Effect of Co-Medication on the Pharmacokinetic Parameters of Phenobarbital in Asphyxiated Newborns

Šíma, Martin; Pokorna, Paula; Hronová, Karolína; Slanař, Ondřej

doi:10.33549/physiolres.933213

Cited by 10 publications

(7 citation statements)

References 21 publications

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“…33 None of the included studies measured the serum levels of phenobarbital metabolites so no final conclusions can be drawn about metabolism. [34][35][36][37][38][39] About 66% of neonates with HIE and seizures respond to phenobarbital. 34 35 Pokorná et al 36 observed decreased clearance during TH, although these changes were not statistically significant (table 2b).…”

Section: Phenobarbitalmentioning

confidence: 99%

“…This suggests that disease severity is a more prominent covariate of phenobarbital clearance compared with TH. 36 Furthermore, concomitant dobutamine administration also had an effect on phenobarbital clearance (although the authors suspect this was an artefact of the small sample size 39 ).…”

Section: Phenobarbitalmentioning

confidence: 99%

“…However, it remains one of the most effective antiepileptic drugs for neonatal seizures. [34][35][36][37][38][39] Pending the outcome of ongoing comparative studies on the use of phenobarbital or levetiracetam as first-line antiepileptic, 76 it is possible that levetiracetam or another antiepileptic drug will replace phenobarbital. However, as phenobarbital has an inducing effect on the metabolism of midazolam (which is often coadministered), if phenobarbital were to be replaced by levetiracetam, the dosage of midazolam needs to be reduced if we aim for similar exposure.…”

Section: Morphinementioning

confidence: 99%

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Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Lutz

Allegaert

Hoon

et al. 2020

bmjpo

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BackgroundNeonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specific pharmacokinetic profile. The aim of this paper is to determine the effect that hypothermia for neonates suffering from hypoxic ischaemic encephalopathy has on the pharmacokinetics and to what extent dosing regimens need adjustments.MethodA systematic search was performed on PubMed, Embase and Cochrane Library of literature (2000–2020) using a combination of the following search terms: therapeutic hypothermia, neonate, hypoxic ischemic encephalopathy and pharmacokinetics. Titles and abstracts were screened, and inclusion/exclusion criteria were applied. Finally, relevant full texts were read, and secondary inclusion was applied on the identified articles.ResultsA total of 380 articles were retrieved, and 34 articles included after application of inclusion/exclusion criteria and duplicate removal, two additional papers were included as suggested by the reviewers. Twelve out of 36 studies on 15 compounds demonstrated a significant decrease in clearance, be it that the extent differs between routes of elimination and compounds, most pronounced for renal elimination (phenobarbital no difference, midazolam metabolite −21%, lidocaine −24%; morphine −21% to −47%, gentamicin −25% to −35%, amikacin −40%) during hypothermia. The data as retrieved in literature were subsequent compared with the dosing regimen as stated in the Dutch paediatric formulary.ConclusionDepending on the drug-specific disposition characteristics, therapeutic hypothermia in neonates with hypoxic ischaemic encephalopathy affects pharmacokinetics.

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Section: Phenobarbitalmentioning

confidence: 99%

Section: Phenobarbitalmentioning

confidence: 99%

Section: Morphinementioning

confidence: 99%

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Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Lutz

Allegaert

Hoon

et al. 2020

bmjpo

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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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“…The 95% confidence intervals (95% CI) for medians were calculated by the Bonett and Price method 11. The possible impact of anticonvulsive co-medication on levetiracetam pharmacokinetic parameters was evaluated using the Mann-Whitney U-test as described previously 12. A linear regression model was used to evaluate the relationships between levetiracetam pharmacokinetic parameters with continuous variables.…”

Section: Methodsmentioning

confidence: 99%

Levetiracetam pharmacokinetics and its covariates: proposal for optimal dosing in the paediatric population

et al. 2021

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ObjectivesLevetiracetam is an anticonvulsive drug increasingly used in paediatric populations. Ontogenesis may alter its pharmacokinetics, demanding dose individualisation of levetiracetam in paediatric populations. We therefore aimed to explore levetiracetam pharmacokinetics and to propose its optimal dosing in the paediatric population.MethodsIndividual levetiracetam pharmacokinetic parameters were calculated based on therapeutic drug monitoring data, using a one-compartmental model, and regression models were used to explore possible covariates.Results56 patients aged from 47 days to 18 years were included in the analysis. The median (IQR) volume of distribution and clearance of levetiracetam were 0.7 (0.58–0.85) L/kg and 0.123 (0.085–0.167) L/hour/kg, respectively. Levetiracetam pharmacokinetics were influenced by postnatal age, body size descriptors and renal functional status.ConclusionsBased on observed relationships, an individualised loading dose of 26.2 mg/kg body weight and maintenance dose of 20.7 mg/mL/min of estimated glomerular filtration rate were calculated as optimal. Since we observed increased levetiracetam clearance in association with valproate co-medication, caution should be used when combining these two drugs.

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Effect of Co-Medication on the Pharmacokinetic Parameters of Phenobarbital in Asphyxiated Newborns

Cited by 10 publications

References 21 publications

Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

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

Levetiracetam pharmacokinetics and its covariates: proposal for optimal dosing in the paediatric population

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