Oseltamivir In Infants Research Articles

Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants.

The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and CES2 abundance (in picomoles per milligram total protein) increased approximately 5-fold (315.2 vs. 1664.4) and approximately 3-fold (59.8 vs. 174.1) from neonates to adults, respectively. CES1 protein abundance in liver cytosol also showed age-dependent maturation. Oseltamivir carboxylase activity was correlated with protein abundance in pediatric and adult liver microsomes. The protein abundance data were then used to model in vivo PK of oseltamivir in infants using pediatric physiologically based PK modeling and incorporating the protein abundance-based ontogeny function into the existing pediatric Simcyp model. The predicted pediatric area under the curve, maximal plasma concentration, and time for maximal plasma concentration values were below 2.1-fold of the clinically observed values, respectively.

Safety of oseltamivir in infants less than one year old: Prospective surveillance during the 2004–2005 influenza season in Japan

The aim of this study was to investigate the treatment of influenza and safety of oseltamivir in infants less than 1 year of age. All-patient surveillance was conducted using centralized enrolment at 219 medical institutions. Safety data were collected for 1,663 patients less than 1 year of age who developed influenza during the 2004–2005 influenza season. Patients were stratified into three groups: patients not treated with a drug (Group A), patients treated with oseltamivir (Group B), and patients treated with a drug other than an antiviral agent (Group C). Significant differences (P = 0.0074, P Our analysis of the safety of oseltamivir in infants less than 1 year of age revealed clinical acceptance of safety issues.

Oseltamivir Pharmacokinetics, Dosing, and Resistance Among Children Aged <2 Years With Influenza

Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Clinical Features, Oseltamivir Treatment and Outcome in Infants Aged &lt;12 Months with Laboratory-Confirmed Influenza a in 2009

Data on the use of oseltamivir in infants is limited. We documented the clinical presentations of infants aged <12 months hospitalized with laboratory-confirmed influenza A in the southern hemisphere winter of 2009 and compared outcomes in relation to oseltamivir therapy. Data were extracted from prospectively collected and collated influenza case reports (June-September 2009) ascertained through Paediatric Active Enhanced Disease Surveillance, an in-patient surveillance system operating at the Children's Hospital at Westmead (CHW), Sydney, NSW, Australia. Nosocomial cases were excluded. Of 56 infants with definite influenza (35 pandemic H1N1 2009) admitted to the CHW, 20 were treated with oseltamivir. Overall, 12 (60%) of those treated with oseltamivir were aged <6 months. Cough, fever and coryza were the most common clinical features (≥70%). Vomiting was present on admission in 31.4%. All 7 cases presenting with vomiting then given antiviral treatment had reduction of vomiting and the other 13 did not develop vomiting on treatment. There were three infants with hypoxaemia (oxygen saturation ≤93%) on presentation in the treatment group compared with none in the control group (P=0.04). The median duration of hospital stay was the same in both groups (2.5 days). The use of oseltamivir was well tolerated in hospitalized infants. Vomiting, one of the widely reported side effects of oseltamivir, was found to be more a presenting symptom of influenza than a side effect of oseltamivir. Based on pulse oximetry, oseltamivir-treated cases may have been more severe on presentation, but there was no significant difference in length of hospital stay.

Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants

Physiologically based pharmacokinetic (PBPK) modelling can assist in the development of drug therapies and regimens suitable for challenging patient populations such as very young children. This study describes a strategy employing PBPK models to investigate the intravenous use of the neuraminidase inhibitor oseltamivir in infants and neonates with influenza. Models of marmoset monkeys and humans were constructed for oseltamivir and its active metabolite oseltamivir carboxylate (OC). These models incorporated physicochemical properties and in vitro metabolism data into mechanistic representations of pharmacokinetic processes. Modelled processes included absorption, whole-body distribution, renal clearance, metabolic conversion of the pro-drug, permeability-limited hepatic disposition of OC and age dependencies for all of these processes. Models were refined after comparison of simulations in monkeys with plasma and liver concentrations measured in adult and newborn marmosets after intravenous and oral dosing. Then simulations with a human model were compared with clinical data taken from intravenous and oral studies in healthy adults and oral studies in infants and neonates. Finally, exposures after intravenous dosing in neonates were predicted. Good simulations in adult marmosets could be obtained after model optimizations for pro-drug conversion, hepatic disposition of OC and renal clearance. After adjustment for age dependencies, including reductions in liver enzyme expression and renal function, the model simulations matched the trend for increased exposures in newborn marmosets compared with those in adults. For adult humans, simulated and observed data after both intravenous and oral dosing showed good agreement and although the data are currently limited, simulations in 1-year-olds and neonates are in reasonable agreement with published results for oral doses. Simulated intravenous infusion plasma profiles in neonates deliver therapeutic concentrations of OC that closely mimic the oral profiles, with 3-fold higher exposures of oseltamivir than those observed with the same oral dose. This work exemplifies the utility of PBPK models in predicting pharmacokinetics in the very young. Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described.

Adverse drug reaction profile of oseltamivir in children

Aim:To monitor and evaluate the pattern of ADRs to oseltamivir in pediatric population suffering from H1N1 influenza at a tertiary care hospital.Materials and Methods:Children offered oseltamivir for treatment and chemoprophylaxis were monitored for adverse events by direct questioning for symptoms and clinical examination on day 5 and day 10. Assessment of neurological events was done by asking the parents or guardians regarding development of specific symptoms. Adverse events obtained were analyzed for severity, causality and age-group wise.Results:Out of 191 children (median age, 3 years), 69 (36.1%) developed ADRs. Most common symptoms were vomiting (16.2%) followed by diarrhea (12.0%), ear disorders (8.9%), and insomnia (6.8%). The incidence of neuropsychiatric symptoms was 12.6% which were mild-to-moderate on severity scale. There was no significant difference in the incidence of adverse events between children less than 1 year and other age groups.Conclusion:Oseltamivir is well tolerated in Indian children with suspected or confirmed H1N1 influenza. Our study also indicates safety of oseltamivir in infants.