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Drugs Sep 2018Intravenous peramivir (Alpivab™; Rapivab; Rapiacta; PeramiFlu), the most recent globally approved inhibitor of influenza neuraminidase, is indicated for the treatment... (Review)
Review
Intravenous peramivir (Alpivab™; Rapivab; Rapiacta; PeramiFlu), the most recent globally approved inhibitor of influenza neuraminidase, is indicated for the treatment of uncomplicated influenza in adults and children from the age of 2 years. This article, written from an EU perspective, reviews the clinical use of peramivir in this indication and summarizes its pharmacological properties. In large, randomized, double-blind, multicentre trials in previously healthy adults with uncomplicated influenza, a single infusion of peramivir 600 mg significantly shortened the median time to resolution of influenza symptoms compared with placebo and was noninferior to the recommended oseltamivir regimen in terms of this primary outcome. Albeit data are limited, results from a noncomparative phase 3 trial in paediatric patients (≈ 95% of whom were aged ≥ 2 years) with acute uncomplicated influenza receiving the recommended dose of peramivir were generally consistent with those in adults. Peramivir was generally well tolerated in children and adults participating in these clinical trials, with most adverse events of mild to moderate intensity. Given its simple single-dose regimen and with intravenous administration offering a potential advantage over oral administration in individuals with nausea, vomiting or having difficulty in swallowing, peramivir provides an additional option for treating uncomplicated influenza infection in adults and children from the age of 2 years.
Topics: Acids, Carbocyclic; Administration, Intravenous; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Treatment Outcome
PubMed: 30196350
DOI: 10.1007/s40265-018-0981-8 -
Regulatory Toxicology and Pharmacology... Apr 2020Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not...
Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not clear if the significant physiological alterations associated with pregnancy affect the pharmacokinetics of oseltamivir and, thus, warrant different dosing regimens to assure efficacy. In this study, we investigated the suitability of rhesus macaques as an animal model for studying oseltamivir pharmacokinetics during all trimesters of pregnancy in comparison to pre-pregnant conditions. Specifically, we compared the pharmacokinetics of oseltamivir and its pharmacologically active metabolite oseltamivir carboxylate in rhesus monkeys after intravenous and nasogastric administration of 2.5 mg oseltamivir phosphate/kg body weight given prior to and during the first, second, and third trimesters of pregnancy. Pregnancy had only a modest effect upon the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate. Monkeys treated intravenously in the third trimester had a reduction in Vd and CL, compared to non-pregnant monkeys. These changes did not occur in the other two trimesters. Pregnant monkeys treated intravenously had 20-25% decrease in AUC of oseltamivir carboxylate and a corresponding increase in Vd and CL. Pregnant monkeys treated nasogastrically with oseltamivir phosphate demonstrated a pattern that recapitulated intravenous dosing. Taken together these data indicate that rhesus monkeys are an acceptable model for studying drug-pregnancy interactions.
Topics: Animals; Antiviral Agents; Dose-Response Relationship, Drug; Female; Injections, Intravenous; Intubation, Gastrointestinal; Macaca mulatta; Molecular Conformation; Oseltamivir; Phosphorous Acids; Pregnancy
PubMed: 31927005
DOI: 10.1016/j.yrtph.2019.104569 -
Current Medicinal Chemistry 2015The annual flu season causes thousands of deaths and millions of hospitalizations, which pose a great burden to global health and economy. Moreover, a flu pandemic... (Review)
Review
The annual flu season causes thousands of deaths and millions of hospitalizations, which pose a great burden to global health and economy. Moreover, a flu pandemic arising from reassortment viruses, such as H5N1 and H1N1, raises even greater concern due to the lack of effective vaccines at the initial stage of flu outbreak. The influenza virus is the causative agent of flu infection. Currently there are four drugs in use to combat influenza infection. Amantadine and rimantadine are M2 proton channel blockers that inhibit virus uncoating; oseltamivir and zanamivir are neuraminidase (NA) inhibitors that inhibit virus release. However, recent years have witnessed a drastic increase in instances of drug resistance, and flu strains that are resistant to both classes of drugs have been reported. Thus, there is a pressing need to develop the next generation of anti-influenza drugs. Among a handful of anti-influenza drug targets, the viral fusion protein hemagglutinin (HA) is one of the most advanced. This review discusses the biological roles of HA during viral replication and highlights peptide- and small molecule-based HA inhibitors, including recent computationally designed HA binders. The text is organized into four sections based on the maturation stages of HA: inhibitors targeting the glycosylation of HA, the proteolytic activation of HA, the attachment of HA to host cell receptors, and peptide- and small molecule-based inhibitors targeting HA-mediated membrane fusion. Of particular interest are advances in the areas of developing dual inhibitors targeting both HA and NA and broad-spectrum HA inhibitors targeting both groups of HAs.
