OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to (1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and (2) estimate the effect of fluid overload on target attainment. Clinical trial simulations were employed to evaluate target attainment of meropenem in various age groups and degrees of fluid overload in children receiving CRRT. Pharmacokinetic parameters were extracted from published literature, and 287 patients from the prospective pediatric CRRT registry database provided realistic clinical covariates including patient weight, fluid overload, and CRRT prescription characteristics. Target attainment at 40% and 75% time above the minimum inhibitory concentration was evaluated. Clinical trial simulations demonstrated that children greater than 5 years of age achieved acceptable target attainment with a dosing regimen of 20 mg/kg every 12 hours. In children less than 5, however, increased dosing of 20 mg/kg every 8 hours was needed to optimize target attainment. Fluid overload did not affect target attainment. These in silico model predictions will need to be verified in vivo in children receiving meropenem and CRRT.

OBJECTIVES Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12–19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12–17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.

Funding information Bill and Melinda Gates Foundation During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based metaanalysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.