Correlation between the saliva and free serum concentration of phenobarbital in epileptic children

Tokugawa, Ken; Ueda, Kohji; Fujito, Hiroshi; Kurokawa, Toru

doi:10.1007/bf00439247

Cited by 21 publications

(13 citation statements)

References 9 publications

(11 reference statements)

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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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“…Some prior studies of phenobarbital in newborns with seizures utilized free levels, because of concern about variable protein binding in critically ill newborns[6]. However, the free plasma phenobarbital level is tightly correlated to the total serum concentration [27, 28]. Finally, our study did not include premature infants, so the findings cannot be directly applied to that population.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Phenobarbital in Infants With Neonatal Encephalopathy Treated With Therapeutic Hypothermia*

Shellhaas

Dillon

et al. 2013

Pediatric Critical Care Medicine

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Objective Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy (HIE) are treated with therapeutic hypothermia (TH) and about 40% have clinical seizures. Little is known about pharmacokinetics of phenobarbital in infants with HIE who undergo TH. The objective of this study was to determine the effect of TH on phenobarbital pharmacokinetics, taking into account maturational changes. Setting Level 3 neonatal intensive care unit. Patients Infants with HIE and suspected seizures, all treated with phenobarbital. Some of these infant also received treatment with TH. Interventions None. Design A retrospective cohort study of 39 infants with HIE treated with phenobarbital (20 were treated with TH and 19 were not). Measurements and main results Data were collected on phenobarbital plasma concentrations on 39 subjects with HIE with or without TH. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance (CL) of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. TH did not influence the pharmacokinetic parameters of phenobarbital. Conclusions TH does not influence the CL of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for initial treatment of seizures in neonates with HIE treated with TH.

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“…26,49,50,53,54,56,57,[73][74][75][134][135][136][137] Two studies have demonstrated that the distribution of phenobarbital into saliva depends on salivary pH 56,136 ; however, other studies have not found an effect of pH. A number of studies in both adults and children with epilepsy have demonstrated that phenobarbital distributes into saliva with saliva/total serum phenobarbital concentration ratios ranging 0.2-0.52, whereas the mean saliva/serum-free phenobarbital concentration ratios ranged 0.63-0.68.…”

Section: Saliva Tdm For Phenobarbitalmentioning

confidence: 99%

Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva

Patsalos¹,

Berry²

2013

Therapeutic Drug Monitoring

170

126

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Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM) has proven to be an invaluable surrogate marker for individualizing and optimizing the drug management of patients with epilepsy. Since 1989, there has been an exponential increase in AEDs with 23 currently licensed for clinical use, and recently, there has been renewed and extensive interest in the use of saliva as an alternative matrix for AED TDM. The advantages of saliva include the fact that for many AEDs it reflects the free (pharmacologically active) concentration in serum; it is readily sampled, can be sampled repetitively, and sampling is noninvasive; does not require the expertise of a phlebotomist; and is preferred by many patients, particularly children and the elderly. For each AED, this review summarizes the key pharmacokinetic characteristics relevant to the practice of TDM, discusses the use of other biological matrices with particular emphasis on saliva and the evidence that saliva concentration reflects those in serum. Also discussed are the indications for salivary AED TDM, the key factors to consider when saliva sampling is to be undertaken, and finally, a practical protocol is described so as to enable AED TDM to be applied optimally and effectively in the clinical setting. Overall, there is compelling evidence that salivary TDM can be usefully applied so as to optimize the treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the data are sparse or nonexistent.

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Correlation between the saliva and free serum concentration of phenobarbital in epileptic children

Cited by 21 publications

References 9 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

Population Pharmacokinetics of Phenobarbital in Infants With Neonatal Encephalopathy Treated With Therapeutic Hypothermia*

Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva

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