BACKGROUND: The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia. METHODS: Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM® version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h. RESULTS: Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital. CONCLUSIONS: Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.
- MeSH
- asfyxie novorozenců * komplikace farmakoterapie MeSH
- asfyxie komplikace farmakoterapie MeSH
- dospělí MeSH
- fenobarbital farmakokinetika terapeutické užití MeSH
- lidé MeSH
- mozková hypoxie a ischemie * terapie MeSH
- novorozenec MeSH
- terapeutická hypotermie * metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
Na úrovni farmakokinetiky jsou lékové interakce antiepileptik spojeny obvykle s enzymatickou indukcí nebo inhibicí. Méně časté jsou interakce v oblasti absorpce, vazby na plazmatické bílkoviny nebo renální exkrece. Farmakodynamické interakce antiepileptik s dalšími látkami se zřídka týkají synergismu s možností snížení dávek, spíše se zvyšuje incidence vedlejších účinků. Čistě farmakodynamické interakce byly popsány u oxcarbazepinu, perampanelu a pregabalinu.
Drug interactions of antiepileptic drugs are mostly connected with enzymatic induction or inhibition. The interaction on level of absorption, plasma-protein binding of renal excretion is less frequent. Pharmacodynamic interaction of antiepileptics with other drugs is seldom synergistic with a possibility of declination of dose. The increase of adverse drug reactions is more common. Purely pharmacodynamic interaction was described with oxcarbazepin, perampanel and pregabalin. The new antiepileptics have lower interaction potential - most of them are excreted either via kidney or extrahepatal (e. g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin). Enzymatic induction is either not present or minimal. The inductive effect is necessary to be taken into account in carbamazepine, phenytoin and phenobarbital. Inhibitive effect is held in valproic acid and felbamate. The interactive potential among newer antiepileptics is the highest in lamotrigine, oxcarbazepine and rufinamide. Drug interactions were not found in lacosamide, pregabalin, stiripentol and vigabatrin.
- MeSH
- antikonvulziva * farmakokinetika krev MeSH
- fenobarbital farmakokinetika MeSH
- fenytoin farmakokinetika MeSH
- gabapentin farmakokinetika MeSH
- karbamazepin farmakokinetika MeSH
- kyselina valproová farmakokinetika MeSH
- lamotrigin farmakokinetika MeSH
- lékové interakce * MeSH
- lidé MeSH
- primidon farmakokinetika MeSH
- topiramat farmakokinetika MeSH
- Check Tag
- lidé MeSH
Na úrovni farmakokinetiky jsou lékové interakce antiepileptik spojeny obvykle s enzymatickou indukcí nebo inhibicí. Méně časté jsou interakce v oblasti absorpce, vazby na plazmatické bílkoviny nebo renální exkrece. Farmakodynamické interakce antiepileptik s dalšími látkami se zřídka týkají synergismu s možností snížení dávek, spíše se zvyšuje incidence vedlejších účinků. Čistě farmakodynamické interakce byly popsány u oxcarbazepinu, perampanelu a pregabalinu. Nová antiepileptika mají nižší interakční potenciál - řada z nich se vylučuje renálně nebo extrahepatálně (např. gabapentin, lacosamid, levetiracetam, topiramát, vigabatrin). K enzymatické indukci pak nedochází vůbec nebo zcela minimálně. Ze starších látek lze počítat s projevem indukčního efektu u karbamazepinu, fenytoinu a fenobarbitalu. Inhibiční efekt se uplatňuje u valproátu a felbamátu. Z nových látek je interakční potenciál nejvyšší u lamotriginu, oxcarbazepinu a rufinamidu. Lékové interakce nebyly popsány u lacosamidu, pregabalinu, stiripentolu a vigabatrinu.
Drug interactions of antiepileptic drugs are mostly connected with enzymatic induction or inhibition. The interaction on level of absorption, plasma-protein binding of renal excretion is less frequent. Pharmacodynamic interaction of antiepileptics with other drugs is seldom synergistic with a possibility of declination of dose. The increase of adverse drug reactions is more common. Purely pharmacodynamic interaction was described with oxcarbazepin, perampanel and pregabalin. The new antiepileptics have lower interaction potential - most of them are excreted either via kidney or extrahepatal (e. g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin). Enzymatic induction is either not present or minimal. The inductive effect is necessary to be taken into account in carbamazepine, phenytoin and phenobarbital. Inhibitive effect is held in valproic acid and felbamate. The interactive potential among newer antiepileptics is the highest in lamotrigine, oxcarbazepine and rufinamide. Drug interactions were not found in lacosamide, pregabalin, stiripentol and vigabatrin.
