Estimation of initial phenobarbital dosing in term neonates with moderate‐to‐severe hypoxic ischaemic encephalopathy following perinatal asphyxia

Šíma, Martin; Pokorná, Pavla; Hartinger, Jan Miroslav; Slanař, Ondřej

doi:10.1111/jcpt.12632

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…Phenobarbital is one of most frequently administered anticonvulsive drugs in pediatric patients due to its well-established efficacy, the availability of an injectable dosage form, and its additional beneficial sedative effect (8). Monitoring serum phenobarbital concentrations is often routinely performed to achieve safe and effective individual therapy (9,10). Despite its widespread use, there is insufficient information on the potential impact of ECMO on the pharmacokinetics of phenobarbital.…”

mentioning

confidence: 99%

Rapid Increase in Clearance of Phenobarbital in Neonates on Extracorporeal Membrane Oxygenation: A Pilot Retrospective Population Pharmacokinetic Analysis

Michaličková

Pokorná²,

Tibboel

et al. 2020

Pediatric Critical Care Medicine

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Objectives: This study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and provide guidance on dosing. Design: Retrospective pilot population pharmacokinetic analysis. Setting: Neonatal ICU. Patients: Thirteen critically ill neonates (birth body weight, 3.21 kg [2.65–3.72 kg]; postnatal age at start of treatment: 2 d [0–7 d]; gestational age: 38 wk [38–41 wk]) receiving venovenous or venoarterial extracorporeal membrane oxygenation. Interventions: Phenobarbital administered in a loading dose of 7.5 mg/kg (8.5–16 mg/kg) and maintenance dose of 6.9 mg/kg/d (4.5–8.5 mg/kg/d). Measurements and Main Results: Therapeutic drug monitoring data were available, yielding 5, 31, and 19 phenobarbital concentrations before, during, and after extracorporeal membrane oxygenation, respectively. Population pharmacokinetic analysis was performed using NONMEM 7.3.0 (ICON Development Solutions, Ellicott City, MD). Maturation functions for clearance and volume of distribution were obtained from literature. In a one-compartment model, clearance and volume of distribution for a typical neonate off extracorporeal membrane oxygenation and with a median birth body weight (3.21 kg) at median postnatal age (2 d) were 0.0096 L/hr (relative se = 11%)) and 2.72 L (16%), respectively. During extracorporeal membrane oxygenation, clearance was found to linearly increase with time. Upon decannulation, phenobarbital clearance initially decreased and subsequently increased slowly driven by maturation. Extracorporeal membrane oxygenation-related changes in volume of distribution could not be identified, possibly due to sparse data collection shortly after extracorporeal membrane oxygenation start. According to the model, target attainment is achieved in the first 12 days of extracorporeal membrane oxygenation with a regimen of a loading dose of 20 mg/kg and a maintenance dose of 4 mg/kg/d divided in two doses with an increase of 0.25 mg/kg every 12 hours during extracorporeal membrane oxygenation treatment. Conclusions: We found a time-dependent increase in phenobarbital clearance during the first 12 days of extracorporeal membrane oxygenation treatment in neonates, which results in continuously decreasing phenobarbital exposure and increases the risk of therapeutic failure over time. Due to high unexplained variability, frequent and repeated therapeutic drug monitoring should be considered even with the model-derived regimen.

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confidence: 99%

Rapid Increase in Clearance of Phenobarbital in Neonates on Extracorporeal Membrane Oxygenation: A Pilot Retrospective Population Pharmacokinetic Analysis

Michaličková

Pokorná²,

Tibboel

et al. 2020

Pediatric Critical Care Medicine

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“…However, other studies have indicated rather inconsistent data, making conclusions on valid covariates for the drug dosing difficult. We have previously noticed an upward relationship between Vd and ABW, height, and body surface area, whereas CL was not associated with either demographic or clinical features [33]. Pitlick et al observed no correlation between Vd and gestational age, while CL increased with postnatal age during the first month [35].…”

Section: Resultsmentioning

confidence: 76%

What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?

