Drug Disposition in Neonatal Göttingen Minipigs: Exploring Effects of Perinatal Asphyxia and Therapeutic Hypothermia.

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy, disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs-midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM)-were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), and hypoxia plus TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (predose) and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, and 24 hours post drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and noncompartmental PK analysis. The study showed a statistically significant decrease in FNT clearance (CL; 66% decrease), with an approximately threefold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL, with a 62% longer t1/2 compared with the C group; however, it was not statistically significant. Although not statistically significant, trends toward lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared with controls. SIGNIFICANCE STATEMENT: The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK using four model drugs. Such insights can subsequently be used to inform and develop a physiologically based pharmacokinetic model, which is useful for drug exposure prediction in human neonates.

Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia.

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.

A combination of phenobarbital and the bumetanide derivative bumepamine prevents neonatal seizures and subsequent hippocampal neurodegeneration in a rat model of birth asphyxia.

OBJECTIVES: Bumetanide was suggested as an adjunct to phenobarbital for suppression of neonatal seizures. This suggestion was based on the idea that bumetanide, by reducing intraneuronal chloride accumulation through inhibition of the Na-K-2Cl cotransporter NKCC1, may attenuate or abolish depolarizing γ-aminobutyric acid (GABA) responses caused by birth asphyxia. However, a first proof-of-concept clinical trial failed. This could have had several reasons, including bumetanide's poor brain penetration, the wide cellular NKCC1 expression pattern in the brain, and problems with the general concept of NKCC1's role in neonatal seizures. We recently replicated the clinical failure of bumetanide to potentiate phenobarbital's effect in a novel rat model of birth asphyxia. In this study, a clinically relevant dose (0.3 mg/kg) of bumetanide was used that does not lead to NKCC1-inhibitory brain levels. The aim of the present experiments was to examine whether a much higher dose (10 mg/kg) of bumetanide is capable of potentiating phenobarbital in this rat model. Furthermore, the effects of the two lipophilic bumetanide derivatives, the ester prodrug N,N-dimethylaminoethylester of bumetanide (DIMAEB) and the benzylamine derivative bumepamine, were examined at equimolar doses. METHODS: Intermittent asphyxia was induced for 30 min by exposing male and female P11 rat pups to three 7 + 3 min cycles of 9% and 5% O2 at constant 20% CO2 . All control pups exhibited neonatal seizures after the asphyxia. RESULTS: Even at 10 mg/kg, bumetanide did not potentiate the effect of a submaximal dose (15 mg/kg) of phenobarbital on seizure incidence, whereas a significant suppression of neonatal seizures was determined for combinations of phenobarbital with DIMAEB or, more effectively, bumepamine, which, however, does not inhibit NKCC1. Of interest, the bumepamine/phenobarbital combination prevented the neurodegenerative consequences of asphyxia and seizures in the hippocampus. SIGNIFICANCE: Both bumepamine and DIMAEB are promising tools that may help to develop more effective lead compounds for clinical trials.

Population Pharmacokinetics of Phenobarbital in Neonates and Infants on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy.

The objective of this study was to describe the pharmacokinetics (PK) of intravenous phenobarbital in neonates and infants on extracorporeal membrane oxygenation (ECMO) and to provide dosing recommendations in this population. We performed a retrospective single-center PK study of phenobarbital in neonates and infants on ECMO between January 1, 2014, and December 31, 2018. We developed a population PK model using nonlinear mixed-effects modeling, performed simulations using the final PK parameters, and determined optimal dosing based on attainment of peak and trough concentrations between 20 and 40 mg/L. We included 35 subjects with a median (range) age and weight of 14 days (1-154 days) and 3.4 kg (1.6-8.1 kg), respectively. A total of 194 samples were included in the analysis. Five children (14%) contributing 30 samples (16%) were supported by continuous venovenous hemodiafiltration (CVVHDF). A 1-compartment model best described the data. Typical clearance and volume of distribution for a 3.4-kg infant were 0.038 L/h and 3.83 L, respectively. Clearance increased with age and CVVHDF. Although on ECMO, phenobarbital clearance in children on CVVHDF was 6-fold higher than clearance in children without CVVHDF. In typical subjects, a loading dose of 30 mg/kg/dose followed by maintenance doses of 6-7 mg/kg/day administered as divided doses every 12 hours reached goal concentrations. Age did not impact dosing recommendations. However, higher doses were needed in children on CVVHDF. We strongly recommend therapeutic drug monitoring in children on renal replacement therapy (excluding slow continuous ultrafiltration) while on ECMO.

Pharmacokinetic variability of phenobarbital: a systematic review of population pharmacokinetic analysis.

AIMS AND BACKGROUND: Population pharmacokinetics with Bayesian forecasting provides for an effective approach when individualized drug dosing, while phenobarbital is a narrow therapeutic index drug that requires therapeutic drug monitoring. To date, several population pharmacokinetic models have been developed for phenobarbital, these showing a number of significant predictors of phenobarbital clearance and volume of distribution. We have therefore conducted a systematic review to summarize how these predictors affect phenobarbital pharmacokinetics as well as their relationships with pharmacokinetic parameters. METHOD: A systematic search for studies of phenobarbital population pharmacokinetics that were carried out in humans and that employed a nonlinear mixed-effect approaches was made using the PubMed, Scopus, CINAHL Complete, and ScienceDirect databases. The search covered the period from these databases' inception to March 2020. RESULTS: Eighteen studies were included in this review, all of which used a one-compartment structure. The estimated phenobarbital clearance and volume of distribution ranged from 0.0034 to 0.0104 L/h/kg and 0.37 to 1.21 L/kg, respectively, with body weight, age, and concomitant antiepileptic drugs being the three most frequently identified predictors of clearance. Most models were validated through the use of an advanced internal approach. CONCLUSION: Phenobarbital clearance may be predicted from previously developed population pharmacokinetic models and their significant covariate-parameter relationships along with Bayesian forecasting. However, when applying these models in a target population, an external evaluation of these models using the target population is warranted, and it is recommended that future research be conducted to investigate the link between population pharmacokinetics and pharmacodynamics.

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic-clonic seizure model in mice.

BACKGROUND: Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug-drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. AIM: To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. MATERIALS AND METHOD: The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. RESULTS: The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. CONCLUSIONS: The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

Nebivolol attenuates the anticonvulsant action of carbamazepine and phenobarbital against the maximal electroshock-induced seizures in mice.

BACKGROUND: Due to co-occurrence of seizures and cardiovascular disorders, nebivolol, a widely used selective ß1-blocker with vasodilatory properties, may be co-administered with antiepileptic drugs. Therefore, we wanted to assess interactions between nebivolol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital in the screening model of tonic-clonic convulsions. METHODS: Seizure experiments were conducted in the electroconvulsive threshold and maximal electroshock tests in mice. The chimney test served as a method of assessing motor coordination, whereas long-term memory was evaluated in the computerized step-through passive-avoidance task. To exclude or confirm pharmacokinetic interactions, we measured brain concentrations of antiepileptic drugs using the fluorescence polarization immunoassay. RESULTS: It was shown that nebivolol applied at doses 0.5-15 mg/kg did not raise the threshold for electroconvulsions. However, nebivolol at the dose of 15 mg/kg reduced the anti-electroshock properties of carbamazepine. The effect of valproate, phenytoin, and phenobarbital remained unchanged by combination with the ß-blocker. Nebivolol significantly decreased the brain concentration of valproate, but did not affect concentrations of remaining antiepileptic drugs. Therefore, contribution of pharmacokinetic interactions to the final effect of the nebivolol/carbamazepine combination seems not probable. Nebivolol alone and in combinations with antiepileptic drugs did not impair motor performance in mice. Nebivolol alone did not affect long-term memory of animals, and did not potentiate memory impairment induced by valproate and carbamazepine. CONCLUSIONS: This study indicates that nebivolol attenuated effectiveness of some antiepileptic drugs. In case the results are confirmed in clinical settings, this ß-blocker should be used with caution in epileptic patients.

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.

BACKGROUND: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. OBJECTIVES: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. METHODS: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. RESULTS: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. CONCLUSIONS: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.

Successful use of the two-tube approach for the treatment of phenobarbital poisoning without hemodialysis.

Half-life of the antipsychotic vegetamin is very long, partially due to the presence of phenobarbital, and mortality due to phenobarbital poisoning is high. Here, we present the case of a 22-year-old female admitted to the emergency department with disturbed consciousness due to vegetamin overdose. Her blood phenobarbital level was elevated to 123 µg/ml. Phenobarbital undergoes enterohepatic circulation, and its retention in the intestine causes its blood levels to remain sustained. The utility of hemodialysis for drug poisoning has been previously reported; however, its efficiency is not yet established and its efficacy is low for drugs with long half-lives such as phenobarbital. Therefore, we performed a two-tube approach to adsorb phenobarbital in the intestines with activated charcoal delivered via a gastric tube and to remove the phenobarbital-adsorbed activated charcoal using whole bowel irrigation via an ileus tube 2 h later. The patient successfully eliminated the charcoal via stool, the blood phenobarbital level decreased drastically without hemodialysis, and the clinical course improved. We propose that this two-tube approach is suitable for treatment of poisoning with drugs that undergo enterohepatic circulation and have long half-lives.

New derivative of 1,2,4-triazole-3-thione (TP427) potentiates the anticonvulsant action of valproate, but not that of carbamazepine, phenytoin or phenobarbital in the mouse tonic-clonic seizure model.

BACKGROUND: To assess the effects of 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP427) on the protective anticonvulsant action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the tonic-clonic seizure model in mice, an isobolographic transformation of data was used. METHODS: Electrically-induced tonic-clonic seizures were experimentally evoked in adult male albino Swiss mice. The anticonvulsant effects of TP427, when used singly, were determined by the calculation of the threshold increasing the dose by 20% (TID20 value). The influence of TP427 on the anticonvulsant potency of four various classical antiepileptic drugs was determined with a subthreshold method. Types of interactions between drugs were determined using the isobolographic transformation of data. Additionally, total brain antiepileptic drug concentrations were measured. RESULTS: TP427, when administered separately, significantly increased the threshold for electroconvulsions. The experimentally determined TID20 value for TP427 was 11.71 mg/kg. Moreover, TP427 (10 mg/kg) significantly increased the anticonvulsant activity of valproate (p < 0.01), but not that of carbamazepine, phenobarbital or phenytoin in the mouse tonic-clonic seizure model. Isobolographic transformation of data confirmed that the interaction between TP427 and valproate was synergistic. Pharmacokinetic study revealed that TP427 increased total brain valproate concentrations, and had no impact on total brain concentrations of carbamazepine, phenobarbital or phenytoin in mice. CONCLUSION: The synergistic interaction between TP427 and valproate in the mouse tonic-clonic seizure model might occur favorable for epilepsy patients in future. The combinations of TP427 with carbamazepine, phenobarbital and phenytoin were additive in the mouse tonic-clonic seizure model and also deserves clinical attention.

Severity of asphyxia is a covariate of phenobarbital clearance in newborns undergoing hypothermia.

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.

Reduced Clearance of Phenobarbital in Advanced Cancer Patients near the End of Life.

