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Infectious Disorders Drug Targets Feb 2013Pharmacokinetic-pharmacodynamic (PKPD) studies have the potential to yield useful information on whether and how a drug works, and what dose to use. This approach is... (Review)
Review
Pharmacokinetic-pharmacodynamic (PKPD) studies have the potential to yield useful information on whether and how a drug works, and what dose to use. This approach is often best suited to situations where dose-response relationships need to be elucidated and where randomisation is not feasible. Children make up around one third of cases during influenza outbreaks, and are more susceptible to certain complications such as otitis media. Despite this, high-quality randomised controlled trials (RCT) of antiviral therapies such as oseltamivir have not been performed, leaving open the question of whether and at what dose to use. This review therefore focusses on the available PKPD data in children. Oseltamivir has complex PK which requires modelling to properly understand the relationship between dose and concentration with time, and there is a lack of clarity on appropriate pharmacodynamic endpoints. Following a general overview of oseltamivir PKPD, this review seeks to summarise the available paediatric PKPD data, identify gaps in our knowledge and priorities for future research.
Topics: Antiviral Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Infant; Infant, Newborn; Influenza, Human; Models, Biological; Neuraminidase; Oseltamivir; Viral Proteins
PubMed: 23675922
DOI: 10.2174/18715265112129990003 -
Antiviral Therapy Apr 2022John Martin's untimely death in March 2021 was a huge loss for us personally, Gilead Sciences, the company he built over 30 years and the scientific community concerned...
John Martin's untimely death in March 2021 was a huge loss for us personally, Gilead Sciences, the company he built over 30 years and the scientific community concerned with antiviral therapies. We wish to honor John's legacy by retelling the discovery and history of Tamiflu and his contributions to it. Without his vision, persistence, and keen eye for opportunities, Tamiflu would not exist and Gilead's path would not have been the same. His strategic thinking around the first oral flu drug is still quite relevant today, when we are still in the SARS-CoV-2 pandemic. John explained it simply in an interview with the Science History Institute in May 2020: "…".
Topics: Humans; Influenza, Human; Oseltamivir; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35499178
DOI: 10.1177/13596535211067598 -
Yonsei Medical Journal Jul 2017Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However,... (Comparative Study)
Comparative Study Meta-Analysis Review
PURPOSE
Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However, limited data are available on intravenous (IV) peramivir treatment compared to oral oseltamivir for these patients.
MATERIALS AND METHODS
With a systematic review and meta-analysis, we compared the efficacy of IV peramivir with oral oseltamivir for treatment of patients with seasonal influenza. MEDLINE, EMBASE, and Cochrane Central Register were searched for relevant clinical trials.
RESULTS
A total of seven trials [two randomized controlled trials (RCTs) and five non-randomized observational trials] involving 1676 patients were finally analyzed. The total number of peramivir- and oseltamivir-treated patients was 956 and 720, respectively. Overall, the time to alleviation of fever was lower in the peramivir-treated group compared with the oseltamivir-treated group [mean difference (MD), -7.17 hours; 95% confidence interval (CI) -11.00 to -3.34]. Especially, pooled analysis of observational studies (n=4) and studies of outpatients (n=4) demonstrated the superiority of the peramivir-treated group (MD, -7.83 hours; 95% CI -11.81 to -3.84 and MD, -7.71 hours; 95% CI -11.61 to -3.80, respectively). Mortality, length of hospital stay, change in virus titer 48 hours after admission, and the incidence of adverse events in these patients were not significantly different between the two groups.
CONCLUSION
IV peramivir therapy might reduce the time to alleviation of fever in comparison with oral oseltamivir therapy in patients with influenza; however, we could not draw clear conclusions from a meta-analysis because of the few RCTs available and methodological limitations.
Topics: Acids, Carbocyclic; Administration, Intravenous; Administration, Oral; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza, Human; Odds Ratio; Oseltamivir; Publication Bias; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome
PubMed: 28540991
DOI: 10.3349/ymj.2017.58.4.778 -
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 -
Birth Defects Research Nov 2019Influenza during pregnancy contributes to maternal morbidity and mortality. Neuraminidase inhibitors, including oseltamivir, are recommended for treating women with...
BACKGROUND
Influenza during pregnancy contributes to maternal morbidity and mortality. Neuraminidase inhibitors, including oseltamivir, are recommended for treating women with influenza during pregnancy.
METHODS
Data from the Slone Birth Defects Study from 2009 to 2015 were used to investigate associations between oseltamivir and specific birth defects. We classified exposures according to timing in pregnancy and examined 52 and 16 defects with early and potential late pregnancy etiology, respectively; we calculated crude odds ratios (ORs) and 95% confidence intervals (CIs) for defects with three or more exposures.
