Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants

Abstract

A mechanistic population‐pharmacokinetic model was developed to predict oseltamivir exposures in neonates and infants accounting for physiological changes during the first 2 years of life. The model included data from 13 studies, comprising 436 subjects with normal renal function (317 pediatric subjects (≥ 38 weeks postmenstrual age (PMA), ≥ 13 days old) and 119 adult subjects < 40 years). Concentration–time profiles of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were characterized by a four‐compartment model, with absorption described by three additional compartments. Renal maturational changes were implemented by description of OC clearance with allometric function of weight and Hill function of PMA. Clearance of OC increased with weight up to 43 kg (allometric coefficient 0.75). Half the adult OC clearance was reached at a PMA of 45.6 weeks (95% confidence interval (CI) 41.6–49.6) with a Hill coefficient of 2.35 (95% CI 1.67–3.04). The model supports the European Union/United States‐approved 3 mg/kg twice‐daily oseltamivir dose for infants < 1 year (PMA ≥ 38 weeks) and allows prediction of exposures in preterm neonates.

Dosing regimen optimisation for oseltamivir in immunocompromised paediatric patients with influenza: Extrapolation of efficacy

“…We used an extrapolation approach alongside clinical data to optimise the dosing regimen of oseltamivir for IC paediatric patients with influenza. In the popPK model, 17 There were no notable PK/PD relationships for any of the virologic analyses, including treatment-emergent resistance and, therefore, no apparent additional benefit with exposures higher than those achieved with the conventional oseltamivir dose in this paediatric IC patient population.…”

“…Exposures of oseltamivir and OC were estimated by a mechanistic popPK model, which accounts for physiological changes during the first 2 years of life. 17 The relationship between OC exposure and PD endpoints and kinetics of naturally occurring influenza infections and the treatment effect of oseltamivir in IC paediatric patients were explored. Models enhance the ability to extend knowledge and clinical experience with oseltamivir and OC into the IC paediatric population.…”

“…PK, PK/PD and effects of oseltamivir and OC on viral kinetics have been investigated in various adult and paediatric patient populations. [17][18][19][20][21][22][23][24] At the time when the oseltamivir treatment in IC patients programme was initiated, it had been postulated that slower immune viral clearance in IC patients might lead to greater reliance on anti-virals for clearance of the virus and that this need might be met by higher doses or longer duration of oseltamivir treatment. Further, analysis of inoculation studies and preliminary results from hospitalized patients suggested increasing effect with increasing exposure.…”

“…To select a suitable dosing regimen for oseltamivir in IC paediatric patients with influenza from studies NV20234 and NV25719, we extended existing population PK (popPK), PK/PD and disease models to IC paediatric patients, while considering efficacy, safety and resistance data. Exposures of oseltamivir and OC were estimated by a mechanistic popPK model, which accounts for physiological changes during the first 2 years of life 17 . The relationship between OC exposure and PD endpoints and kinetics of naturally occurring influenza infections and the treatment effect of oseltamivir in IC paediatric patients were explored.…”

Pharmacotherapy for acute respiratory infections caused by influenza viruses: current possibilities

“…Наиболее назначаемым препаратом в ряду иНа является осельтамивир. Осельтамивира фосфатпролекарство, его активация с образованием осельтамивира карбоксилата достигается за счет гидролиза в печени под действием карбоксилэстеразы-1 [17]. Осельтамивира карбоксилат выводится в неизменном виде почками путем канальцевой секреции с участием системы транспортеров органических анионов.…”