RESUMO
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.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Criança , Endopeptidases , Humanos , Lactente , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureusRESUMO
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.
Assuntos
Uso de Medicamentos/tendências , Preparações Farmacêuticas , Estudos de Coortes , Bases de Dados Factuais , Uso de Medicamentos/estatística & dados numéricos , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Estados UnidosRESUMO
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.
Assuntos
Recém-Nascido Prematuro/sangue , Modelos Biológicos , Inibidores da Fosfodiesterase 5/farmacocinética , Citrato de Sildenafila/farmacocinética , Administração Oral , Estudos de Coortes , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Fluconazol/administração & dosagem , Fluconazol/farmacocinética , Idade Gestacional , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/tratamento farmacológico , Lactente , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/tratamento farmacológico , Injeções Intravenosas , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/sangue , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/sangue , Citrato de Sildenafila/uso terapêuticoRESUMO
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.
Assuntos
Aminas/administração & dosagem , Analgésicos/administração & dosagem , Benzodiazepinas/administração & dosagem , Ácidos Cicloexanocarboxílicos/administração & dosagem , Hiperalgesia/tratamento farmacológico , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Ácido gama-Aminobutírico/administração & dosagem , Aminas/efeitos adversos , Analgésicos/efeitos adversos , Benzodiazepinas/efeitos adversos , Ácidos Cicloexanocarboxílicos/efeitos adversos , Feminino , Gabapentina , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Ácido gama-Aminobutírico/efeitos adversosRESUMO
Dexamethasone is a synthetic glucocorticoid approved for treating disorders of various organ systems in both adult and pediatric populations. Currently, approved pediatric dosing recommendations are weight-based, but it is unknown whether differences in dexamethasone drug disposition and exposure exist for children with obesity. This study aimed to develop a population pharmacokinetic (PopPK) model for dexamethasone with data collected from children with obesity. Dexamethasone was given as either IV or oral/enteral administration, and a salt factor correction was used for dexamethasone sodium phosphate injection. A PopPK analysis using dexamethasone plasma concentration versus time was performed using the software NONMEM. A virtual population of 1000 children with obesity across three age groups was generated for dosing simulations. Data from 59 study participants with 82 PK plasma samples were used in the PopPK analysis. A one-compartment model with first-order absorption and the inclusion of total body weight as a covariate characterized the data. No other covariates were included in the PopPK model. Single and multiple IV dose(s) of 0.5 and 1 mg/kg every 8 h resulted in 68% or more of virtual children with obesity attaining simulated exposures that were within exposure ranges previously reported in adult studies. In conclusion, this was the first study to characterize dexamethasone's PopPK in children with obesity. Simulation results suggest that virtual children with obesity receiving oral doses of 0.5 and 1 mg/kg had generally comparable dexamethasone exposures as adult estimates. Additional studies are needed to characterize the dexamethasone's target exposure in children.
RESUMO
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.
Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Recém-Nascido , Humanos , Cafeína , Estudos Retrospectivos , Cardiopatias Congênitas/cirurgia , Injúria Renal Aguda/epidemiologia , Fatores de Risco , Ponte CardiopulmonarRESUMO
BACKGROUND: Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity. OBJECTIVE: This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework. METHODS: A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models. RESULTS: Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature. CONCLUSIONS: PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.
Assuntos
Anticonvulsivantes , Levetiracetam , Modelos Biológicos , Humanos , Levetiracetam/farmacocinética , Levetiracetam/administração & dosagem , Pré-Escolar , Criança , Lactente , Adolescente , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/administração & dosagem , Masculino , Feminino , Fatores Etários , Recém-Nascido , Adulto Jovem , Obesidade/metabolismo , Estudos Prospectivos , Simulação por ComputadorRESUMO
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.
Assuntos
Receptores Proteína Tirosina Quinases , Receptores Colinérgicos , Humanos , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/patologia , Síndromes Miastênicas Congênitas/diagnóstico , Domínios Proteicos/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/química , Índice de Gravidade de Doença , Masculino , Feminino , Recém-NascidoRESUMO
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.
Assuntos
Dexmedetomidina , Hipnóticos e Sedativos , Modelos Biológicos , Humanos , Dexmedetomidina/farmacocinética , Dexmedetomidina/administração & dosagem , Dexmedetomidina/sangue , Lactente , Criança , Pré-Escolar , Adolescente , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/administração & dosagem , Masculino , Feminino , Adulto Jovem , Recém-Nascido , Estudos ProspectivosRESUMO
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.
RESUMO
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.
Assuntos
Analgésicos Opioides , Humanos , Criança , Método Duplo-Cego , Fatores de TempoRESUMO
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.
RESUMO
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.
Assuntos
Sífilis Congênita , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Penicilina G/uso terapêutico , Gravidez , Reaginas , Estudos Retrospectivos , Sífilis Congênita/diagnóstico , Sífilis Congênita/tratamento farmacológicoRESUMO
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.
RESUMO
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.
Assuntos
Hipotensão , Doenças do Prematuro , Humanos , Hipotensão/induzido quimicamente , Hipotensão/tratamento farmacológico , Lactente Extremamente Prematuro , Recém-Nascido de Baixo Peso , Recém-Nascido , Doenças do Prematuro/tratamento farmacológico , Citrato de Sildenafila/efeitos adversosRESUMO
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.
RESUMO
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.
Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas/fisiologia , Fluconazol/farmacocinética , Citrato de Sildenafila/farmacocinética , Adolescente , Adulto , Idoso , Área Sob a Curva , Feminino , Humanos , Recém-Nascido Prematuro , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto JovemRESUMO
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.
Assuntos
Unidades de Terapia Intensiva Neonatal , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Inquéritos e QuestionáriosRESUMO
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.
Assuntos
Antibacterianos/farmacocinética , Ceftazidima/farmacocinética , Obesidade Infantil/tratamento farmacológico , Adolescente , Antibacterianos/uso terapêutico , Teorema de Bayes , Ceftazidima/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Adulto JovemRESUMO
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.