Pharmacokinetic Considerations in the Treatment of Childhood Epilepsy

Gilman, Jamie T.; Duchowny, Michael; Campo, Ana E.

doi:10.2165/00128072-200305040-00005

Cited by 17 publications

(5 citation statements)

References 58 publications

(27 reference statements)

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“…In these mice, the anticonvulsants yielded longer half-lives and were at or above therapeutic plasma concentrations for extended periods. Human infants have been shown to be hypometabolic compared to adults [4]. Antiepileptic drugs are administered chronically to neonates presenting with seizures at doses designed to maintain therapeutic trough concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Pediatric patients have faster drug absorption times, higher peak drug concentrations, and more rapid clearing of anticonvulsants, leading to more adverse effects, less effective seizure control, or both [4]. Recent literature using rodent models has indicated the existence of possible negative consequences of anticonvulsant administration for brain development and cognition.…”

Section: Introductionmentioning

confidence: 99%

“…Concentrations of anticonvulsants in the brain in humans are developmentally-dependent and different drug doses are efficacious at different ages [4]. Elements of the blood-brain barrier, and the tight junctions between the cerebral endothelial cells that make up the blood-brain barrier themselves, develop as the brain matures [7].…”

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice

Markowitz

Kadam²,

Boothe

et al. 2010

NeuroReport

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Rodents eliminate antiepileptic drugs (AEDs) faster than humans, creating challenges for designing clinically-relevant protocols. Half-lives of AEDs in immature mice are unknown. The pharmacokinetics of commonly-used AEDs were examined in CD1 mice using a single-dose protocol at post-natal day 19. Following intraperitoneal therapeutic dosing, blood serum concentrations spanning 1–48 hours post-administration and corresponding brain tissue concentrations at 4 hours were analyzed. Half-lives of valproate, phenobarbital, diazepam (and metabolites), phenytoin, and levetiracetam were 2.6, 15.8, 22.3, 16.3, and 3.2 hours respectively, compared to 0.8, 7.5, 7.7, 16.0, and 1.5 hours reported for adult mice. Brain-to-blood ratios were comparable to adult ratios. AEDs tested had longer half-lives and maintained therapeutic plasma concentrations longer than reported in mature mice, making clinically-relevant protocols feasible.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice

Markowitz

Kadam²,

Boothe

et al. 2010

NeuroReport

View full text Add to dashboard Cite

show abstract

“…Drug distribution in neonates is also variable, leading to the likelihood of a need for higher loading doses and lower-thanexpected serum concentrations on a milligram per kilogram basis compared with older children. Protein binding is lower, leading to higher free fractions (21). By the age of 3 to 6 months old, clearance through metabolism speeds up and surpasses adult values.…”

Section: Issues Related To Change In the Body Over Timementioning

confidence: 99%

AED Treatment through Different Ages: As Our Brains Change, Should Our Drug Choices Also?

French

Staley

2012

Epilepsy Curr

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The management of epilepsy can be difficult owing to the inherently complex nature of the disorder. Pharmacotherapy with antiepileptic drugs (AEDs) is the most common treatment approach. Thirteen new AEDs have been approved by the FDA since 1993. The increase in available drugs provides more options for the prescribing physician, but it has also increased the complexity of drug selection. Determining which of the many AEDs is the best "fit" for a patient can be a challenge. It is increasingly taught that AED selection can be "personalized, " based on patient characteristics such as age, gender, and the presence of comorbidities. These patient characteristics may be related to the efficacy, safety, and tolerability of AEDs and can help determine the most appropriate drug therapy for an individual.In this review, we focus on age as a factor in selecting the most appropriate AED. There are a number of reasons why age may be a factor in AED selection. Most physicians are aware that many seizure types and syndromes have specific ages of onset, and because many AEDs are more effective for subsets of seizure types and syndromes, some drugs will be more appropriate for individuals of certain ages. For example, ethosuximide, is a drug used to treat absence seizures, a seizure type found most commonly in children and adolescents. This issue will not be discussed further, as it relates more to drug selection based on seizure type. But there may also be other issues that make some drugs more or less appropriate or useful at different ages, even if the seizure type and syndrome are the same. It is these issues that will be discussed in the current review. Examples include changes in brain function at different ages, changes in underlying epilepsy etiology, changes in pharmacokinetics, and changes in frequency and types of adverse effects. There is a great need for data regarding AED efficacy relative to age from randomized control trials (RCTs) to guide clinical decision-making, but these types of studies are few. Until those studies are completed, clinicians may give consideration to patient age when determining a treatment plan for epilepsy, but there will be a paucity of scientifically rigorous data to guide them. Differences in Underlying Brain FunctionHow does the brain differ at different ages, and how can those differences impact drug selection? In newborn infants, seizures are different that those seen at later ages, both semiologically and possibly in regards to underlying pathophysiology and development of neurotransmission. Seizures can present as focal or migrating and multifocal (1) and may be subtle and fragmented. The circuitry in the immature brain is different. The infant brain shows an overdevelopment of excitatory neurotransmission, and a relative underdevelopment of inhibitory transmission. Moreover, even the traditional neurotransmitter GABA may behave differently in the neonatal brain, activating excitatory rather than inhibitory pathways (2). Clearly, these and other differences related to brain matura...

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“…In addition to resistance mechanisms, a critical issue contributing to the slow pace of novel ASM discovery is reliability of evaluation of compound efficacy in human patients starting from data generated with rodent models or NAMs. Performing the ADME (administration, distribution, metabolism and excretion) profiling of a molecule and assessing its capacity to cross the blood brain barrier (BBB) are challenging tasks and the results might not accurately predict the outcomes in patients, also considering inter individual susceptibility and differential response based on age to compound administration ( 37 ). Regarding ADME in in vivo models, it has to be taken into account that rodents eliminate drugs at a quicker rate than humans, making the generation of dose–response efficacy curves complicated.…”

Section: Introduction To Causes Of Epilepsy and Available Treatmentsmentioning

confidence: 99%

Toward the use of novel alternative methods in epilepsy modeling and drug discovery

Miguel Sanz,

Martinez Navarro,

Caballero Diaz

et al. 2023

Front. Neurol.

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Epilepsy is a chronic brain disease and, considering the amount of people affected of all ages worldwide, one of the most common neurological disorders. Over 20 novel antiseizure medications (ASMs) have been released since 1993, yet despite substantial advancements in our understanding of the molecular mechanisms behind epileptogenesis, over one-third of patients continue to be resistant to available therapies. This is partially explained by the fact that the majority of existing medicines only address seizure suppression rather than underlying processes. Understanding the origin of this neurological illness requires conducting human neurological and genetic studies. However, the limitation of sample sizes, ethical concerns, and the requirement for appropriate controls (many patients have already had anti-epileptic medication exposure) in human clinical trials underscore the requirement for supplemental models. So far, mammalian models of epilepsy have helped to shed light on the underlying causes of the condition, but the high costs related to breeding of the animals, low throughput, and regulatory restrictions on their research limit their usefulness in drug screening. Here, we present an overview of the state of art in epilepsy modeling describing gold standard animal models used up to date and review the possible alternatives for this research field. Our focus will be mainly on ex vivo, in vitro, and in vivo larval zebrafish models contributing to the 3R in epilepsy modeling and drug screening. We provide a description of pharmacological and genetic methods currently available but also on the possibilities offered by the continued development in gene editing methodologies, especially CRISPR/Cas9-based, for high-throughput disease modeling and anti-epileptic drugs testing.

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Pharmacokinetic Considerations in the Treatment of Childhood Epilepsy

Cited by 17 publications

References 58 publications

The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice

The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice

AED Treatment through Different Ages: As Our Brains Change, Should Our Drug Choices Also?

Toward the use of novel alternative methods in epilepsy modeling and drug discovery

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