinetic or clinical studies comparing different doses of oseltamivir, particularly in the critically ill patient population. Additional articles were identified through a manual search of the references obtained from the MEDLINE search.
Animal Data A thorough literature search tracking the origins of higher oseltamivir dosing leads back to 2 animal studies performed by the same research group.5,6 Yen et al5 studied varying doses and durations of oseltamivir prophylaxis in mice inoculated with the avian H5N1 virus. Mice were given placebo, 0.1 mg/kg/d, 1 mg/kg/d, or 10 mg/kg/d for 5 or 8 days, with the first dose given 4 hours prior to inoculation. A dose-dependent survival was observed across the 5- and 8-day treatment groups. The highest survival rate (80%) occurred in the mice (n = 10) receiving 10 mg/kg/d for 8 days (death hazard ratio = 0.04; P < 0.01). The 10-mg/kg/d dosing (n = 10) was associated with the highest survival in the 5-day treatment group as well (death hazard ratio = 0.03; P < 0.01). This dose (10 mg/kg/d) in mice has been reported to achieve comparable plasma concentrations in humans as the 75-mg twice daily regimen.5 An increase in lung virus titers at day 9 was noted in the 5-day treatment group receiving the 1 and 10 mg/kg/d dosing, indicating replication of the residual virus following the 5-day regimen. This fact, coupled with improved survival across all dosing regimens in the 8-day group, led to the suggestion that longer courses of treatment may be necessary.5 The same research group subsequently studied oseltamivir therapy in ferrets exposed to the H5N1 influenza virus.6
In a delayed treatment arm of the experiment, investigators waited 24 hours following inoculation prior to starting treatment with 10 versus 25 mg/kg/d of oseltamivir or placebo. The 10-mg/kg/d dose is reported to be equivalent to the 75-mg twice daily dose in humans. Treatment with the higher dose of oseltamivir resulted in 100% survival as compared with 0% survival in the 10-mg/kg/d and placebo groups. Of note, these data only included 9 test subjects.6 These animal studies were the first suggestion that inoculum of influenza virus may influence the dose of oseltamivir needed to treat, particularly if delayed treatment is sought.
Human Studies In the largest study to date of critically ill patients with (H1N1)pdm09, an analysis of 1859 severe influenza cases in California admitted to an ICU from April 2009 to August 2010, patients who received neuraminidase inhibitors were compared with those who did not. Neuraminidase inhibitor administration in critically ill patients was associated with a survival benefit (75% vs 58%; P < 0.0001). Of patients receiving treatment, 17% (n = 278) received the double dosing of oseltamivir.7 Despite a letter to the editor questioning if the higher dose and/or prolonged treatment was associated with improved outcomes in the data set, that particular analysis has unfortunately not been published.8,9 Recently, the South East Asia Infectious Disease Clinical Research Network conducted a multicenter, double-blind, dose-comparison study of patients with severe influenza.10 Severe influenza was defined as hospital admission plus one of the following predefined clinical characteristics: new infiltrate on chest X ray, tachypnea, dyspnea, or hypoxia. Patients testing positive for H5N1 were also included in the study along with those with severe influenza. A total of 326 patients of all age groups were randomized to either standard dose oseltamivir (75 mg twice daily) or double-dose oseltamivir (150 mg twice daily) or their pediatric equivalents. The primary outcome, virological clearance of the virus as assessed by polymerase chain reaction (PCR) from nasal and throat swabs, was similar between the 2 dosing groups on day 5. Using the higher dose of oseltamivir failed to show improvement in any of the secondary outcomes, including clinical failure, duration of mechanical ventilation, duration of ICU stay, and mortality. Despite a number of post hoc exploratory analyses, the authors were unable to find any significant differences in clinical or virological outcomes between the 2 dosing regimens among a variety of subgroups. This study has a number of considerations that limit its applicability to the drug information question proposed. First, the majority of participants were children (75.5%). Only 18.7% needed admission to the intensive care unit at enrollment, and only 10.4% required mechanical ventilation; thus, only a small proportion of patients can be classified as critically ill.10 Additionally, there was a
