Peramivir injection in the treatment of acute influenza: a review of the literature

Figures & data

Figure 1 Chemical structure of peramivir.

Table 1 PK parameters after a single dose of peramivir

PK parameter	Value in adult with normal renal function
Route	Intravenous
Dose	600 mg
Kinetics	Linear
Protein binding	<30%
Cmax	46,800 ng/mL
AUC0–∞	102,700 ng∙h/mL
Plasma t1/2 elimination in healthy adults	Approximately 20 hours
Vd	12.56 L
Metabolism	Minimal
Excretion	Renal (90%)
Dose adjustment for renal insufficiency	Yes
Dose adjustment for hepatic insufficiency	No

Abbreviations: PK, pharmacokinetic; max, maximum; AUC, area under the curve; V_d, volume of distribution; C_max, maximum serum concentration.

Table 2 In vitro neuraminidase inhibitor activity against influenza A and B viruses

Study	Virus	Duration	N	Oseltamivir IC50 (nM)		Zanamivir IC50 (nM)		Peramivir IC50 (nM)		Laninamivir IC50 (nM)
				Range	Mean±SD	Range	Mean±SD	Range	Mean±SD	Range	Mean±SD
Dapat et al^Citation34	A(H1N1) pdm09	2009–2010	57	1.48–10.91	1.88±0.25	0.49–1.92	0.69±0.09	0.04–0.22	0.07±0.01	0.16–0.49	0.24±0.05
	A(H1N1) pdm09	2010–2011	60	0.72–443.95	1.37±0.31	0.30–1.79	0.63±0.14	0.07–37.09	0.12±0.03	0.20–0.66	0.27±0.05
	A(H3N2)	2010–2011	59	0.46–2.12	0.73±0.20	0.41–2.66	0.63±0.17	0.10–0.33	0.17±0.04	0.30–1.09	0.65±0.15
	B	2010–2011	18	16.97–59.12	27.09±11	29.33–92.3	53.74±17.25	1.22–4.77	2.31±0.88	4.69–15.23	8.44±3.33
Leang et al^Citation35	A(H1N1) pdm09	2009–2012	580	–	–	–	–	–	0.17±0.10	–	0.27±0.05
	A(H3N2)	2009–2012	1,949	–	–	–	–	–	0.18±0.08	–	0.62±0.05
	B	2009–2012	1,231	–	–	–	–	–	0.74±0.33	–	3.26±0.26

Note: Data from previous studies.^34,35

Abbreviations: IC₅₀, half-maximal inhibitory concentration; SD, standard deviation.

Table 3 Clinical efficacy of peramivir: randomized controlled trials of IV or IM peramivir in adults

