Pharmacokinetics of phenobarbital in childhood

Heimann, G.; Gladtke, E

doi:10.1007/bf00607431

Cited by 49 publications

(22 citation statements)

References 19 publications

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“…All the children achieved plasma phenobarbital concentrations of greater than 10 mg l −1 within 10 min after the loading dose, and peak phenobarbital plasma concentrations of greater than 15 mg l −1 . Mean clearance, steady state volume of distribution, fraction unbound and CSF:plasma ratio were comparable to reported values in paediatric patients [11,[15][16][17], whereas the mean elimination half-life was comparable to values previously reported in children with severe malaria [4].…”

Section: Discussionsupporting

confidence: 67%

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

Kokwaro

Ogutu

Muchohi

et al. 2003

Brit J Clinical Pharma

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Aims Phenobarbital is commonly used to treat status epilepticus in resource‐poor countries. Although a dose of 20 mg kg−1 is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15‐mg kg−1 intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus.Methods Twelve children (M/F: 11/1), aged 7–62 months, received a loading dose of phenobarbital (15 mg kg−1) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg−1 at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx® fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l−1 for 72 h.Results All the children achieved plasma concentrations above 15 mg l−1 by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, ∞) ]: 4259 (3169, 5448) mg l−1.h, : 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg−1 h−1, Vss: 0.8 (0.7, 0.9) l kg −1, CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n= 6) and Cmax: 19.9 (17.9–27.9) mg l−1. Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg−1 followed by two maintenance doses of 2.5 mg kg−1 at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l−1 for 72 h.Conclusions Phenobarbital, given as an i.v. loading dose, 15 mg kg−1, achieves maximum plasma concentrations of greater than 15 mg l−1 with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg−1 at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15–20 mg l−1 for 72 h, and may be a suitable regimen for treatment of convulsions in these children.

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Section: Discussionsupporting

confidence: 67%

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

Kokwaro

Ogutu

Muchohi

et al. 2003

Brit J Clinical Pharma

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“…One patient（Case 8）／ had a high plasma drug concentration of 45.3 mg／mL prior to the final dose of maintenance therapy, which was very different from those observed in the remaining patients. It remains unknown why the plasma drug level increased before the final dose of maintenance therapy in this patient, but a low clearance and a protracted elimination half-life of phenobarbital in newborns at the early postnatal stage 11) could explain the elevation, particularly since the maintenance therapy was started at a relatively high dose in this patient. A previous study has shown that maintenance therapy with phenobarbital at 5 ／／ mg／kg／day may result in an increased plasma drug ／ level of approximately 40 mg／mL 12) .…”

Section: Discussionmentioning

confidence: 94%

A Clinical Trial Assessing the Efficacy and Safety of a New Injectable Formula of Sodium Phenobarbital Containing No Additives for the Treatment of Neonatal Seizures

Kawada

Itoh

Itani

et al. 2011

Jpn. J. Clin. Pharmacol. Ther.

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Aims：A new phenobarbital preparation for injection containing no additives（NOBELBAR® ）was developed in Japan for safer use in neonates with seizures. This study was conducted to evaluate the clinical efficacy and safety of NOBELBAR®for the treatment of neonatal seizures. Methods：This investigator-initiated clinical trial was an open-label, uncontrolled, multicenter study, conducted in compliance with the good clinical practice. Phenobarbital was initially administered intravenously at a loading ／／ dose of 20 mg／kg. An additional dose of 20 mg／kg was given if the seizures did not resolve. The primary efficacy was evaluated 30 minutes after the administration of the loading dose. Infants who responded to the loading ／ administration received maintenance therapy with 2.5 to 5 mg／kg intravenous phenobarbital once daily for 6 days. Results：NOBELBAR®was administered to 10 neonates with seizures. The primary efficacy was evaluated as complete response in all patients. Adverse events were reported in 9 of the 10 patients（90％), most of which ／ were mild. Plasma phenobarbital concentrations ranged from 18.7 to 45.3 mg／mL. Conclusion：The study demonstrated that NOBELBAR®was effective for the control of neonatal seizures, and plasma drug concentrations were maintained within the therapeutic range. Approved for manufacturing and marketing was obtained based on the results of this study and other relevant data. （Clinical Trials. number, UMIN-C000000410, JMA-ⅡA00002.)

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“…The relative consistency of this parameter is surprising in view of the wide range of birth weights and gestational ages of our patient population. Several inves tigators have suggested that the Vd of phénobarbital, because of its pKa of 7.4, may be greatly affected by variations of acid-base balance of blood pH [11,12]. Waddell et al [11], in a study in dogs, found that the Vd of phé nobarbital increased significantly as blood pH decreased, resulting in lower plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Population Pharmacokinetics of Phénobarbital Derived from Routine Clinical Data

Grasela

Donn

1985

Dev Pharmacol Ther

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Routine clinical pharmacokinetic (PK) data collected from 59 preterm infants who received phénobarbital were analyzed to estimate population PK parameters. Birth weights ranged from 600 to 3,620 g (mean 1,520 g), and gestational ages ranged from 24 to 42 weeks (mean 31 weeks). Data were analyzed using NONMEM, a computer program designed for population PK analysis. The mean (±CV) clearance of phénobarbital was 0.0047 liter/h/kg (± 19%) and the mean (±CV) volume of distribution (Vd) was 0.96 liter/kg (± 16%). The calculated mean serum half-life was 141 h. Clearance was not affected by gestational age, sex, asphyxia, or duration of therapy. Vd was not affected by gestational age or sex but was increased by 13% in the presence of asphyxia (5-min Apgar score <5, p < 0.05).

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Pharmacokinetics of phenobarbital in childhood

Cited by 49 publications

References 19 publications

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

A Clinical Trial Assessing the Efficacy and Safety of a New Injectable Formula of Sodium Phenobarbital Containing No Additives for the Treatment of Neonatal Seizures

Neonatal Population Pharmacokinetics of Phénobarbital Derived from Routine Clinical Data

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