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Flannery and Bastin significant delay (median of 5 days) in this study from onset of illness to treatment with oseltamivir, which may further limit the generalizability.10 In a second dose-comparison study published in 2013, investigators in Hong Kong conducted a prospective, openlabel study in adults hospitalized with influenza, comparing standard dose (75 mg twice daily) versus higher dose (150 mg twice daily) in 157 patients.11 Similar to the previous study, no difference in viral RNA negativity or clinical outcomes, including duration of hospitalization, was demonstrated between the 2 dosing regimens. Although the higher dose trended toward significance being associated with faster rate of viral RNA decline for influenza B, this association was not observed with any of the influenza A subtypes. With only 2 patients in the study requiring ICU admission, this study population best represents non–critically ill patients, which limits its applicability to the drug information question at hand.11 Most recently, a dose-comparison study was presented in abstract form at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).12 The ROSII study investigators performed a double-blind, randomized controlled study across 25 Canadian ICUs, randomizing patients to either standard (75 mg twice daily) or triple (225 mg twice daily) therapy. The primary end point was complete viral clearance on the fifth day of therapy among patients with a positive PCR nasal swab or tracheal aspirate. Because of the difficulty in timing a randomized controlled trial during a seasonal pandemic as well as the fact that inclusion criteria included suspected versus confirmed influenza, recruiting enough patients who were H1N1 positive was likely a challenge. Although 59 patients were randomized, only 18 patients were pandemic H1N1 PCR positive on study entry. The study population had a fairly high severity of illness with Acute Physiology and Chronic Health Evaluation II scores of approximately 20 in both groups. Of those treated with triple-dose therapy, 7/9 (78%) cases were PCR negative (nasal and tracheal aspirate testing) on day 5 compared with 1/9 (11%) cases in the standard therapy group. Despite the difference observed in viral clearance, no differences were found in secondary end points, including survival, duration of mechanical ventilation, and Sequential Organ Failure Assessment scores, although the study was not sufficiently powered to do so. The authors claim the study provides a rationale for higher dose therapy “insofar as more rapid clearance of pathogens has been associated with improved clinical outcomes in other infectious syndromes.”12
Characterization of Oseltamivir Carboxylate Levels in Critically Ill Patients Pharmacokinetic studies in healthy volunteers support the excellent absorption and easily obtainable therapeutic levels
of oseltamivir carboxylate; however, numerous concerns exist in the critically ill patient population that may interfere with absorption of medications.3,13 A study of enteric absorption in critically ill patients determined the area under the curve (AUC) of oseltamivir carboxylate at standard doses (75 mg twice daily) far exceeds the IC50 required for viral replication.14 The ability to achieve this pharmacokinetic goal was not affected by the presence of vasopressors or enteral feeding in any of the patients assessed. Although there was a small delay in gastrointestinal absorption after nasogastric or nasojejunal administration, the average oseltamivir carboxylate concentration in this evaluation of critically ill patients exceeded the IC50 by a factor of 2000- to 4000-fold. These authors also found no correlation between trough or AUC values and clinical outcomes, including length of hospital stay and survival, suggesting that levels obtained with standard dosing are already in excess of any pharmacodynamic threshold.14
Safety Despite higher concentrations of oseltamivir and its metabolites, serious adverse effects have not emerged from studies looking at higher doses.10,11 Reported adverse effects with higher doses have been similar to those observed in ambulatory patients and include nausea, vomiting, and dizziness.10,11 Dosages of up to 450 mg twice daily have been studied in healthy volunteers without serious side effects; nausea and vomiting are the most commonly reported side effects associated with higher dose.13 Although higher doses have not appeared harmful to date in the critically ill population, a limited amount of adult patient data are available, and actual safety remains largely unknown at this time.
Dosing Strategies in Altered Organ Function Critically ill patients commonly have impairments in renal function, leading to renal failure, and may be placed on continuous renal replacement therapy (CRRT). Additionally, patients with severe cases of influenza may be supported with extracorporeal membrane oxygenation (ECMO). Because of potential alterations in circuit binding, alterations in volume of distribution, effluent rates, and other factors, optimal dosing of oseltamivir with concurrent CRRT or ECMO therapy must be given consideration. The enteral absorption study previously discussed had 12% of patients on CRRT and recommended a dose of 30 mg daily or 75 mg every 48 hours based on clearance of the oseltamivir carboxylate metabolite during the study.14 However, the mode of CRRT and effluent rates used were not reported, making this recommendation difficult to apply to individual patient cases across different institutions with differing modalities of CRRT. Although scarce, the literature for oseltamivir
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dosing in different modalities of CRRT and ECMO deserves mention. These studies are summarized in Table 1.