2021

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Phenobarbital is a first-line treatment of various seizure types in newborns. Dosage individualization maximizing the proportion of patients with drug levels in therapeutic range or sufficient treatment response is still challenging. The aim of this review was to summarize the available evidence on phenobarbital pharmacokinetics in neonates and to identify its possible covariates suitable for individualization of initial drug dosing. Several covariates have been considered: body weight and height, body surface area, gestational and postnatal age, laboratory parameters of renal and hepatic functions, asphyxia, therapeutic hypothermia, extracorporeal membrane oxygenation (ECMO), drug interactions, and genetic polymorphisms. The most frequently studied and well-founded covariate for the estimation of phenobarbital dosing is actual body weight. Loading dose of 15–20 mg/kg followed by a maintenance dose of 3–5 mg/kg/day seems to be accurate. However, the evidence for the other covariates with respect to dosing individualization is not sufficient. Doses at the lower limit of suggested range should be preferred in patients with severe asphyxia, while the upper limit of the range should be targeted in neonates receiving ECMO support.

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“…The half‐life of PB is approximately 100 hours in adults and 141 hours in preterm infants, decreasing to 67 hours in infants at 4 weeks old 6 . There is no clear consensus regarding the acceptable therapeutic range of PB, 7 but 10‐40 mg/L has been reported to be effective and safe 8–13 . Serum concentrations of PB up to 100 mg/L are needed in some infants with refractory seizures 9 .…”

Section: Introductionmentioning

confidence: 99%

External evaluation of the predictive performance of seven population pharmacokinetic models for phenobarbital in neonates

Ryu

Jung

Jiao

et al. 2021

Brit J Clinical Pharma

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Aim Several studies have reported population pharmacokinetic models for phenobarbital (PB), but the predictive performance of these models has not been well documented. This study aims to do external evaluation of the predictive performance in published pharmacokinetic models. Methods Therapeutic drug monitoring data collected in neonates and young infants treated with PB for seizure control was used for external evaluation. A literature review was conducted through PubMed to identify population pharmacokinetic models. Prediction‐ and simulation‐based diagnostics, and Bayesian forecasting were performed for external evaluation. The incorporation of allometric scaling for body size and maturation factors into the published models was also tested for prediction improvement. Results A total of 79 serum concentrations from 28 subjects were included in the external dataset. Seven population pharmacokinetic studies of PB were identified as relevant in the literature search and included for our evaluation. The model by Voller et al showed the best performance concerning prediction‐based evaluation. In simulation‐based analyses, the normalized prediction distribution error of two models (those of Shellhaas et al and Marsot et al) obeyed a normal distribution. Bayesian forecasting with more than one observation improved predictive capability. Incorporation of both allometric size scaling and maturation function generally enhanced the predictive performance, with improvement as observed in the model of Vucicevic et al. Conclusions The predictive performance of published pharmacokinetic models of PB was diverse. Bayesian forecasting and incorporation of both size and maturation factors could improve the predictability of the models for neonates.

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Estimation of initial phenobarbital dosing in term neonates with moderate‐to‐severe hypoxic ischaemic encephalopathy following perinatal asphyxia

Cited by 12 publications

References 27 publications

Rapid Increase in Clearance of Phenobarbital in Neonates on Extracorporeal Membrane Oxygenation: A Pilot Retrospective Population Pharmacokinetic Analysis

Rapid Increase in Clearance of Phenobarbital in Neonates on Extracorporeal Membrane Oxygenation: A Pilot Retrospective Population Pharmacokinetic Analysis

What Is the Best Predictor of Phenobarbital Pharmacokinetics to Use for Initial Dosing in Neonates?

External evaluation of the predictive performance of seven population pharmacokinetic models for phenobarbital in neonates

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