Study	Location/sponsor/trial ID	Design	Population/sample size	Regimen	Results
Ambulatory patients with acute uncomplicated influenza (normal hosts)
BiocrystNCT0419263^Citation45	US/Canada/Biocryst	Phase II, randomized, double-blind, placebo- controlled, multicenter	Adults with positive rapid antigen test for influenza	Peramivir 150 mg, 300 mg, or placebo as IM single dose <48 hours of symptom onset	Completed (n=344) No statistically significant differences between treatment groups for time to alleviation of symptoms (primary endpoint) Improvement over placebo was 22.9 hours with 150 mg dose (P=0.284) and 21.1 hours with the 300 mg dose (P=0.152)
Atiee et al^Citation46	US, Australia, New Zealand, South Africa/Biocryst	Phase II, randomized, double-blind, placebo- controlled, multicenter	Adults with positive influenza A or B (by RAT) with symptom duration ≤48 hours	Peramivir 600 mg versus placebo as IM single dose	Completed (n=402, n=334 efficacy analyses) No statistically significant differences between treatment groups for time to alleviation of symptoms (primary endpoint) Median time to alleviation 91.1 hours for 600 mg IM injection of peramivir and 106.1 hours for placebo Peramivir generally safe and well tolerated
Kohno et al^Citation47	Japan/Shionogi/0722T0621	Phase II, randomized, double-blind, placebo- controlled multicenter	Adults aged 20–64 years with influenza symptoms and positive influenza A or B (by RAT)	Peramivir 300 or 600 mg IV single dose versus placebo <48 hours of onset of symptoms	Completed (n=300, n=296 efficacy analyses) Statistically significant difference for both doses of peramivir compared with placebo for time to symptom alleviation (HR, 0.681 [P=0.0092] in 300 mg group and 0.666 [P=0.0092] in the 600 mg group compared to placebo; adjusted P-value 0.0092 for both comparisons) The median time to alleviation of symptoms was 59.1 hours after 300 mg peramivir, 59.9 hours after 600 mg peramivir compared to 82 hours for placebo
Kohno et al^Citation49	Japan/Shionogi/0815T0631	Phase III, randomized, double-blind, double-dummy, controlled, multicenter	Adults aged ≥20 years with influenza symptoms and positive influenza A or B (by RAT)	Peramivir 300 mg or 600 mg IV single dose versus oral oseltamivir 75 mg BID ×5 days	Completed (n=1,093, n=1,091 efficacy analyses) Similar time to symptom alleviation (primary endpoint) for all three treatment groups (78 hours for 300 mg peramivir, 81 hours for 600 mg peramivir, and 81.8 hours for oseltamivir) The hazard ratios of the 300- and 600-mg groups compared to the oseltamivir group were 0.946 (97.5% 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)
High-risk ambulatory patients with acute uncomplicated influenza
Kohno et al^Citation48	Japan/Shionogi/0816T0632	Phase III, randomized, double-blind, uncontrolled, multicenter	High-risk patients with influenza symptoms and positive influenza A or B (by RAT)	Peramivir 300 or 600 mg IV ×1–5 days	Completed (n=37 efficacy analyses) The median time to symptom alleviation was 68.6 hours (90% CI, 41.5–113.4 hours) in all patients The duration of influenza illness was significantly shorter (hazard ratio, 0.497; 90% CI, 0.25–0.984) in the 600 mg group than in the 300 mg group Patients who received multiple doses of peramivir showed more rapid symptom alleviation compared to those who received single doses
Hospitalized patients with influenza
Ison et al^Citation50	US, Australia, Canada, Hong Kong, New Zealand, Singapore, South Africa/Biocryst/NCT0453999	Phase II, randomized, double-blind, double dummy, placebo- controlled, multicenter	Hospitalized patients with acute or potentially life- threatening influenza	Peramivir 200, 400 mg, or placebo IV QD ×5 days plus either oseltamivir oral suspension or placebo 75 mg BID ×5 days	Completed (n=137, n=122 efficacy analyses) No significant differences in the time to clinical stability (primary end point) or time to resumption of normal activities and change in viral titers at 48 hours (secondary end points) between any of the treatment groups Peramivir was non-inferior to oseltamivir in hospitalized patients with acute influenza and demonstrated similar tolerability No significant difference in dose response among the peramivir groups
Hernandez et al^Citation51	USA, Australia, Canada, New Zealand, Mexico, Puerto Rico/Biocryst & US DHHS/NCT0957996	Phase III, randomized, open-label	Hospitalized adults and adolescents (14–92 years) with confirmed or suspected 2009 pandemic influenza (H1N1)	Peramivir 300 mg IV BID or 600 mg IV QD	Completed (n=234) Primary outcome: similar reduction in influenza virus titer in nucleoprotein samples over the first 48 hours for both groups (–1.66 [95% CI, –2.32 to –0.61] for 300 mg peramivir twice daily and –1.47 [95% CI, –1.89 to –0.75] for 600 mg peramivir once daily) The analysis of the combined intention-to-treat population showed median time to resolution of fever was 25.3 hours; time to clinical resolution, 92 hours; time to alleviation of symptoms, 145 hours; and time to resumption of usual activities, 26.8 days
de Jong et al^Citation52	North and South America, Europe, South Africa/Biocryst & US DHHS/NCT0958776	Phase III, randomized, double-blind, controlled, multicenter	Hospitalized adolescents and adults (≥12 years) who have suspected or confirmed influenza as shown by positive influenza A/B RAT	Peramivir + SOC versus SOC + placebo without NAI; peramivir + SOC versus placebo + SOC with NAI; adults: peramivir 600 mg IV QD; adolescents: peramivir 10 mg/kg (max. 600 mg) QD	Terminated during preplanned interim analysis for futility (n=338) Primary outcome for non-NAI group: time to clinical resolution at day 5 was similar between groups (42.5 hours for peramivir versus 49.5 hours for placebo; P=0.97) Secondary outcome: greater reductions in viral shedding were observed in patients who received peramivir, though not statistically significant Incidence and severity of adverse events were similar between groups

Abbreviations: BID, two times a day; CI, confidence interval; HR, hazard ratio; IM, intramuscular; IV, intravenous; NAIs, neuraminidase inhibitors; QD, every day; RAT, rapid antigen test; SOC, standard of care.