Continuous Veno-Venous Hemodialysis In 13 patients receiving 150 mg oseltamivir twice daily and receiving continuous veno-venous hemodialysis (CVVHD) and/or ECMO, the median 12-hour oseltamivir carboxylate concentration was greater than 9000-fold higher than a previously reported IC50 for the 2009 H1N1 influenza pandemic, suggesting that 150 mg twice daily is a supratherapeutic dose for these patients.15 The authors recommended a dose of 75 mg once daily for patients on CVVHD.
Continuous Veno-Venous Hemofiltration In 3 patients treated with oseltamivir 150 mg twice daily receiving continuous veno-venous hemofiltration (CVVH), oseltamivir carboxylate exhibited marked variability.16 The 3 patients had oseltamivir carboxylate concentrations ranging from 1.3 to 9 times and AUCs that were 1.2 to 7 times higher than that of normal, healthy volunteers. Based on the finding that the oseltamivir carboxylate removal was minimal at the ultrafiltration rates used, the authors concluded that a compensatory dose increase is not warranted. Based on the variability and data from 3 individuals, optimal dosing in CVVH cannot be concluded, but as previous studies in CRRT suggest, 150 mg twice daily is likely supratherapeutic in these patients.
Continuous Veno-Venous Hemodiafiltration In 3 patients on ECMO and continuous veno-venous hemodiafiltration (CVVHDF) receiving oseltamivir 150 mg twice daily, the mean Cmax was >7 times higher and the mean AUC >8 times higher than that observed in healthy volunteers.17 Although not recommending a specific dose for patients on CVVHDF, the authors concluded that CVVHDF had little impact on oseltamivir carboxylate concentrations.17 As always, when considering dosing in CRRT, effluent rates, filter types, and other settings may dictate additional dosing considerations on an individual basis.
Extracorporeal Membrane Oxygenation In the largest series evaluating pharmacokinetic parameters of oseltamivir in ECMO, 14 adult patients on 75 mg
oseltamivir twice daily receiving ECMO, with varying degrees of renal function and requirement for CRRT, were studied.18 When compared with pharmacokinetic parameters in ambulatory adults, the ECMO group was found to exhibit a significantly larger volume of distribution of oseltamivir carboxylate (179 vs 26 L). Despite this, and likely as a result of variations in renal function, the mean systemic exposure of oseltamivir carboxylate in patients on 75 mg twice daily on ECMO were in excess of levels obtained in healthy volunteers receiving the same dose. The authors concluded that dosage adjustment for ECMO, particularly if there is any degree of renal insufficiency, is not necessary, despite theoretical concerns of reduced levels secondary to increased volume of distribution and binding to the circuit components.18 Smaller studies prior to publication of this study suggested similar conclusions regarding the lack of dosage adjustment required for ECMO.15,17
Discussion Although higher doses of oseltamivir do not appear to be harmful, based on limited published data, the evidence reviewed above does not support routine use of higher doses of oseltamivir in critically ill patients infected with influenza A(H1N1)pdm09. These data are mostly consistent with previous studies in outpatients demonstrating no significant difference in virological or clinical outcomes between the 2 dosing regimens.19,20 The exception to this of course is the Canadian study presented in abstract form at ICAAC, suggesting more rapid virological clearance at 5 days with triple dose therapy.12 Whereas faster virological clearance of influenza may affect isolation time and resources for an ICU, the relationship between virological clearance and clinical outcomes is less well described, particularly in the critically ill. As evidenced by the review of the literature, oseltamivir levels are highly variable during critical illness and are commonly well in excess of IC50 values. Of all ICU patients, pregnant patients may require higher doses because of their larger volume of distribution. Based on animal data with H5N1, those patients seeking delayed treatment for this specific viral infection may potentially benefit from higher dosing because of its increased virulence relative to H1N1. If severe diarrhea is present, or other gastrointestinal disorder that may affect absorption, consideration may be given to the higher doses. Unfortunately, the question of which patients would benefit from higher doses remains largely expert opinion at the current time. Based on our literature review, there is no evidence that higher oseltamivir dosing in the critically ill affects clinical outcomes. In an era of unpredictable drug shortages and pandemics, the dosing strategy used by institutions during the flu season for hospitalized and critically ill patients, many of whom are treated empirically for influenza, may have far-reaching effects on supply of
