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Clinical Trial
. 2014 Jun;58(6):3013-20.
doi: 10.1128/AAC.02374-13. Epub 2014 Mar 10.

Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design

Adriana Tremoulet  1 , Jennifer Le  2 , Brenda Poindexter  3 , Janice E Sullivan  4 , Matthew Laughon  5 , Paula Delmore  6 , Andrea Salgado  7 , Sandy Ian-U Chong  2 , Chiara Melloni  8 , Jamie Gao  9 , Daniel K Benjamin Jr  8 , Edmund V Capparelli  10 , Michael Cohen-Wolkowiez  11 ; Administrative Core Committee of the Best Pharmaceuticals for Children Act-Pediatric Trials Network
Collaborators, Affiliations
Clinical Trial

Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design

Adriana Tremoulet et al. Antimicrob Agents Chemother. 2014 Jun.

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.

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Figures

FIG 1
FIG 1
Clearance (A) and half-life (B) versus postmenstrual age.
FIG 2
FIG 2
Observed versus population (A) and individual (B) predictions, final model.
FIG 3
FIG 3
Visual predictive check. Circles, observed concentrations (Conc); solid line, predicted median concentration; dashed lines: 90% confidence intervals.
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