Table 4 Other clinical studies of peramivir in influenza infection in adult and pediatric patients

Study	Design	Population/sample size	Regimen	Results/conclusion
Adults
Yoshino et al^Citation53	Retrospective cohort	Adults >18 years of age hospitalized from October 2012 to March 2013; n=32	Peramivir 300 mg IV once (or adjusted for renal dysfunction or severity) versus oral oseltamivir 75 mg BID for 5 days	n=23 in peramivir group, n=9 in oseltamivir group No difference between peramivir and oseltamivir groups for time to defervescence (30.9±18.7 hours versus 34.7±18.6 hours) or survival rate (95.7% versus 100%) respectively Concluded that the clinical efficacy of peramivir is noninferior to that of oseltamivir
Ison et al^Citation54	Open-label, randomized trial	Hospitalized patients ≥6 years of age; n=234	Peramivir 300 mg IV twice daily versus peramivir 600 mg IV once daily for adults ≥18 years or 5 mg/kg twice daily versus 10 mg/kg once daily for children and adolescents	Viral titers declined similarly without difference between regimens; no significant differences in virologic endpoints between arms Peramivir was found to be safe and well tolerated
Children
Sugaya et al^Citation55	Multicenter, open-label, uncontrolled trial	Hospitalized children age ≥28 days to <16 years with influenza infection during the 2009 pandemic A (H1N1) epidemic; n=106	Peramivir IV 10 mg/kg (max. 600 mg) once daily	Median time to alleviation of symptoms was 29.1 hours (95% CI, 22.1–32.4 hours) Concluded that peramivir is clinically and virologically effective and safe in children with pH1N1 virus infection
Shobugawa et al^Citation56	Observational trial	Outpatient pediatric patients; n=263; oseltamivir = 104, peramivir = 4; patients treated with peramivir were age 8.8±3.9 years	Peramivir IV 10 mg/kg (max. 600 mg) as a single dose; oseltamivir 150 mg per day divided BID for children >37.5 kg or 4 mg/kg per day divided BID for children <37.5 kg	Peramivir group had the fastest time to fever alleviation of all groups (median 17.0 hours; 95% CI, 7.2–26.8 hours); result was statistically significant compared to oseltamivir group (P=0.044)
Hikita et al^Citation48	Retrospective chart review	Outpatient pediatric patients aged 0–18 years; total n=223 • influenza A patients aged 5–18 years: peramivir =15, laninamivir =1, zanamivir =18 • influenza B patients aged 5–18 years: peramivir =13, laninamivir =13, zanamivir =20	Peramivir IV 10 mg/kg (max. 300 mg) once daily	In influenza A patients aged 5–18 years, median fever duration with peramivir was shorter at 1 day compared to that of zanamivir at 2 days (P=0.0242) In influenza B patients aged 5–18 years, median fever duration was 3 days with laninamivir versus 1 day with peramivir (P=0.0097) Concluded that peramivir is very useful in pediatric influenza patients
Critically ill patients (adults and children)
Sorbello et al^Citation9	Retrospective chart review of adverse events reported during the EUA	Hospitalized patients aged <1 to 90 years; n=344	Not described, median duration of peramivir was 5 days	The only treatment-emergent adverse event found to be attributable to peramivir was rash
Louie et al^Citation60	Retrospective comparative analysis of critically ill patients who received peramivir versus critically ill patients treated with other neuraminidase inhibitors	Hospitalized patients with A(H1N1)pdm09 infection aged 5 months to 81 years; n=57 patients who received peramivir	Not described	Twenty-nine (51%) patients treated with peramivir died Fatal peramivir cases were more likely to have acute renal failure (P=0.02), shorter length of hospital stay (P=0.002), and shorter duration or peramivir (7 versus 9 days; P=0.02) compared to nonfatal cases Peramivir patients were more likely to die than non-peramivir patients (P<0.0001), which could be due to the preexisting severity of disease prior to peramivir treatment

Abbreviations: BID, twice daily; CI, confidence interval; EUA, emergency use authorization; IV, intravenous.

Table 5 Safety summary for peramivir

Commonly reported adverse events

• Gastrointestinal: diarrhea, nausea, vomiting, constipation

• Neurologic: insomnia

• Cardiovascular: hypertension

Contraindications

• No contraindications in manufacturer labeling

Warnings and precautions

• Serious skin/hypersensitivity reactions: erythema multiform and Stevens–Johnsons syndrome are rare but have been reported in postmarketing experience

• Neuropsychiatric events: delirium and abnormal behavior have been reported but appear to be uncommon; of note, these events may be related to encephalitis or encephalopathy experienced by influenza patients regardless of treatment status

• Risk of bacterial infections: peramivir has not been shown to prevent the development of influenza-associated bacterial infections

Laboratory abnormalities in ≥2% of subjects

• Alanine aminotransferase elevation (>2.5× ULN)

• Serum glucose elevation (>160 mg/dL)

• Creatine phosphokinase elevation (≥6.0× ULN)

• Neutrophil reduction (<1.000×10^9/L)

Recommended monitoring

• Renal function assessment

• Vital signs

• Liver function tests

• Complete blood count

• Urinalysis if clinically indicated

Note: Data from previous research.⁶³

Abbreviation: ULN, upper limit of normal.

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