Peramivir for the treatment of influenza

Peramivir (BioCryst Pharmaceuticals) is a novel investigational intravenous neuraminidase inhibitor that exhibits potent antiviral activity against influenza A and B viruses. Peramivir is created by a structure-based drug design and consists of a cyclopentane backbone with a positively charged guanidinyl group and lipophilic side chains. Peramivir was made available in the USA through the Emergency Investigational New Drug regulations and under an Emergency Use Authorization for hospitalized patients with known or suspected influenza during the 2009 H1N1 influenza pandemic. In trials involving ambulatory adult subjects, intravenous peramivir is safe and has a pharmacokinetic profile that supports once-daily dosing. The drug is licensed in Japan and South Korea and is currently undergoing Phase III trials in the USA. Viral resistance mechanisms to peramivir have not been fully delineated and ongoing surveillance is important. Given the serious health threat of influenza at all ages and limitations in vaccine delivery, peramivir is a promising addition to the currently limited treatment options for the treatment of severe influenza infection.     

The emergency use authorization of peramivir IV: a view from the manufacturer

The 2009 H1N1 influenza pandemic prompted the US Food and Drug Administration (FDA) to issue an emergency use authorization (EUA) for the intravenous antiviral peramivir, an unapproved neuraminidase inhibitor (NAI) currently under development. Peramivir use was limited to patients for whom other NAI therapy had failed or in whom oral or inhalational drug absorption was believed to be unreliable. This introduced a patient selection bias that precluded safety and efficacy assessment. Despite the challenges and risks, there was a compelling public health need for an intravenous agent during the 2009 H1N1 pandemic.     

Efficacy, safety, and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza A virus infection

Peramivir is a new neuraminidase inhibitor for intravenous administration that was first introduced in clinical practice in Japan. We conducted a multicenter, open-label, uncontrolled study in children with influenza virus infection ranging in age from ≥28 days to <16 years during the 2009 pandemic A (H1N1) influenza epidemic to evaluate the efficacy, safety, and pharmacokinetics of peramivir in children after intravenous infusion of 10 mg/kg (600 mg maximum) once daily. Among the 106 children (125 days to 15 years old) confirmed to have been infected with the pH1N1 virus by the PCR who were treated with peramivir, the median time to alleviation of symptoms was 29.1 h (95% confidence interval = 22.1 to 32.4), and the proportion of the 106 children who were virus positive was 78.2% on day 2 after the start of treatment and had decreased to 7.1% on day 6. The results of the safety evaluation among 117 patients enrolled in this study showed that adverse events and adverse drug reactions were reported in 62.4 and 29.1%, respectively, of the patients. All of the adverse events and adverse drug reactions resolved or improved rapidly. A population pharmacokinetic analysis was performed on the basis of 297 observed plasma concentration data obtained from 115 children with influenza virus infection. Peramivir exposure in children was within the range of levels within which the efficacy and safety was confirmed in adults, and it is considered that peramivir is clinically and virologically effective and safe in children with pH1N1 virus infection.     

Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir (I): A drug use investigation

Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. We conducted a drug use investigation of peramivir from October 2010 to February 2012 and evaluated its safety and effectiveness under routine clinical settings. We collected data of 1309 patients from 189 facilities across Japan and examined safety in 1174 patients and effectiveness in 1158 patients. In total, 143 adverse events were observed with an incidence rate of 7.33% (86/1174). Of these, 78 events were adverse drug reactions (ADRs) with an incidence rate of 4.34% (51/1174). The most frequently reported ADRs were diarrhea, vomiting, and nausea, with incidence rates of 1.87% (22/1174), 0.85% (10/1174), and 0.68% (8/1174), respectively. Moreover, no ADR was reported as serious. ADR onset was within 3 days after the start of peramivir administration in 91.0% (71 events) of the 78 ADRs, and ADRs were resolved or improved within 7 days after onset in 96.2% (75 events) of the 78 ADRs. Neither patient characteristics nor treatment factors appeared to significantly affect drug safety. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. The present study demonstrates the safety and effectiveness of peramivir under routine clinical settings.     