- MeSH
- antikonvulziva * farmakokinetika krev MeSH
- fenobarbital farmakokinetika MeSH
- fenytoin farmakokinetika MeSH
- gabapentin farmakokinetika MeSH
- karbamazepin farmakokinetika MeSH
- kyselina valproová farmakokinetika MeSH
- lamotrigin farmakokinetika MeSH
- lékové interakce * MeSH
- lidé MeSH
- primidon farmakokinetika MeSH
- topiramat farmakokinetika MeSH
- Check Tag
- lidé MeSH
AIM: Phenobarbital (PB) pharmacokinetics (PK) in asphyxiated newborns show large variability, not only explained by hypothermia (HT). We evaluated potential relevant covariates of PK of PB in newborns treated with or without HT for hypoxic-ischemic encephalopathy (HIE). METHODS: Clearance (CL), distribution volume (Vd) and elimination half-life (t1/2) were calculated using one-compartment analysis. Covariates were clinical characteristics (weight, gestational age, hepatic, renal, and circulatory status), comedication and HIE severity [time to reach normal aEEG pattern (TnormaEEG), dichotomous, within 24 h] and asphyxia severity [severe aspyhxia = pH ≤7.1 + Apgar score ≤5 (5 min), dichotomous]. Student's t-test, two-way ANOVA, correlation and Pearson's chi-square test were used. RESULTS: Forty newborns were included [14 non-HT; 26 HT with TnormaEEG <24 h in 14/26 (group1-HT) and TnormaEEG ≥24 h in 12/26 (group2-HT)]. Severe asphyxia was present in 26/40 [5/14 non-HT, 11/14 and 10/12 in both HT groups]. PB-CL, Vd and t1/2 were similar between the non-HT and HT group. However, within the HT group, PB-CL was significantly different between group1-HT and group2-HT (p = .043). ANOVA showed that HT (p = .034) and severity of asphyxia (p = .038) reduced PB-CL (-50%). CONCLUSION: The interaction of severity of asphyxia and HT is associated with a clinical relevant reduced PB-CL, suggesting the potential relevance of disease characteristics beyond HT itself.
- MeSH
- analýza rozptylu MeSH
- antikonvulziva aplikace a dávkování farmakokinetika MeSH
- Apgar skóre MeSH
- asfyxie novorozenců komplikace terapie MeSH
- fenobarbital aplikace a dávkování farmakokinetika MeSH
- lidé MeSH
- metabolická clearance MeSH
- mozková hypoxie a ischemie etiologie terapie MeSH
- novorozenec MeSH
- prospektivní studie MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci * MeSH
- terapeutická hypotermie metody MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
WHAT IS KNOWN AND OBJECTIVE: Phenobarbital is the first-line treatment of seizures in asphyxiated neonates; however, due to the high pharmacokinetic variability in this population, there is no consensus on the optimal dosage regimen. This study was conducted to identify variables that affect phenobarbital fate during routine clinical care and then to evaluate the dosage schedule that could be applied in term asphyxiated neonates with respect to achieving the target therapeutic range. METHODS: Phenobarbital pharmacokinetics was calculated based on serum concentrations measurements using one-compartmental model. Body weight, body surface area, gestational age, creatinine clearance, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, Apgar scores, umbilical cord arterial pH and base excess were explored as covariates in linear regression models. Based on this analysis, phenobarbital loading and maintenance dose regimen were projected. RESULTS AND DISCUSSION: In the whole study population (N = 36), phenobarbital volume of distribution, clearance and half-life median (interquartile range) values were 0.49 (0.38-0.59) L/kg, 0.0045 (0.0034-0.0055) L/h/kg and 75.1 (60.2-103.3) hours, respectively. The drug volume of distribution was associated with body weight, length and body surface area, whereas clearance was not in relationship with any explored features. Weight-normalized loading dose of 15 mg/kg and weight-normalized daily maintenance dose of 3 mg/kg proved to be optimal in our study population to reach phenobarbital therapeutic range. WHAT IS NEW AND CONCLUSIONS: This study presents basis for phenobarbital initial dosing in term asphyxiated neonates during first week of life. Phenobarbital weight-normalized loading dose of 15 mg/kg lead to simulated target peak concentrations in 72% of neonates, weight-normalized maintenance dose of 3 mg/kg lead to steady state within therapeutic window in the same proportion of patients.
- MeSH
- asfyxie farmakoterapie metabolismus MeSH
- fenobarbital aplikace a dávkování farmakokinetika MeSH
- gestační stáří MeSH
- lidé MeSH
- mozková hypoxie a ischemie farmakoterapie metabolismus MeSH
- novorozenec MeSH
- poločas MeSH
- retrospektivní studie MeSH
- tkáňová distribuce MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
INTRODUCTION: The disposition of drugs is potentially changed due to extracorporeal membrane oxygenation (ECMO) in neonates and infants. METHODS: The aim of the study was to evaluate the individual pharmacokinetics (PK) of phenobarbital and the effect of PK covariates in neonates and infants undergoing ECMO. Sixteen patients (7 neonates, 9 infants) treated with phenobarbital during ECMO (centrifugal-flow pump circuits) were enrolled in the PK study. Phenobarbital serum concentrations were measured using a fluorescence polarization immunoassay. Individual PK parameters - volume of distribution (Vd) and clearance (CL) were calculated in a one-compartmental pharmacokinetic model. RESULTS: The mean (SD) Vd and CL values in neonates were 0.46 (0.24) L/kg and 8.0 (4.5) mL/h/kg, respectively. Respective values in infants were 0.56 (0.23) L/kg and 8.5 (3.1) mL/h/kg. PK parameters in neonates and infants were not significantly different. We observed high inter-individual variability in PK parameters (coefficients of variation [CV] were 52% and 53% for CL and Vd, respectively). Doses were adjusted based on therapeutic drug monitoring (TDM) in 87.5% patients. Only 50% of the first measured phenobarbital serum concentrations in each patient were within the therapeutic range of 10-40 mg/L, in comparison with 88.6% concentration measured after TDM implementation. Linear regression models showed that both Vd and CL are significantly related with body weight (BW) and length. Median optimal phenobarbital loading dose (LD) and maintenance dose (MD), calculated from pharmacokinetic data, were 15 mg/kg and 4 mg/kg/day, respectively. CONCLUSIONS: Body weight was shown to be the main PK covariate of phenobarbital disposition. Subsequent dosing nomograms are provided for phenobarbital dosing during ECMO.
- MeSH
- fenobarbital farmakokinetika terapeutické užití MeSH
- kojenec MeSH
- lidé MeSH
- mimotělní membránová oxygenace metody MeSH
- novorozenec MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Terapeutické monitorování hladin léčiv se používá jako nástroj k optimalizaci farmakoterapie epilepsie již téměř 60 let. Tato metoda je založena na předpokladu těsnější korelace klinického účinku s koncentrací léčiva než s jeho dávkou. Terapeutické monitorování se snaží optimalizovat pacientovu kompenzaci epilepsie úpravou dávkovacího režimu antiepileptik s využitím informací o jejich koncentraci v séru, plazmě nebo ve slinách s cílem potlačit záchvaty a minimalizovat nežádoucí účinky antiepileptik. U většiny antiepileptik je uváděno „referenční rozmezí“, které definuje sérové koncentrace, při kterých je u většiny pacientů očekáváno dosažení optimální klinické odpovědi. Přesto však, vzhledem k individuálním odchylkám, může vyžadovat mnoho pacientů koncentrace antiepileptik mimo tato referenční rozmezí. V těchto případech by měla být terapie vedena na základě „individuální terapeutické koncentrace“, definované jako koncentrace, při které je dosažen stav bez záchvatů s dobrou snášenlivostí medikace, případně jako nejlepší kompromis mezi zlepšením kontroly záchvatů a na koncentraci závislými nežádoucími účinky.
Therapeutic drug concentration monitoring has been used as a tool to optimize treatment of epilepsy for almost 60 years. The concept of the method rests on the assumption that clinical effects correlate better with drug concentrations than with the dose. It seeks to optimize the seizure suppressing effects of antiepileptic drugs while minimizing their adverse effects by managing their medication regimen with the assistance of information on the concentration of antiepileptic drugs in the serum, plasma or saliva. For most antiepileptic drugs, “reference ranges” have been reported which define the serum concentrations at which most patients are expected to exhibit an optimal clinical response. Due to individual variation, however, many patients may require concentrations outside the reference ranges. In many situations, patient management is best guided by determination of the “individual therapeutic concentration,” defined as the concentration at which an individual has been found to achieve seizure freedom with good tolerability, or the best compromise between improvement in seizure control and concentration-related adverse effects.
