title: Oseltamivir pharmacokinetics and clinical experience in neonates and infants during an outbreak of H1N1 influenza A virus infection in a neonatal intensive care unit.
abstract: Detailed oseltamivir pharmacokinetics have yet to be reported in neonates and infants; this group is at high risk of serious influenza-associated complications. Extrapolation of doses from older patients is complicated by rapid organ and drug-metabolizing enzyme maturation. A pharmacokinetic study has been conducted during an influenza A(H1N1) outbreak in a neonatal intensive care unit. Each included patient provided 4 samples for oseltamivir and 4 samples for its active metabolite oseltamivir carboxylate. A population pharmacokinetic model was developed with NONMEM. Allometric weight scaling and maturation functions were added a priori to scale for size and age based on literature values. Nine neonates and infants were recruited. A physiologically parameterized pharmacokinetic model predicted typical day 1 area under the curve (AUC(0-12)) values of 1,966 and 2,484 μg · h/liter for neonates and infants of ≤ 37 weeks of postmenstrual age (PMA) and >37 weeks of PMA treated with 1 mg/kg of body weight and 2 mg/kg, respectively. The corresponding steady-state AUC(0-12) values were 3,670 and 4,559 μg · h/liter. Premature neonates treated with 1 mg/kg and term babies treated with 2 mg/kg should have average oseltamivir carboxylate concentrations in a range similar to that for adults treated with 75 mg, corresponding to >200-fold above the half-maximal inhibitory concentration (IC(50)) value for influenza A(H1N1) from the start of therapy.
authors.affiliation: Infectious Diseases and Microbiology Unit, University College London, Institute of Child Health, London, United Kingdom. j.standing@ucl.ac.uk
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Standing
authors.forename: Angela
authors.initials: A
authors.lastname: Nika
authors.forename: Vasileios
authors.initials: V
authors.lastname: Tsagris
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kapetanakis
authors.forename: Helena C
authors.initials: HC
authors.lastname: Maltezou
authors.forename: Dimitris A
authors.initials: DA
authors.lastname: Kafetzis
authors.forename: Maria N
authors.initials: MN
authors.lastname: Tsolia
mesh_terms: D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004196:Disease Outbreaks; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000472:pathogenicity*; D007251:Influenza, Human / Q000188:drug therapy*; D007362:Intensive Care Units; D008297:Male; D053139:Oseltamivir / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir