title: Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design.
abstract: Although ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (≤ 34 or >34 weeks) and postnatal age (PNA) (≤ 7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of ≤ 34 weeks and PNA of ≤ 7 days, 75 mg/kg every 12 h for GA of ≤ 34 weeks and PNA of ≥ 8 and ≤ 28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of ≤ 28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.
authors.affiliation: University of California, San Diego, School of Medicine, San Diego, California, USA Rady Children's Hospital, San Diego, California, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Tremoulet
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy, San Diego, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Le
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Poindexter
authors.affiliation: University of Louisville & Kosair Children's Hospital, Louisville, Kentucky, USA.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Sullivan
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Laughon
authors.affiliation: Wesley Medical Center, Wichita, Kansas, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Delmore
authors.affiliation: University of California, San Diego, School of Medicine, San Diego, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Salgado
authors.affiliation: University of California, San Diego, Skaggs School of Pharmacy, San Diego, California, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Ian-U Chong
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Durham, North Carolina, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Melloni
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Durham, North Carolina, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.affiliation: University of California, San Diego, School of Medicine, San Diego, California, USA University of California, San Diego, Skaggs School of Pharmacy, San Diego, California, USA.
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA Duke Clinical Research Institute, Durham, North Carolina, USA michael.cohenwolkowiez@duke.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
mesh_terms: D000667:Ampicillin / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009010:Monte Carlo Method; D011446:Prospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D000667:Ampicillin