The role of clinical pharmacology in supporting the emergency use authorization of an unapproved anti-influenza drug, peramivir

On 23 October 2009, the commissioner of the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection, an unapproved neuraminidase inhibitor used for treating certain hospitalized adult and pediatric patients infected with 2009 H1N1 influenza. This was the first EUA of an unapproved drug product. This report summarizes the critical contributions of the clinical pharmacology review team in support of the peramivir EUA.     

Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.     

Prophylactic Activity of Intramuscular Peramivir in Mice Infected with a Recombinant Influenza A/WSN/33 (H1N1) Virus Containing the H274Y Neuraminidase Mutation

Peramivir is a neuraminidase (NA) inhibitor (NAI) under development that must be administered by the systemic route. The prophylactic activity of intramuscular (IM) peramivir was evaluated with mice infected with wild-type (WT) and oseltamivir-resistant (H274Y NA mutant) recombinant influenza A/WSN/33 (H1N1) viruses. Treatment regimens consisted of IM injections starting 1 h before viral challenge that were single (45 mg/kg or 90 mg/kg) or multiple (45 mg/kg daily for 5 days). All peramivir regimens prevented mortality and weight loss while significantly reducing lung viral titers (LVT) in mice infected with the WT virus. For animals infected with the H274Y mutant, the multiple-dose regimen completely prevented mortality and was associated with significant reduction in weight loss and LVT compared to untreated animals. In contrast, both single-treatment regimens reduced mortality and weight loss but did not significantly reduce LVT. Although further experiments using different influenza A/H1N1 virus strains and other animal models are needed, our results suggest that 5-day IM peramivir therapy may be considered a prophylactic alternative to control influenza infections caused by oseltamivir-resistant viruses with the H274Y mutation.Neuraminidase (NA) inhibitors (NAIs) constitute one of the most valuable options for the control of influenza epidemics and pandemics. Two NAIs, inhaled zanamivir and oral oseltamivir, have been approved for the treatment and prevention of influenza infections in many countries (16). In addition, other NAIs are at different stages of development. Peramivir, which is a cyclopentane analogue compound, has shown potent in vitro activity against influenza A and B viruses (4). By the use of NAI assays, we previously demonstrated that peramivir 50% inhibitory concentration (IC₅₀) values for Canadian clinical influenza A/H3N2, A/H1N1, and B viruses were lower than those of zanamivir and oseltamivir (10). In other studies, mean IC₅₀ values of clinical influenza A/H1N1 viruses from untreated individuals against peramivir were also lower than those against oseltamivir and zanamivir (14, 15). Furthermore, on-site dissociation studies demonstrated that peramivir remained tightly bound to the NA enzyme with a half-time for the substrate conversion of >24 h compared to 1.25 h for both zanamivir and oseltamivir (5).In controlled trials of prophylaxis and treatment, oral peramivir was associated with reduced viral titers but no significant decrease in time to relief of symptoms, a feature that could be attributed to a low oral bioavailability in humans (6). The bioavailability of peramivir may be improved by using intravenous (IV) or intramuscular (IM) injections. Indeed, comparison of single IM versus oral peramivir with the same dose (10 mg/kg), administered 4 h prior to a lethal influenza A/WSN/33 (H1N1) virus challenge, demonstrated that the IM route was associated with a higher survival rate in mice than that of the oral route (100% versus 50%) (5). Also, a single IV injection of 3 mg/kg of peramivir provided a significant therapeutic effect that was superior to that of oral oseltamivir in a lethal mouse model of influenza A and B virus infections (18). The emergence and rapid dissemination of the seasonal A/Brisbane/59/2007 (H1N1) virus containing the NA mutation H274Y in N2 numbering (H275Y in N1 numbering), which is associated with a high level of resistance to oseltamivir and moderate cross-resistance to peramivir in vitro (9), are a major clinical concern. The aim of the present study was to evaluate the prophylactic efficacy of IM injections of peramivir in mice infected with a recombinant influenza A/WSN/33 (H1N1) virus containing or not containing the H274Y NA mutation, which has been associated with 427- and 48-fold increases in oseltamivir and peramivir IC₅₀ values, respectively, in NAI assays (1).     

Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment

OBJECTIVE: Oseltamivir is the only oral neuraminidase inhibitor currently available; we determined the tolerability and antiviral efficacy of oral peramivir for treatment and prophylaxis of experimental human influenza A and B. PARTICIPANTS: 288 susceptible, healthy volunteers (ages 18-45) were inoculated intranasally with A/Texas/36/ 91/H1N1 or B/Yamagata/16/88 virus in four randomized, double-blind, placebo-controlled trials. INTERVENTIONS: For treatment dosing was initiated at 24 h after inoculation with peramivir doses ranging from 100-800 mg/day for 5 days. For prophylaxis dosing was initiated 24 h before inoculation and continued for 4 days with peramivir doses ranging from 50-800 mg/day. OUTCOMES: The primary outcome measure for treatment was quantitative viral detection defined by the area under the curve (AUC) for nasal wash viral titres. For prophylaxis the primary outcome measure was the incidence of virus recovery. RESULTS: In influenza A treatment, peramivir 400 mg q24h and 200mg q12h, but not lower doses, resulted in significant reductions in viral titre AUC. In influenza B treatment, both 400 and 800/400 mg once daily dose groups reduced AUC values. In influenza A prophylaxis, the percentage of individuals with nasal viral shedding did not differ significantly in the placebo (58%), 50 mg (61%), 200 mg (37%) and 400 mg (31%) dose groups. In influenza B prophylaxis, shedding frequencies were similar in placebo (55%), 200 mg (41%), 400 mg (35%) and 800 mg (47%) dose groups. The drug was well tolerated in all four studies, with nausea and headache being the most common side effects. No drug-resistant variants were detected. CONCLUSION: Early treatment with peramivir was associated with significant antiviral effects in experimentally induced influenza in humans. Prophylaxis did not significantly reduce viral shedding. The relatively low blood peramivir concentrations observed may explain the lack of more robust antiviral effects, and parenteral dosing should be studied.     

Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection

Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged ≥ 20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of peramivir, 600 mg of peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection.     

Efficacy of single intravenous injection of peramivir against influenza B virus infection in ferrets and cynomolgus macaques

We evaluated the efficacy of a single intravenous dose peramivir for treatment of influenza B virus infection in ferrets and cynomolgus macaques in the present study. A single dose of peramivir (60 mg/kg of body weight) given to ferrets on 1 day postinfection with influenza B virus significantly reduced median area under the curve (AUC) virus titers (peramivir, 8.3 log(10) 50% tissue culture infective doses [TCID(50)s] · day/ml; control, 10.7 log(10) TCID(50)s · day/ml; P < 0.0001). Furthermore, nasal virus titers on day 2 postinfection in ferrets receiving a single injection of peramivir (30 mg/kg) and AUCs of the body temperature increase in ferrets receiving a single injection of peramivir (30 and 60 mg/kg) were lower than those in ferrets administered oral oseltamivir phosphate (30 and 60 mg/kg/day twice daily for 3 days). In macaques infected with influenza B virus, viral titers in the nasal swab fluid on days 2 and 3 postinfection and body temperature after a single injection of peramivir (30 mg/kg) were lower than those after oral administration of oseltamivir phosphate (30 mg/kg/day for 5 days). The two animal models used in the present study demonstrated that inhibition of viral replication at the early time point after infection was critical in reduction of AUCs of virus titers and interleukin-6 production, resulting in amelioration of symptoms. Our results shown in animal models suggest that the early treatment with a single intravenous injection of peramivir is clinically recommended to reduce symptoms effectively in influenza B virus infection.     

Comparative effectiveness of neuraminidase inhibitors in patients with influenza: A systematic review and network meta-analysis

The aim of this study was to use a network meta-analysis (NWA) to evaluate the relative efficacy and safety of various neuraminidase inhibitors (NAIs) in reducing the duration of influenza symptoms, and thereby, informing the selection of suitable therapeutic regimens for patients with influenza. We conducted a systematic review of randomized controlled trials comparing the clinical effects of four NAIs administered to patients with influenza and placebo. Relevant studies were found in the PubMed and Cochrane databases. Unpublished studies were collected from the ClinicalTrials.gov registry and through hand searching. We carried out NWA to compare the different regimens with each other and across subgroups of age and medical status (high-risk patients). A total of 58 two-arm studies were identified. Five regimens were efficacious in reducing the time to alleviation of influenza symptoms in all populations; this efficacy was comparable. No significant improvements were seen in combination therapy groups. The mean difference in the time to alleviation of symptoms ranged from 12.78 to 19.51 h. According to the summarized mean difference and surface under the cumulative ranking curve (SUCRA), peramivir (SUCRA = 82.6%), zanamivir (SUCRA = 64%), and oseltamivir (SUCRA = 55.1%) were the three top-ranking drugs for treating influenza. Zanamivir and peramivir were the preferred pharmacologic intervention among all investigated interventions based on the calculated “value preference of SUCRA.” This study is a network meta-analysis to explore the therapeutic effects of NAIs in patients with influenza. Peramivir might be the best choice for reducing the time to alleviation of symptoms.     

Efficacy of Repeated Intravenous Administration of Peramivir against Highly Pathogenic Avian Influenza A (H5N1) Virus in Cynomolgus Macaques

Highly pathogenic avian influenza A (H5N1) viruses cause severe and often fatal disease in humans. We evaluated the efficacy of repeated intravenous dosing of the neuraminidase inhibitor peramivir against highly pathogenic avian influenza virus A/Vietnam/UT3040/2004 (H5N1) infection in cynomolgus macaques. Repeated dosing of peramivir (30 mg/kg/day once a day for 5 days) starting immediately after infection significantly reduced viral titers in the upper respiratory tract, body weight loss, and cytokine production and resulted in a significant body temperature reduction in infected macaques compared with that of macaques administered a vehicle (P < 0.05). Repeated administration of peramivir starting at 24 h after infection also resulted in a reduction in viral titers and a reduction in the period of virus detection in the upper respiratory tract, although the body temperature change was not statistically significant. The macaque model used in the present study demonstrated that inhibition of viral replication at an early time point after infection by repeated intravenous treatment with peramivir is critical for reduction of the production of cytokines, i.e., interleukin-6 (IL-6), tumor necrosis factor α, gamma interferon, monocyte chemotactic protein 1, and IL-12p40, resulting in amelioration of symptoms caused by highly pathogenic avian influenza virus infection.     

Effectiveness of intravenous peramivir for the treatment of influenza A/H3N2 and influenza B/Victoria in hospitalized children

ObjectiveTo optimize the medication administered to children with influenza, we evaluated the effectiveness of peramivir in hospitalized children with influenza A/H3N2 and influenza B/Victoria.MethodsA retrospective study was conducted from October 2019 to March 2020 in children aged 29 days to 18 years with influenza A/H3N2 or B/Victoria. A total of 97 patients were enrolled and treated with intravenous infusion of peramivir.ResultsThe duration of influenza virus nucleic acid positivity in the influenza A/H3N2 group (3 days) was shorter than that in the influenza B/Victoria group (4 days) (P = 0.008). The remission time of fever symptoms in the influenza A/H3N2 group was 14 h, which was significantly shorter than that in the influenza B/Victoria group (26 h) (P = 0.042). In the 6–18 years age group, the median duration of virus nucleic acid positivity for children with influenza B/Victoria (4 days) was longer than that for children with influenza A/H3N2 (2 days) (P = 0.005). The incidence of adverse drug reactions (ADRs) with peramivir in the influenza A/H3N2 group and the influenza B/Victoria group was 2.04% (n = 1/49) and 4.17% (n = 2/48), respectively (P = 0.617).ConclusionsA difference in the effectiveness of peramivir against different subtypes of influenza was observed. Compared to those infected with influenza B/Victoria, the children infected with influenza A/H3N2 experienced a significantly shorter duration of influenza virus nucleic acid positivity and remission time of fever symptoms.     

Clinical and virologic effects of four neuraminidase inhibitors in influenza A virus-infected children (aged 4–12 years): an open-label,randomized study in Japan

Background: Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670).

Methods: Patients (n = 123) aged 4–12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint.

Results: Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups.

Conclusions: The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation.     

New antiviral agents of influenza

Influenza is a serious health threat for people all over the world and the new and more effective antiviral drugs such as peramivir, laninamivir, and favipiravir have been developed. In this article we review new drugs and drug candidates of newer compounds, which are currently undergoing testing, against influenza with an emphasis on the recent progress of targeting of pathogen replication system, as well as a comprehensive, state-of-the-art picture of drug therapy.     

Assessment of Antiviral Properties of Peramivir against H7N9 Avian Influenza Virus in an Experimental Mouse Model

The H7N9 influenza virus causes a severe form of disease in humans. Neuraminidase inhibitors, including oral oseltamivir and injectable peramivir, are the first choices of antiviral treatment for such cases; however, the clinical efficacy of these drugs is questionable. Animal experimental models are essential for understanding the viral replication kinetics under the selective pressure of antiviral agents. This study demonstrates the antiviral activity of peramivir in a mouse model of H7N9 avian influenza virus infection. The data show that repeated administration of peramivir at 30 mg/kg of body weight successfully eradicated the virus from the respiratory tract and extrapulmonary tissues during the acute response, prevented clinical signs of the disease, including neuropathy, and eventually protected mice against lethal H7N9 influenza virus infection. Early treatment with peramivir was found to be associated with better disease outcomes.     

Grippe et antiviraux

Neuraminidase inhibitors, including oseltamivir and zanamivir are the recommended licensed anti-influenza drugs. However, the emergence in 2007 of oseltamivir-resistant and in 2009 of pandemic A(H1N1) influenza viruses highlighted the need for more efficient antiviral agents for influenza treatment. In this article, we review the advances in knowledge, based on experience from the last pandemic in particular, for patients admitted to the intensive care unit for severe influenza infection. We also focus on undergoing trials evaluating the efficiency of parenteral administration of oseltamivir, zanamivir or peramivir, the associations of antiviral agents, as well as laninamivir, a new long-acting neuraminidase inhibitor. Favipiravir, a polymerase inhibitor and DAS181, a sialidase removing the sialic acids within the host epithelial respiratory tract, are also undergoing clinical trials. In vitro studies showed that small interfering RNAs are able to inhibit the expression of influenza viral RNA and nitazoxide to block the terminal glycosylation of haemagglutinins. To date, new drugs are being actively developed to improve influenza treatment.     

Anti-influenza virus agent

The necessity of newly anti-influenza agents is increasing rapidly after the prevalence of pandemic influenza A (H1N1) 2009. In addition to the existing anti-influenza drugs, novel neuraminidase inhibitors such as peramivir (a first intravenous anti-influenza agent) and laninamivir (long acting inhaled anti-influenza agent) can be available. Moreover favipiravir, which shows a novel anti-influenza mechanism acting as RNA polymerase inhibitor, has been developing. These drugs are expected to improve the prognosis of severe cases caused by not only seasonal influenza but pandemic influenza A (H1N1) 2009 virus and H5N1 avian influenza, and also treat oseltamivir-resistant influenza effectively.     

Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients

Influenza virus infections are known to persist longer in patients with underlying diseases, including respiratory tract diseases, and tend to become complicated by secondary influenza-associated infections, such as pneumonia. To assess the efficacy and safety of the novel anti-influenza virus drug peramivir in high-risk patients, we conducted a clinical trial of patients with diabetes or chronic respiratory tract diseases and patients being treated with drugs that suppress immune function. In this multicenter, uncontrolled, randomized, double-blind study, peramivir was intravenously administered at 300 or 600 mg/day for 1 to 5 days, as needed. Efficacy was investigated in 37 patients (300 mg, n = 18 patients; 600 mg, n = 19 patients). The median durations of influenza illness were 68.6 h (90% confidence interval, 41.5 to 113.4 h) overall, 114.4 h (90% confidence interval, 40.2 to 235.3 h) in the 300-mg group, and 42.3 h (90% confidence interval, 30.0 to 82.7 h) in the 600-mg group. The hazard ratio for the 600-mg group compared to the 300-mg group was 0.497 (90% confidence interval, 0.251 to 0.984), and the duration of influenza illness was significantly shorter in the 600-mg group than in the 300-mg group. Among the 42 patients in the safety analysis set, adverse events occurred in 73.8% and adverse drug reactions in 33.3%. No adverse events were particularly problematic clinically, and all patients recovered quickly from all events. The measured blood drug concentrations showed no tendency toward accumulation. Drug accumulation with repeated doses was thus considered to be of little concern. Intravenous peramivir appears to offer a potentially useful treatment for high-risk patients in the future.