RESULTS
Among 8,379 cases and 4,190 nonmalformed controls, we identified 79 and 42 oseltamivir exposures, respectively. The majority of defects had no exposures. ORs were elevated for several defects, but the CI excluded the null only for intestinal malrotation (OR: 10.7 [1.8, 45.2]; three exposures).
CONCLUSIONS
Largely null findings for specific defects are reassuring. The association with intestinal malrotation, while unstable, warrants further investigation.
Topics: Adult; Case-Control Studies; Congenital Abnormalities; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Odds Ratio; Oseltamivir; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Young Adult
PubMed: 31397115
DOI: 10.1002/bdr2.1563 -
The Journal of Infectious Diseases Sep 2012We conducted a 2-sample pharmacokinetic study of oseltamivir in 12 premature infants. Oseltamivir 1 mg/kg/dose twice daily in infants <38 weeks postmenstrual age (n=8)... (Clinical Trial)
Clinical Trial
We conducted a 2-sample pharmacokinetic study of oseltamivir in 12 premature infants. Oseltamivir 1 mg/kg/dose twice daily in infants <38 weeks postmenstrual age (n=8) resulted in oseltamivir carboxylate exposure comparable to previously published pediatric data, which helps prospectively validate this regimen. Oseltamivir 3 mg/kg/dose once daily in premature infants >38 weeks postmenstrual age (born prematurely but chronologically past term, n=4) resulted in similar oseltamivir and oseltamivir carboxylate exposure. Although these results suggest persistence of immature renal function in this subgroup, further pharmacokinetic/pharmacodynamic description is required to confirm the appropriateness of this regimen.
Topics: Absorption; Antiviral Agents; Area Under Curve; Drug Administration Schedule; Humans; Infant, Newborn; Infant, Premature; Kidney; Models, Biological; Oseltamivir; Prospective Studies
PubMed: 22807525
DOI: 10.1093/infdis/jis471 -
The Journal of Infectious Diseases Oct 2010
Topics: Animals; Antiviral Agents; Disease Notification; Humans; Influenza A Virus, H5N1 Subtype; Influenza, Human; Oseltamivir; Time Factors
PubMed: 20831386
DOI: 10.1086/656317 -
Carbohydrate Research May 2019A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase...
A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase was prepared via click reaction. The primary structure activity relationship study demonstrated that appropriate distance between two oseltamivir monomers around 30 Å can crosslink two adjacent neuraminidase tetramers on the virion surface and result in highly effective NA inhibitors against three strains of influenza virus and H7N9 virus like particle. This strategy also provides a basis for the multivalent modification on oseltamivir.
Topics: Antiviral Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Neuraminidase; Orthomyxoviridae; Oseltamivir; Structure-Activity Relationship
PubMed: 30954773
DOI: 10.1016/j.carres.2019.03.012 -
PLoS Computational Biology Jul 2022Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However,...
Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.
Topics: Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza, Human; Neuraminidase; Oseltamivir
PubMed: 35901128
DOI: 10.1371/journal.pcbi.1010343 -
Paediatric Drugs Feb 2011Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that... (Review)
Review
Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that infection-associated deaths among individuals without pre-existing conditions (e.g. immunosuppression) are clustered in pregnant women and young infants. In developing countries where the availability of influenzae vaccine is limited, the only currently available pharmacologic counter-measure for H1N1 disease is oseltamivir, a neuraminidase inhibitor with excellent in vitro activity against the virus. This drug is available in oral solid and liquid formulations, has excellent peroral bioavailability in adults, and generally has a very favorable safety profile. Many observational studies indicate that oseltamivir treatment is associated with symptomatic improvement in pediatric patients with H1N1 infection and, therefore, is considered to represent a viable therapeutic option for use in children. However, the disposition of the ethyl ester prodrug and its active metabolite has not been well characterized in infants and children. Presently, data are available from only two published investigations and preliminary summary information from a recent presentation of an ongoing study. Given that recent in vitro data support the importance of a target exposure-response profile for the active metabolite of oseltamivir and that many processes known to modulate drug disposition have a developmental basis, understanding the potential impact of age on oseltamivir disposition becomes crucial in the development of age-appropriate dosing regimens for the drug. In this review, the impact of ontogeny on processes that are important in regulating the absorption, distribution, metabolism, and excretion of oseltamivir and its active metabolite are considered. Data from both animal and human investigations are presented in the context of defining how development might influence the dose-exposure relationship and, most importantly, the significant variability associated with it. In addition, the available pediatric pharmacokinetic data for oseltamivir and its active metabolite are summarized and current 'information gaps' deserving of future study are presented.
Topics: Adult; Age Factors; Animals; Antiviral Agents; Biological Availability; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Pregnancy; Prodrugs
PubMed: 21162598
DOI: 10.2165/11536950-000000000-00000