- Klíčová slova
- sultiam,
- MeSH
- antikonvulziva * farmakokinetika krev škodlivé účinky MeSH
- epilepsie farmakoterapie MeSH
- ethosuximid farmakokinetika krev MeSH
- fenobarbital farmakokinetika krev MeSH
- fenytoin farmakokinetika krev MeSH
- karbamazepin farmakokinetika krev MeSH
- klonazepam farmakokinetika krev MeSH
- kyselina valproová farmakokinetika krev MeSH
- lidé MeSH
- monitorování léčiv * MeSH
- primidon farmakokinetika krev MeSH
- referenční hodnoty * MeSH
- thiaziny farmakokinetika krev MeSH
- Check Tag
- lidé MeSH
Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.
- MeSH
- analgetika aplikace a dávkování farmakokinetika MeSH
- antikonvulziva aplikace a dávkování farmakokinetika MeSH
- fenobarbital aplikace a dávkování farmakokinetika MeSH
- kombinovaná farmakoterapie MeSH
- lékové interakce fyziologie MeSH
- lidé MeSH
- mozková hypoxie a ischemie diagnóza farmakoterapie metabolismus MeSH
- novorozenec MeSH
- prospektivní studie MeSH
- vazokonstriktory aplikace a dávkování farmakokinetika MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- farmakodynamika,
- MeSH
- antagonisté excitačních aminokyselin MeSH
- antikonvulziva aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- dítě MeSH
- farmakokinetika MeSH
- fenobarbital * aplikace a dávkování farmakokinetika škodlivé účinky terapeutické užití MeSH
- GABA modulátory MeSH
- hodnocení léčiv MeSH
- hypnotika a sedativa MeSH
- indukovaná hypertermie využití MeSH
- induktory cytochromu P450 CYP2B6 farmakokinetika MeSH
- induktory cytochromu P450 CYP3A farmakokinetika MeSH
- klinické zkoušky jako téma MeSH
- komorbidita MeSH
- křeče u dětí patologie terapie MeSH
- lékové interakce MeSH
- lidé MeSH
- mozková hypoxie a ischemie * diagnóza terapie MeSH
- multiorgánové selhání diagnóza terapie MeSH
- novorozenec * MeSH
- terapeutická hypotermie využití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec * MeSH
- Publikační typ
- abstrakty MeSH
Prezentujeme případ smrtelné otravy psychotropními drogami. Kvantitativní toxikologická analýza prokázala ve femorální krvi tyto koncentrace fenobarbitalu, promethazinu, chlorpromazinu, alprazolamu a bromazepamu: 69.51μg/ml, 32.73μg/ml 24.76μg/ml, 0.04μg/ml and 0.31μg/ml; velké množství těchto látek bylo prokázáno i v žaludečním obsahu. Soudíme, že příčinou smrti bylo především předávkování fenobarbitalem, promethazinem a chlorpromazinem při jejich masivní ingesci. Dále diskutujeme přínos pleurálního výpotku jako alternativního vzorku pro toxikologické vyšetření.
A fatal poisoning case involving multiple psychotropic drugs is presented. Quantitative toxicological analysis showed that the concentrations of phenobarbital, promethazine, chlorpromazine, alprazolam and bromazepam in the femoral blood were 69.51μg/ml, 32.73μg/ml 24.76μg/ml, 0.04μg/ml and 0.31μg/ml respectively, and large amounts of drugs were also detected in the stomach contents. We concluded that the cause of death was mainly due to overdose of phenobarbital, promethazine and chlorpromazine by massive ingestion, and we also discuss the value of pleural effusions as an alternative specimen for toxicological examination.
- Klíčová slova
- mnohočetné drogy, kapalinová chromatografie s hmotnostní spektrometrií,
- MeSH
- chlorpromazin analýza farmakokinetika otrava MeSH
- chromatografie kapalinová MeSH
- fenobarbital analýza farmakokinetika otrava MeSH
- hmotnostní spektrometrie MeSH
- lidé MeSH
- mladý dospělý MeSH
- otrava krev metabolismus moč MeSH
- pitva MeSH
- pleurální výpotek metabolismus patologie MeSH
- posmrtné změny MeSH
- předávkování léky MeSH
- promethazin analýza farmakokinetika otrava MeSH
- psychotropní léky analýza farmakokinetika otrava MeSH
- referenční hodnoty MeSH
- soudní toxikologie metody MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