BACKGROUND AND OBJECTIVES: Little is known about the pharmacokinetics of phenobarbital in terminally ill cancer patients. We investigated whether phenobarbital clearance alters depending on the length of survival. METHODS: We retrospectively reviewed the clinical, laboratory, and therapeutic drug monitoring (TDM) records of patients who received parenteral or oral phenobarbital for 21 consecutive days or longer between 2000 and 2016. Patients were divided into non-cancer and cancer groups. Cancer patients were further stratified according to the survival interval after TDM: those who survived > 3 months were classified as long-surviving and the remainders short-surviving cancer patients. Phenobarbital clearance (CLPB) was calculated at steady state. Multiple comparisons of median CLPB were conducted among the three groups. RESULTS: Data were collected from 44 non-cancer patients and 34 cancer patients comprising 24 long-surviving and 10 short-surviving cancer patients. Among 10 short-surviving cancer patients, 4 had hepatic metastasis. Median CLPB (range) in short-surviving cancer patients [0.076 (0.057‒0.114) L/kg/day] was significantly (p < 0.05) lower than that in non-cancer patients [0.105 (0.060‒0.226) L/kg/day] and in long-surviving cancer patients [0.100 (0.082‒0.149) L/kg/day]. CONCLUSION: Terminally ill patients with advanced cancer may have reduced CLPB, thereby TDM is recommended for these patients particularly near the end of life.

Evaluation of Transdermal Administration of Phenobarbital in Healthy Cats.

The purpose was to determine the safety and achievable serum concentrations of transdermally administered phenobarbital in healthy cats. The hypothesis was that transdermal phenobarbital would achieve therapeutic serum concentrations (15-45 µg/mL) with minimal short-term adverse effects. Enrolled cats had normal physical and neurologic exams and unremarkable bloodwork. Transdermal phenobarbital in a pluronic lecithin organogel-based vehicle was administered at a dosage of 3.0-3.1 mg/kg per ear pinna (total of 6.0-6.2 mg/kg) every 12 hr for 14 days. Serum phenobarbital concentrations were measured 3-6 hr after dosing at seven different times over 15 days. The mean and median serum concentration of phenobarbital at study completion were 5.57 and 4.08 µg/mL, respectively. Mean peak concentration and mean time to peak concentration were 5.94 µg/mL and 13.3 days, respectively. Mild adverse effects were observed. Potency was analyzed in three replicates of the transdermal phenobarbital gel administered; potencies ranged from 62.98 to 82.02%. Transdermal application of phenobarbital in healthy cats achieves a detectable, but subtherapeutic, serum concentration and appears safe in the short term. The use of therapeutic drug monitoring is recommended when this formulation of phenobarbital is used to ensure therapeutic serum concentrations are achieved.

The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CLpop) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CLpop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CLpop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CLpop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CLpop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CLTV) at a relevant weight to evaluate the precision of CL predictions.

Bumepamine, a brain-permeant benzylamine derivative of bumetanide, does not inhibit NKCC1 but is more potent to enhance phenobarbital's anti-seizure efficacy.

Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of its physicochemical properties, bumetanide only poorly penetrates through the blood-brain barrier. Thus, concentrations needed to inhibit NKCC1 in hippocampal and neocortical neurons are not reached when using doses (0.1-0.5 mg/kg) in the range of those approved for use as a diuretic in humans. This prompted us to search for a bumetanide derivative that more easily penetrates into the brain. Here we show that bumepamine, a lipophilic benzylamine derivative of bumetanide, exhibits much higher brain penetration than bumetanide and is more potent than the parent drug to potentiate phenobarbital's anticonvulsant effect in two rodent models of chronic difficult-to-treat epilepsy, amygdala kindling in rats and the pilocarpine model in mice. However, bumepamine suppressed NKCC1-dependent giant depolarizing potentials (GDPs) in neonatal rat hippocampal slices much less effectively than bumetanide and did not inhibit GABA-induced Ca2+ transients in the slices, indicating that bumepamine does not inhibit NKCC1. This was substantiated by an oocyte assay, in which bumepamine did not block NKCC1a and NKCC1b after either extra- or intracellular application, whereas bumetanide potently blocked both variants of NKCC1. Experiments with equilibrium dialysis showed high unspecific tissue binding of bumetanide in the brain, which, in addition to its poor brain penetration, further reduces functionally relevant brain concentrations of this drug. These data show that CNS effects of bumetanide previously thought to be mediated by NKCC1 inhibition can also be achieved by a close derivative that does not share this mechanism. Bumepamine has several advantages over bumetanide for CNS targeting, including lower diuretic potency, much higher brain permeability, and higher efficacy to potentiate the anti-seizure effect of phenobarbital.

Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide.

BACKGROUND: Extended-release levetiracetam (LEV-XR) has gained acceptance as an antiepileptic drug in dogs. No studies have evaluated its disposition in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: To evaluate the pharmacokinetics of LEV-XR in epileptic dogs when administered alone or with phenobarbital or zonisamide. ANIMALS: Eighteen client-owned dogs on steady-state maintenance treatment with LEV-XR (Group L, n = 6), LEV-XR and phenobarbital (Group LP, n = 6), or LEV-XR and zonisamide (Group LZ, n = 6). METHODS: Pharmacokinetic study. Blood samples were collected at 0, 2, 4, 8, and 12 hours after LEV-XR was administered with food. Plasma LEV concentrations were determined by high-pressure liquid chromatography. A population pharmacokinetic approach and nonlinear mixed effects modeling were used to analyze the data. RESULTS: Treatment group accounted for most of the interindividual variation. The LP group had lower CMAX (13.38 µg/mL) compared to the L group (33.01 µg/mL) and LZ group (34.13 µg/mL), lower AUC (134.86 versus 352.95 and 452.76 hours·µg/mL, respectively), and higher CL/F (0.17 versus 0.08 and 0.07 L/kg/hr, respectively). The half-life that defined the terminal slope of the plasma concentration versus time curve (~5 hours) was similar to values previously reported for healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Considerable variation exists in the pharmacokinetics of LEV-XR in dogs with epilepsy being treated with a common dose regimen. Concurrent administration of phenobarbital contributed significantly to the variation. Other factors evaluated, including co-administration of zonisamide, were not shown to contribute to the variability. Drug monitoring may be beneficial to determine the most appropriate dose of LEV-XR in individual dogs.

Phenobarbital population pharmacokinetics across the pediatric age spectrum.

OBJECTIVE: Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. METHODS: A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19 years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient. Data collection included the following: age, weight, height, gestational age, core body temperature, serum creatinine, blood urea nitrogen, aspartase aminotransferase, alanine aminotransferase, urine output over the prior 12 hours, phenobarbital doses and serum concentrations, and potential drug-drug interactions. Descriptive statistical methods were used to summarize the data. Pharmacokinetic analysis was performed with NONMEM and simulation was performed for doses of 10, 20, 30, and 40 mg kg-1  dose-1 , iv, followed by enteral doses of 3, 4, 5, and 6 mg kg-1  d-1 . RESULTS: A total of 355 patients (50.3% male, median gestational age 39 weeks (interquartile range [IQR] 35, 40), median age 0.28 years (IQR 0.06, 0.82). Median phenobarbital dose was enteral = 2.6 (IQR 1.9, 3.9) mg kg-1  dose-1 ; intravenous = 2.6 (IQR 2.2, 4.9) mg kg-1  dose-1 ) and mean serum concentration was 41.1 ± 23.9 mg/L at median 6.5 (IQR 2.9, 11.1) hours after a dose. A one-compartment proportional error model best fit the data where clearance and volume of distribution were allometrically scaled using fat-free mass. Significant covariates included serum creatinine, postmenstrual age, and drug-drug interactions on clearance, and age in years on volume of distribution. SIGNIFICANCE: Phenobarbital dosing of 30 mg kg-1  dose-1 ,iv, followed by 4 mg kg-1  d-1 had the highest probability of attaining a therapeutic concentration at 7 days. Postmenstrual age and drug-drug interactions should be incorporated into dosing decisions.

Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation.

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.

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

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.

The Use of Peritoneal Dialysis in Phenobarbitone Toxicity in a Critically Unwell Neonate.

BACKGROUND: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported. OBJECTIVE: To report a case of neonatal severe PB toxicity and review the elimination of PB by PD. METHODS: Assessment of PD drug clearance. RESULTS: A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications. CONCLUSIONS: PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination.