The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.

Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants.

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.

Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS-AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age-, disease-, and bypass-related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS-AKI using population PK modeling techniques and an opportunistic, electronic health record-integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS-AKI. Twenty-seven neonates were included in model development. A 1-compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty-three neonates with caffeine exposure and 109 controls were included in the exposure-response analysis. Over half of neonates developed CS-AKI. On multivariable analysis, there were no significant differences between CS-AKI with and without caffeine exposure. Neonates with single-ventricle heart disease without CS-AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease- and bypass-specific effects on drug disposition and identify populations where caffeine may be beneficial.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity.

OBJECTIVE: Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS: Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS: The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49-10.44] and 3.71 [0.86-13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS: Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Mechanisms to expedite pediatric clinical trial site activation: The DOSE trial experience.

BACKGROUND: Timely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting. METHODS: The three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects. RESULTS: Twenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation. CONCLUSION: Study start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved. CLINICALTRIALS: gov #: NCT03938857.

Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial.

Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to alveolar simplification, impaired alveolar-capillary development, interstitial fibrosis, and often pulmonary hypertension. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus is a promising candidate for BPD. Following phase I studies, we developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD. SIL02 is a randomized, double-blind, placebo-controlled, 3-cohort, sequential dose-escalating trial of enteral or intravenous (IV) sildenafil dosed every 8 h for up to 34 days. The target IV doses were 0.125, 0.5 and 1 mg/kg/dose in cohorts 1, 2 and 3, respectively; while the enteral doses will be double the IV doses. Eligible infants must be < 29 weeks' gestation at birth and requiring respiratory support at 7-28 days' postnatal age. Adverse events and preliminary effectiveness will be compared by treatment group. Using the final population PK model, empirical Bayesian estimates will be generated for each patient. Preliminary effectiveness will be measured by the incidence of moderate to severe BPD or death at 36 weeks and change in the BPD risk estimation.

External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data.

Risperidone is approved to treat schizophrenia in adolescents and autistic disorder and bipolar mania in children and adolescents. It is also used off-label in younger children for various psychiatric disorders. Several population pharmacokinetic models of risperidone and 9-OH-risperidone have been published. The objectives of this study were to assess whether opportunistically collected pediatric data can be used to evaluate risperidone population pharmacokinetic models externally and to identify a robust model for precision dosing in children. A total of 103 concentrations of risperidone and 112 concentrations of 9-OH-risperidone, collected from 62 pediatric patients (0.16-16.8 years of age), were used in the present study. The predictive performance of five published population pharmacokinetic models (four joint parent-metabolite models and one parent only) was assessed for accuracy and precision of the predictions using statistical criteria, goodness of fit plots, prediction-corrected visual predictive checks (pcVPCs), and normalized prediction distribution errors (NPDEs). The tested models produced similarly precise predictions (Root Mean Square Error [RMSE]) ranging from 0.021 to 0.027 nmol/ml for risperidone and 0.053-0.065 nmol/ml for 9-OH-risperidone). However, one of the models (a one-compartment mixture model with clearance estimated for three subpopulations) developed with a rich dataset presented fewer biases (Mean Percent Error [MPE, %] of 1.0% vs. 101.4, 146.9, 260.4, and 292.4%) for risperidone. In contrast, a model developed with fewer data and a more similar population to the one used for the external evaluation presented fewer biases for 9-OH-risperidone (MPE: 17% vs. 69.9, 47.8, and 82.9%). None of the models evaluated seemed to be generalizable to the population used in this analysis. All the models had a modest predictive performance, potentially suggesting that sources of inter-individual variability were not entirely captured and that opportunistic data from a highly heterogeneous population are likely not the most appropriate data to evaluate risperidone models externally.

Safety of sildenafil in extremely premature infants: a phase I trial.

OBJECTIVE: To characterize the safety of sildenafil in premature infants. STUDY DESIGN: A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. RESULTS: Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. CONCLUSION: Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants. CLINICAL TRIAL: ClinicalTrials.gov Identifier: NCT01670136.

Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018.

OBJECTIVE: To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time. STUDY DESIGN: We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies. RESULTS: The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin. CONCLUSION: Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.

Safety and Pharmacokinetics of Exebacase in an Infant With Disseminated Staphylococcus aureus Infection.

Exebacase, an antistaphylococcal lysin produced from a bacteriophage-encoded gene, is a promising adjunctive therapy for severe methicillin-resistant Staphylococcus aureus infections. We describe the first infant to receive exebacase, dosing, and pharmacokinetics. Exebacase may be safe and efficacious in children; however, further clinical trials are needed to optimize dosing.

Severe Congenital Syphilis in the Neonatal Intensive Care Unit: A Retrospective Case Series.

BACKGROUND: There has been a 291% relative increase in congenital syphilis (CS) cases in the United States from 2015 to 2019. Although the majority of affected fetuses/infants are stillborn or are asymptomatic, a subset is born with severe clinical illness. We describe a series of severe CS cases in the neonatal intensive care unit. METHODS: Retrospective review of infants with CS, admitted to the Duke Intensive Care Nursery from June 2016 to February 2020. We recorded birthweight, gestational age, medications, procedures, diagnoses, laboratory data and outcomes. Severe symptoms included: birth depression, hypoxic ischemic encephalopathy (HIE), disseminated intravascular coagulopathy and/or persistent pulmonary hypertension (PPHN). RESULTS: Seven infants with CS were identified and 5 with severe presentations were included. Median gestational age was 35.1 weeks (range: 29-37 weeks, median: 35 weeks). All infants required intubation at birth, 2 required chest compressions and epinephrine in the delivery room. One had hydrops fetalis and died in the delivery room. All 4 surviving infants had HIE, severe PPHN, hepatitis and seizures. All infants had a positive rapid plasma reagin, and were treated with penicillin G. Maternal rapid plasma reagin was pending for 3 of 5 infants at delivery, and later returned positive; 2 were positive during pregnancy but not treated. Other infectious work-up was negative. Three infants survived to discharge. CONCLUSION: CS can be associated with HIE, PPHN and disseminated intravascular coagulopathy in affected infants. Clinicians should have a high index of suspicion and include CS in their differential diagnoses. This study also highlights the importance of adequate treatment of identified cases and screening during the third trimester and at delivery.

Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity.

PURPOSE: The aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies. METHODS: A population PK model was developed using opportunistically collected plasma samples. For each dosing strategy, model-based probability of target attainment (PTA) estimates were computed for study participants using empirical Bayes estimates. In addition, the effects of body size and renal function on PTA were evaluated using stochastic model simulations with virtually generated subjects. RESULTS: Twenty-nine participants, 24 of whom were obese, contributed data towards the analysis. The median (range) age, body weight, and body mass index of participants were 12.2 years (2.3-20.6), 59.2 kg (8.4-121), and 25.2 kg/m2 (13.8-42.9), respectively. Administration of 50 mg/kg intravenously (IV) every 8 hours (q8h; max 6 g/day) or 40 mg/kg IV q6h (max 6 g/day) resulted in PTA values of ≥ 90% (minimum inhibitory concentration 8 mg/L) for the subset of obese participants with estimated glomerular filtration rates (GFR) ≥ ~ 80 mL/min/1.73 m2. However, for both regimens, stochastic model simulations denoted lower PTA values (< 90%) with increasing body weight for virtual subjects with GFR ≥ 120 mL/min/1.73 m2. Alternatively, permitting for a maximum daily dose of 8 g/day using a 40 mg/kg IV q6h regimen provided PTA values that were near or above target (90%) for virtual subjects between 10 to 120 kg with GFR ≥ 80 mL/min/1.73 m2. CONCLUSION: Our analysis suggests administration of 40 mg/kg IV q6h (max 8 g/day) maximizes PTA in children and adolescents with obesity and GFR ≥ 80 mL/min/1.73 m2. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01431326.

Review of Fluconazole Treatment and Prophylaxis for Invasive Candidiasis in Neonates.

Invasive candidiasis accounts for approximately 10% of nosocomial infections in preterm infants, with an incidence of 1% to 4% among neonatal intensive care unit (NICU) admissions and a mortality as high as 20% to 30%. These outcomes warrant improved treatment and prevention strategies for infants at highest risk. The Infectious Diseases Society of America provides guidelines on antifungal medications for the prophylaxis and treatment of candidiasis in NICUs; however, there are still variations in practice on the use of fluconazole for prophylaxis and treatment of invasive candidiasis. This review provides specific information regarding fluconazole activity, pharmacokinetics, and a literature evaluation of dosing strategies and comparisons to other treatments in the neonatal population.

Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants.

Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (KI ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUCss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUCss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.

Association between neonatal intensive care unit medication safety practices, adverse events, and death.

OBJECTIVE: Determine the associations between neonatal intensive care unit (NICU) medication safety practices, laboratory-based adverse events (lab-AEs), and death. STUDY DESIGN: We combined data from a 2016 survey of Pediatrix NICUs on use of medication safety practices with 2014-2016 infant data. We grouped NICUs based on the number of safety practices used (≤5, 6-7, and 8-10) and evaluated the association between the number of safety practices used and lab-AEs and deaths using logistic regressions. RESULTS: Of the 94 NICUs included, 17% used ≤5 medication safety practices, 51% used 6-7, and 32% used 8-10. NICUs with more safety practices did not have a difference in lab-AEs or death. CONCLUSION: In this cohort, the use of more medication safety practices was not associated with fewer lab-AEs or decreased death.

Pharmacokinetic, efficacy, and safety considerations for the use of antifungal drugs in the neonatal population.

INTRODUCTION: Invasive fungal infections are an important cause of morbidity and mortality in infants, particularly in extreme prematurity. Successful systemic treatment requires consideration of antifungal efficacy, safety, and pharmacokinetics, including optimization of dosing in this population. AREAS COVERED: This review summarizes published pharmacokinetic data on four classes of antifungal agents used in the neonatal population. Alterations in absorption, distribution, drug metabolism and clearance in infants compared to adult populations are highlighted. Additionally, pharmacodynamics, safety, and therapeutic drug monitoring are discussed. Recent advancements in neonatal antifungal pharmacotherapies are examined, with emphasis on clinical application. EXPERT OPINION: Over the last two decades, published studies have provided increased knowledge on pharmacokinetic considerations in the neonatal population. Future research should focus on filling in the knowledge gaps that remain regarding the benefits and risks of combination antifungal therapy, the rising use of micafungin for invasive candidiasis given its fungicidal activity against polyene and azole-resistant Candida species and its minimal adverse effect profile, and the need for pharmacokinetic and safety data of broad spectrum triazoles, like voriconazole and posaconazole, in infants. Furthermore, efforts should focus on well-designed trials, including population pharmacokinetic studies, to develop dosing recommendations with subsequent implementation into clinical practice.

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019.

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. Design, Setting, and Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. Main Outcomes and Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). Conclusions and Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

Population pharmacokinetics of sildenafil in extremely premature infants.

AIMS: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. METHODS: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®. RESULTS: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. CONCLUSIONS: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.

Gabapentin Use in the Neonatal Intensive Care Unit.

Gabapentin was used for the treatment of term and preterm infants with suspected visceral hyperalgesia caused by a variety of neurologic and gastrointestinal morbidities. Improved feeding tolerance and decreased irritability were seen, as well as decreased usage of opioids and benzodiazepines. Adverse events occurred with abrupt discontinuation of this medication.