• Pediatric drug development (PDD)
• children as therapeutic orphans
• conflict of interests
• developmental pharmacology
• international council of medical journal editors (ICMJE)
• off-label

• Humans
• Drug Development/legislation & jurisprudence
• Child
• Off-Label Use/legislation & jurisprudence
• Orphan Drug Production/legislation & jurisprudence
• Infant, Newborn
• Minors/legislation & jurisprudence
• Infant
• Age Factors

• Better Medicines for Children (BMfC)
• COVID-19
• Children as “Therapeutic Orphans“
• Conflict of Interests (CoI)
• Developmental Pharmacology
• Ethics Committees
• Institutional Review Boards (IRBs)
• International Committee of Medical Journal Editors (ICMJE)
• Pediatric Drug Development (PDD)
• Pediatric Pharmacotherapy

• Future improvements
• Geriatrics
• MIDD applications
• Pediatrics
• Physiological changes
• Policies
• Pregnancy

• Humans
• Drug Development/methods
• Pregnancy
• Female
• Child
• Aged
• Models, Biological

• Antiseizure medications
• Clinical pharmacology
• Epilepsy
• Pediatric drug development
• Pediatric investigation plan
• Therapeutic orphans

• Epilepsy Management
• Expert Consensus
• Focal Epilepsy
• Patient-Centered Care
• Unmet Needs

• Humans
• Italy
• Delphi Technique
• Epilepsies, Partial/therapy
• Consensus
• Patient Reported Outcome Measures

• Epilepsy
• Modeling
• Pharmacodynamics
• Pharmacokinetics
• Population

• Humans
• Levetiracetam/pharmacokinetics
• Levetiracetam/pharmacology
• Anticonvulsants/pharmacokinetics
• Anticonvulsants/administration & dosage
• Child, Preschool
• Pyrrolidinones/pharmacokinetics
• Pyrrolidinones/pharmacology
• Infant
• Child
• Male
• Female
• Adolescent
• Adult
• Dose-Response Relationship, Drug
• Epilepsy/drug therapy
• Young Adult
• Infant, Newborn
• Age Factors
• Seizures/drug therapy

• United States
• Infant
• Infant, Newborn
• Humans
• Child
• Pharmacology, Clinical
• Research
• Seizures/drug therapy
• Computer Simulation
• Epilepsy/drug therapy

• K24 AI143971 NIAID NIH HHS
• R01 HD096435 NICHD NIH HHS
• R01 HD102949 NICHD NIH HHS
• T32 HD104576 NICHD NIH HHS

• Epilepsy
• anti-seizure medications
• neuropharmacology.
• pharmacotherapy
• precision medicine
• seizures

• Humans
• Anticonvulsants/therapeutic use
• Epilepsy/drug therapy
• Seizures/drug therapy
• Drug Interactions

• Antiseizure medications
• adverse events
• children
• cognition
• developmental and epileptic encephalopathies
• drug therapy
• epilepsy
• precision medicine

• Adolescent
• Child
• Child, Preschool
• Humans
• Infant
• Infant, Newborn
• Anticonvulsants/therapeutic use
• Epilepsy/drug therapy
• Epilepsy, Generalized/drug therapy
• Seizures/drug therapy

• Antiseizure medication
• Childhood epilepsy
• Pharmacotherapy
• Prescription patterns

• Male
• Female
• Humans
• Child
• Infant
• Child, Preschool
• Lamotrigine/therapeutic use
• Oxcarbazepine/therapeutic use
• Levetiracetam/therapeutic use
• Sweden/epidemiology
• Valproic Acid
• Triazines/adverse effects
• Epilepsy/drug therapy
• Epilepsy/epidemiology
• Anticonvulsants/therapeutic use

• Anti-seizure medication
• Enzyme-inducing anti-seizure medication
• Epilepsy
• Focal to bilateral tonic-clonic seizures
• Focal-onset seizures

• epilepsy disorders
• heath related quality of life
• newer antiepileptics
• pediatric seizure
• seizure free status
• univariate analysis