Topics: Amantadine; Antiviral Agents; Enzyme Inhibitors; Hemagglutinin Glycoproteins, Influenza Virus; Neuraminidase; Orthomyxoviridae; Oseltamivir; Rimantadine; Zanamivir
PubMed: 25723505
DOI: 10.2174/0929867322666150227153919 -
Antiviral Research Aug 2023Our previous study shows favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, but...
Our previous study shows favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, but its effect on virological evolution and resistance mutation against oseltamivir is still unknown. In this study, we collected longitudinal respiratory samples from influenza patients who underwent combination therapy and applied them to next generation sequencing of the whole genome of the influenza A virus (IAV). We also included a cohort untreated with any antivirals to serve as the control. In total, 62 samples from 19 patients treated with combination therapy and 20 samples from 20 patients untreated were successfully sequenced. The nucleotide diversity in the whole genome of IAV in the combination group showed no difference compared to that in the control group (P > 0.05). Moreover, we observed 174 kinds of nonsynonymous nucleotide substitutions in patients with combination therapy, mostly in NA (n = 44) and HA (n = 43). Of them, the G→A transition was the dominant variant type (27%) and 46/174 (26%) was reported to have biological effects, such as increased pathogenicity and polymerase activity. Among the 29 mutations conferring reduction in oseltamivir sensitivity we investigated, H275Y was the only mutation detected in the 4 samples from 1 of 19 patients and demonstrated increasing frequency during the treatment. Mutations conferring favipiravir resistance were not observed. Our studies showed combination therapy of favipiravir and oseltamivir has little effect on virus nucleotide diversity, nor prevents the increase of oseltamivir-resistant variants.
Topics: Humans; Oseltamivir; Influenza, Human; Influenza A virus; Influenza A Virus, H1N1 Subtype; Drug Resistance, Viral; Antiviral Agents; Neuraminidase
PubMed: 37369282
DOI: 10.1016/j.antiviral.2023.105657 -
Clinical Pharmacology and Therapeutics Oct 2015Pregnancy heightens the risk of adverse outcomes from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Seasonal influenza... (Review)
Review
Pregnancy heightens the risk of adverse outcomes from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Seasonal influenza vaccines are the focus of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu) is currently the recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease after exposure, treat infected individuals, as well as lessen the likelihood of complications. The physiologic adaptations of pregnancy alter the pharmacokinetics of this important drug. Evidence of these alterations, knowledge gaps, and future investigative directions to fill these knowledge gaps are highlighted.
Topics: Animals; Antiviral Agents; Enzyme Inhibitors; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Neuraminidase; Oseltamivir; Pregnancy; Pregnancy Complications, Infectious; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 26108913
DOI: 10.1002/cpt.179 -
The American Journal of Managed Care Mar 2022To determine whether baloxavir use is associated with lower health care resource utilization (HCRU) and costs for secondary influenza complications post treatment...
OBJECTIVES
To determine whether baloxavir use is associated with lower health care resource utilization (HCRU) and costs for secondary influenza complications post treatment compared with oseltamivir.
STUDY DESIGN
Retrospective cohort study.
METHODS
Patients filling a prescription for baloxavir or oseltamivir within 48 hours following an influenza-related outpatient visit were identified in the 2018-2019 influenza season from the US Truven MarketScan Research Databases and propensity matched 1:2 (baloxavir:oseltamivir). Outcomes were assessed 15 and 30 days after antiviral treatment and included all-cause, all respiratory-related, and select respiratory-related (influenza, asthma, chronic obstructive pulmonary disease, or infection) HCRU and costs.
RESULTS
The study included 5080 baloxavir-treated and 10,160 matched oseltamivir-treated patients. All-cause emergency department (ED) visits and inpatient hospitalizations were lower in baloxavir-treated patients, with a statistically significant difference in the percentage hospitalized at 30 days (0.3% vs 0.5%; P = .04). ED visits for all or select respiratory-related conditions were significantly reduced with baloxavir (P < .01 for all comparisons). Mean per-patient cost savings at day 30 for all-cause, all respiratory-related, and select respiratory-related conditions were $79, $50, and $51, respectively, despite slightly higher prescription costs for baloxavir. In high-risk patients (baloxavir: n = 1958; oseltamivir: n = 3949), the incidence of ED visits was significantly lower for all respiratory-related and select respiratory-related conditions (P < .01); cost savings with baloxavir in the high-risk cohort were substantially greater than in the overall cohort.
CONCLUSIONS
Treatment of patients with influenza with single-dose baloxavir was generally associated with lower HCRU and costs post treatment compared with oseltamivir, particularly in high-risk patients.
Topics: Antiviral Agents; Dibenzothiepins; Humans; Influenza, Human; Morpholines; Oseltamivir; Pyridones; Retrospective Studies; Triazines
PubMed: 35404552
DOI: 10.37765/ajmc.2022.88786 -
Antiviral Research Apr 2024While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant... (Observational Study)
Observational Study
While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.
