RESUMO
OBJECTIVE: To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. METHODS: A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. RESULTS: A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. CONCLUSIONS: To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment.
Assuntos
Apneia/tratamento farmacológico , Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Citratos/administração & dosagem , Doenças do Prematuro/tratamento farmacológico , Peso ao Nascer , Cafeína/farmacocinética , Cafeína/uso terapêutico , Estimulantes do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Citratos/farmacocinética , Citratos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Aumento de PesoRESUMO
OBJECTIVES: To develop a mathematical, semimechanistic model characterizing physiological weight changes in term neonates, identify and quantify key maternal and neonatal factors influencing weight changes, and provide an online tool to forecast individual weight changes during the first week of life. STUDY DESIGN: Longitudinal weight data from 1335 healthy term neonates exclusively breastfed up to 1 week of life were available. A semimechanistic model was developed to characterize weight changes applying nonlinear mixed-effects modeling. Covariate testing was performed by applying a standard stepwise forward selection-backward deletion approach. The developed model was externally evaluated on 300 additional neonates collected in the same center. RESULTS: Weight changes during first week of life were described as a function of a changing net balance between time-dependent rates of weight gain and weight loss. Males had higher birth weights (WT0) than females. Gestational age had a positive effect on WT0 and weight gain rate, whereas mother's age had a positive effect on WT0 and a negative effect on weight gain rate. The developed model showed good predictive performance when externally validated (bias = 0.011%, precision = 0.52%) and was able to accurately forecast individual weight changes up to 1 week with only 3 initial weight measurements (bias = -0.74%, precision = 1.54%). CONCLUSIONS: This semimechanistic model characterizes weight changes in healthy breastfed neonates during first week of life. We provide a user-friendly online tool allowing caregivers to forecast and monitor individual weight changes. We plan to validate this model with data from other centers and expand it with data from preterm neonates.