• drug development
• pediatric efficacy
• pediatric extrapolation

• antiseizure medications
• clinical trials
• extrapolation
• pediatric epilepsy

• Best Pharmaceuticals for Children Act
• FDA
• drug approval
• pediatric drugs
• pediatric research equity act
• rare pediatric drug designation

• Multiple sclerosis
• children as therapeutic orphans
• developmental pharmacology
• pain
• pediatric drug development
• pediatric legislation

• Adult
• Child
• Humans
• Neurology
• United States
• United States Food and Drug Administration

• antiseizure medication
• children
• epilepsy
• etiology
• focal-onset seizure
• syndrome

• exposure-response
• extrapolation
• pediatric drug development
• regulatory science

• better medicines for children
• children as therapeutic orphans
• covid-19
• developmental pharmacology
• pediatric drug development
• pediatric legislation

Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure–response (E‐R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E‐R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one‐compartment disposition model was used, with first‐order absorption and body surface area‐normalized creatinine clearance on clearance. Individual pregabalin average steady‐state concentrations were predicted and used in an E‐R analysis of efficacy. The E‐R relationship of pregabalin was similar in pediatric (4–16 years) and adult patients with FOS after accounting for differences in baseline natural log‐transformed 28‐day seizure rate and placebo effect. Population PK simulations showed that children aged 4–16 years and weighing ≥ 30 kg required pregabalin 2.5–10 mg/kg/day to achieve similar pregabalin exposure at steady‐state to adult patients receiving the approved doses of 150–600 mg/day. For children 4–16 years weighing < 30 kg, a higher pregabalin dose of 3.5–14 mg/kg/day was required to achieve equivalent exposure at steady‐state. The results support the dosage guidance provided in the pregabalin prescribing label, whereby pediatric patients (4–16 years) weighing < 30 kg should receive a 40% higher pregabalin dose (per kg of body weight) than patients weighing ≥ 30 kg to achieve similar exposure. Our combined modeling approach may provide guidance for future extrapolation assessment from adult to pediatric patients.

• Oxtellar
• adjunctive therapy
• monohydroxy derivative
• monotherapy
• oxcarbazepine

• Supernus Pharmaceuticals, Inc
• Verna Ilacqua, ID&A

• adolescents
• antiepileptic drugs
• antiseizure drugs
• children
• epilepsy
• pediatric
• refractory
• seizures

Study 311 (NCT02849626) was a global, multicenter, open‐label, single‐arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once‐daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic‐clonic seizures [FBTCS]) or generalized tonic‐clonic seizures (GTCS).

In the 311 Core Study, a 4‐week Pre‐treatment Period (Screening/Baseline) preceded a 23‐week Treatment Period (11‐week Titration; 12‐week Maintenance) and 4‐week Follow‐up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure‐freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme‐inducing anti‐seizure drug (EIASD) use.

One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment‐emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure‐freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use.

Results from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

• anti-seizure drug
• enzyme-inducing anti-seizure drug
• epilepsy
• focal to bilateral tonic-clonic seizures
• seizure freedom

Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration–effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A).

The existing adult PK/PD model for brivaracetam was applied to a combined adult–pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged ≥4 to <16 years as adjunctive treatment for focal (partial onset) seizures. The existing model described daily seizure counts using a negative binomial distribution, taking previous-day seizure frequencies into account, and using a mixture model to separate ‘placebo-like’ and ‘responder’ subpopulations. The model was adapted to describe aggregated monthly seizure counts for adult patients in the levetiracetam studies: daily seizure counts were only available for children in the levetiracetam studies.

The levetiracetam PK/PD model successfully described both the adult and pediatric data using the same drug effect parameters, and using a model structure similar to the existing adult brivaracetam PK/PD model.

Simulation with the adult brivaracetam PK/PD model in combination with an existing pediatric brivaracetam population PK model allowed characterization of the dose–response curve, suggesting maximum response at brivaracetam 4 mg/kg/day dosing (capped at 200 mg/day, the maximum adult dose) in children aged ≥4 years.