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Eyler et al,15 2012 12; *1 patient received ECMO only which is not reviewed here
Mulla et al,18 2013
14
7
Lemaitre et al,17 2012
20
Number of Patients
Product information oseltamivir 2008
Study
CRRT Settings/ Filter
Dose of Oseltamivir Notable PK Findings
Conclusion
(continued)
75 mg twice daily Oseltamivir Pharmacokinetics of oseltamivir and OC in •• Cmax: 65 (26) ng/mL; AUC0-12h: normal healthy volunteers for comparison. 112 (25) ng·h/mL Oseltamivir carboxylate •• Cmax: 348 (18) ng/mL; AUC0: 2719 (20) ng·h/mL 12h Vd in 24 patients 23-26 L; **mean (coefficient of variation) ECMO + Dialysate flow rate: 150mg twice daily Oseltamivir carboxylate ECMO had no effect on OC pharmacokinetics. CVVHDF (3) 1500 mL/h; UF (all) •• Cmax: 4173 (3944-4551) ng/mL High dose (150mg twice daily) is unnecessary •• AUC0-12: 42 730 (39 200-49 flow rate: 1500 for patients on CVVHDF and should be 400) ng h/mL mL/h; Prismaflex reserved for patients with normal renal **mean (range) ST 150 with AN function. One patient in the ECMO group 69ST filter was pregnant and had significantly lower Cmax and AUC concentrations. ECMO alone (4); 150 mg twice Oseltamivir carboxylate CrCl 86 ± 46 daily (2); 75 mg •• Cmax: 1029 (349-1470) ng/mL mL/min twice daily (2) •• AUC0-12: 9000 (2200-14 500) ng h/mL **mean ± SD **mean (range) ECMO only Dose adjustments are unnecessary in ECMO. Not stated 75 mg twice daily Oseltamivir carboxylate (10); ECMO Doses should be reduced in patients •• Cmax: 509 (54-1277) ng/mL •• AUC0-12: 4346 (644-13 660) + CVVH (4); with reduced renal function. All OC ng h/mL CrCl 146 ± 75 concentrations exceeded the IC50 of H1N1 virus. Vd was significantly greater in these Vd: 179 (61-436) L; **median mL/min ECMO patients than ambulatory patients but (range) **mean ± SD comparable to previously measured Vd in critically ill patients. Preoxygenation and postoxygenation filter OC CVVHD only (8) Dialysate flow 150 mg twice Oseltamivir carboxylate rate: 2420 ± 764 daily •• Cmax: 2670 (1710–3580) ng/mL concentrations did not differ, suggesting that •• AUC0-12: 29 500 (17 600-35 drug binding to oxygenator filter in ECMO mL/h; effluent 800) ng h/mL is not a significant source of clearance. For flow rate: 3300 ± **median (interquartile range) the patients who received CVVHD, the mean 919 mL/h; dose: saturation coefficient for oseltamivir was 0.62 30.8 ± 3.57 mL/ ± 0.11 and for oseltamivir carboxylate was kg/h; Prismaflex 0.94 ± 0.11. Thus, the authors concluded machine with that oseltamivir carboxylate is freely dialyzed HF1000 or through the CVVHD membrane. All OC HF1400 filters; concentrations exceeded the IC50 of H1N1. A **mean ± SD dose decrease of 75mg daily may be indicated in patients receiving CVVHD.
Healthy volunteers
Mode of CRRT or ECMO ± CrCl
Table 1. Summary of Pharmacokinetic Studies
6
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Dose of Oseltamivir Notable PK Findings
Conclusion
Oseltamivir carboxylate •• Cmax: 981 (553-1670) ng/mL •• AUC0-12: 9390 (5000-17 600) ng h/mL **median (interquartile range) •• UF rate Patient 150mg twice daily Oseltamivir carboxylate Oseltamivir carboxylate concentrations directly A: 2750 mL/h correlated to the UF rates on the CVVH •• Patient A: •• Patient B: 2200 setting. Authors concluded that patient C Cmax: 591 ng/mL AUC0-12: 5932 ng h/mL mL/h could have been treated with a reduced dose •• Patient B: •• Patient C: 2000 of oseltamivir and experienced the same Cmax: 1210 ng/mL mL/h virological clearance. AUC0-12:10 951 ng h/mL AN69 •• Patient C: Hemofilter dose: Cmax: 1270 ng/mL 45 mL/kg/h AUC0-12: 34 670 ng h/mL
CRRT Settings/ Filter
Abbreviations: CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; AUC, area under the curve; Vd, volume of distribution; CrCl, creatinine clearance; PK, pharmacokinetic; OC, oseltamivir carboxylate; CVVHDF, continuous veno-venous hemodiafiltration; UF, ultrafiltration; CVVHD, continuous veno-venous hemodialysis; CVVH, continuous veno-venous hemofiltration.
CVVH (3)
3
Taylor et al,16 2008
Mode of CRRT or ECMO ± CrCl ECMO + CVVHD (4)
Number of Patients
Study
Table 1. (continued)
7
Flannery and Bastin the medication during difficult times. Additional data and adequately powered studies to detect the impact of higher doses on duration of mechanical ventilation and survival as well as provide additional scrutiny of safety with higher doses in the critically ill are needed to definitively answer this question. The challenge to optimal dosing of oseltamivir lies in a number of factors. First, the response of the virus to oseltamivir may very well depend on the viral characteristics. Different influenza virus strains demonstrate different in vivo susceptibilities to neuraminidase inhibitors.5 The dosecomparison studies in humans discussed previously had a mix of viral strains, including influenza A—A(H3N2), A(H1N1)pdm09, seasonal A(H1N1), and A(H5N1) or avian flu—and B, which differ in their pathogenicity.10,11 For example, H5N1 is associated with higher viral levels and more sustained viral replication than seasonal influenza.21 The wide variability observed in the pharmacokinetics of oseltamivir in the critically ill has led some to propose monitoring levels to optimize area under the concentrationtime curve.22 A case report published has questioned whether the 75 mg twice-daily dose would achieve the oseltamivir carboxylate AUC target in critically ill pregnant patients because of their increased volume of distribution and increased clearance. However, the pharmacokineticpharmacodynamic relationship of oseltamivir in influenza remains poorly understood. Although much of the available data focus on plasma concentrations of oseltamivir carboxylate, the drug levels in the respiratory mucosa and pulmonary parenchyma, where the virus may be actively replicating, remain poorly understood.23 The use of PCR as an outcome measure in many of these trials may be called into question as well. Even if not replicating, PCR will detect viable virus. PCR samples from the lower respiratory tract would be more desirable as an outcome measure as compared with nasal and throat swabs. Whereas microbiological clearance of the pathogen is generally considered to be correlated well with outcome, this issue with regard to clearance of influenza remains inconclusive and widely debated. Proponents of using higher doses have suggested that development of resistance be one rationale for use of higher dosing. Sporadic reports of resistance emerged in 2009 from immunosuppressed patients on prolonged treatment or in those receiving prophylaxis.21 Although the development of resistance involving the H275Y mutation was noted with the seasonal H1N1 virus in the South East Asia study, emergence of oseltamivir resistance in the A(H1N1)pdm09 strain was not documented in either of the 2 largest human studies published to date comparing higher versus lower dosing strategies.10,11 Of note, intravenous zanamivir is currently undergoing phase III studies for adult and adolescent patients hospitalized with influenza.24 In addition to being available intravenously and minimizing the variability of
oral absorption, zanamivir remains stable to many of the mutations resulting in oseltamivir resistance, including H274Y and H275Y.25 One hypothesis supporting the failure of higher doses of oseltamivir to provide benefit is that the inhibition of neuraminidase by oseltamivir may be a saturable process.10 A trial of intravenous peramivir, which has peak active metabolite concentrations well in excess of oseltamivir, showed similar decreases in titers of influenza A when compared with oral oseltamivir.26 The possibility that standard doses of oseltamivir saturate this process may explain why no strong clinical benefit for higher dosing has emerged from the literature. A compromising solution, and one that deserves further investigation, includes the use of a loading dose to reduce the time to reach steady-state drug levels.23 Future trials would benefit from a randomized, dose-blinded design and risk stratification at enrollment.27 Guidance on clinical trials in severe influenza recommend that virological end points be considered as the primary outcome measure while acknowledging that more data are needed to characterize the relationship between virological and clinical outcomes in patients with severe influenza.27 Evidence suggests that administration of neuraminidase inhibitors up to 5 days from symptom onset is associated with a statistically significant survival benefit (P < 0.05 for each day, 0 to 5) in critically ill patients.7 The timing of initiation of oseltamivir treatment in critically ill patients appears far more critical than the actual dose itself.7
Conclusion Based on limited published evidence, higher doses of oseltamivir in the critically ill do not appear to be associated with significant side effects. Although additional data are needed to make a definitive conclusion, the small body of literature available in humans does not support routine use of high-dose oseltamivir in critically ill patients. Limiting the use of higher doses in the critically ill during pandemic seasons in an era of drug shortages may help conserve supply. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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