Topics: Humans; Influenza, Human; Oseltamivir; Neuraminidase; Influenza A Virus, H3N2 Subtype; Outpatients; Seasons; Prospective Studies; Antiviral Agents; Pyridones; Enzyme Inhibitors; Guanidines; Fever; Dibenzothiepins; Morpholines; Triazines
PubMed: 38430970
DOI: 10.1016/j.antiviral.2024.105853 -
BMJ (Clinical Research Ed.) Jul 2017
Topics: Antiviral Agents; Humans; Influenza, Human; Observational Studies as Topic; Oseltamivir; Strategic Stockpile; World Health Organization
PubMed: 28701339
DOI: 10.1136/bmj.j3266 -
British Journal of Clinical Pharmacology Jun 2016The aims of the present study were to compare the pharmacokinetics of oseltamivir and its active antiviral metabolite oseltamivir carboxylate in obese and non-obese...
AIMS
The aims of the present study were to compare the pharmacokinetics of oseltamivir and its active antiviral metabolite oseltamivir carboxylate in obese and non-obese individuals and to determine the effect of obesity on the pharmacokinetic properties of oseltamivir and oseltamivir carboxylate.
METHODS
The population pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated in 12 obese [body mass index (BMI) ≥30 kg m(-2) ) and 12 non-obese (BMI <30 kg m(-2) ) Thai adult volunteers receiving a standard dose of 75 mg and a double dose of 150 mg in a randomized sequence. Concentration-time data were collected and analysed using nonlinear mixed-effects modelling.
RESULTS
The pharmacokinetics of oseltamivir and oseltamivir carboxylate were described simultaneously by first-order absorption, with a one-compartment disposition model for oseltamivir, followed by a metabolism compartment and a one-compartment disposition model for oseltamivir carboxylate. Creatinine clearance was a significant predictor of oseltamivir carboxylate clearance {3.84% increase for each 10 ml min(-1) increase in creatinine clearance [95% confidence interval (CI) 0.178%, 8.02%]}. Obese individuals had an approximately 25% (95% CI 24%, 28%) higher oseltamivir clearance, 20% higher oseltamivir volume of distribution (95% CI 19%, 23%) and 10% higher oseltamivir carboxylate clearance (95% CI 9%, 11%) compared with non-obese individuals. However, these altered pharmacokinetic properties were small and did not change the overall exposure to oseltamivir carboxylate.
CONCLUSIONS
The results confirmed that a dose adjustment for oseltamivir in obese individuals is not necessary on the basis of its pharmacokinetics.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Models, Biological; Obesity; Oseltamivir; Volunteers; Young Adult
PubMed: 26810861
DOI: 10.1111/bcp.12892 -
Pediatrics International : Official... Jan 2022Previous reports have not clarified the difference in clinical efficacy between baloxavir and oseltamivir against influenza. (Observational Study)
Observational Study
BACKGROUND
Previous reports have not clarified the difference in clinical efficacy between baloxavir and oseltamivir against influenza.
METHODS
A prospective observational study was performed during 2017-2018, 2018-2019, and 2019-2020 influenza seasons. The primary endpoint of this study was to compare the duration of fever between patients who received baloxavir and those who received oseltamivir.
RESULTS
A total of 235 influenza-infected patients (3-18 years of age), including 91 who received oseltamivir and 144 who received baloxavir, were enrolled. The proportions of influenza A(H3N2) virus, influenza A(H1N1)pdm09 virus, and influenza B virus-infected patients were 31.5%, 42.6%, and 26.0%, respectively. Patients who received oseltamivir were significantly younger than those who received baloxavir. Univariate analyses showed that the duration of fever was shorter with baloxavir than with oseltamivir against influenza virus overall, influenza A virus, influenza B virus, and influenza A(H1N1)pdm09 virus, but not for influenza A(H3N2) virus. In multivariate analyses, hazard ratios for influenza virus overall (0.53 [95% CI, 0.38-0.73]), influenza B virus (0.16 [95% CI, 0.07-0.41]), and influenza A(H1N1)pdm09 virus (0.55 [95% CI, 0.32-0.93]) were significantly lower in the patients who received baloxavir than those who received oseltamivir. However, the differences between influenza A virus and influenza A(H3N2) virus were not significant between the two groups.
CONCLUSION
For influenza virus overall, influenza B virus, and influenza A(H1N1)pdm09 virus, baloxavir treatment resulted in shorter duration of fever than oseltamivir treatment, but not for influenza A virus and influenza A(H3N2) virus.
Topics: Antiviral Agents; Dibenzothiepins; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza B virus; Influenza, Human; Morpholines; Oseltamivir; Pyridones; Seasons; Treatment Outcome; Triazines
PubMed: 35790049
DOI: 10.1111/ped.15169