The online version of this article (doi:10.1007/s40262-017-0597-2) contains supplementary material, which is available to authorized users.

• Administration, Oral
• Adolescent
• Adult
• Aged
• Anticonvulsants/administration & dosage
• Anticonvulsants/metabolism
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Epilepsies, Partial/drug therapy
• Epilepsies, Partial/metabolism
• Female
• Humans
• Levetiracetam/administration & dosage
• Levetiracetam/pharmacokinetics
• Male
• Middle Aged
• Models, Theoretical
• Pyrrolidinones/administration & dosage
• Pyrrolidinones/metabolism
• Seizures/drug therapy
• Seizures/metabolism
• Young Adult

• UCB Pharma

• Clobazam
• Dravet syndrome
• Epilepsy
• Pediatric dosing
• Pharmacometrics
• Population pharmacokinetic modeling

• antiepileptic drugs
• enzyme-inducing
• epilepsy
• pediatric
• perampanel
• serum concentrations

• clinical pharmacology
• drug regulation
• evidence-based medicine
• optimal design pharmacodynamics
• paediatrics

Modeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4–17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2–18 years of age treated with ESL 5–30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (including body weight and concomitant use of carbamazepine, levetiracetam, and phenobarbital-like antiepileptic drugs [AEDs]) on variability in PK parameters. Model evaluation performed using a simulation-based visual predictive check and a non-parametric bootstrap procedure indicated no substantial bias in the overall model and in the accuracy of estimates. The model estimated that concomitant use of carbamazepine or phenobarbital-like AEDs with ESL would decrease the exposure of eslicarbazepine, and that concomitant use of levetiracetam with ESL would increase the exposure of eslicarbazepine, although the small effect of levetiracetam may not represent a true difference. Model-based simulations were subsequently performed to apply target exposure matching of selected ESL doses for pediatric subjects (aged 4–17 years) to attain eslicarbazepine exposures associated with effective and well-tolerated ESL doses in adults. Overall, model-based exposure matching allowed for extrapolation of efficacy to support pediatric dose selection as part of the submission to obtain FDA approval for ESL (adjunctive therapy and monotherapy) in subjects aged 4–17 years, without requiring an additional clinical study.

• Epilepsy
• Eslicarbazepine
• Modeling and simulations
• Pediatric
• Population pharmacokinetic model

• Children
• Effectiveness
• Lacosamide
• Pediatric epilepsy
• Refractory epilepsy
• Safety

• Adolescent
• Anticonvulsants/adverse effects
• Anticonvulsants/therapeutic use
• Ataxia/chemically induced
• Child
• Dizziness/chemically induced
• Drug Resistant Epilepsy/drug therapy
• Epilepsies, Partial/drug therapy
• Female
• Humans
• Lacosamide/adverse effects
• Lacosamide/therapeutic use
• Male
• Quality of Life
• Retrospective Studies
• Seizures/drug therapy
• Spain
• Treatment Outcome

• antiepileptic drugs
• epilepsy
• meta-analysis
• pediatric
• randomized clinical trial

• Adolescent
• Adrenal Cortex Hormones/therapeutic use
• Adrenocorticotropic Hormone/therapeutic use
• Anticonvulsants/therapeutic use
• Carbamazepine/therapeutic use
• Child
• Child, Preschool
• Drug Resistant Epilepsy/drug therapy
• Epilepsies, Partial/drug therapy
• Epilepsy/drug therapy
• Epilepsy, Absence/drug therapy
• Ethosuximide/therapeutic use
• Hormones/therapeutic use
• Humans
• Infant
• Lamotrigine
• Levetiracetam
• Nitriles
• Odds Ratio
• Piracetam/analogs & derivatives
• Piracetam/therapeutic use
• Pyridones/therapeutic use
• Spasms, Infantile/drug therapy
• Treatment Outcome
• Triazines/therapeutic use
• Valproic Acid/therapeutic use

• adverse drug effects
• anticonvulsant
• antiepileptic
• maximum dosage
• therapeutic
• toxicity

• AMPA
• GABA
• NMDA
• Pharmacokinetics
• Potassium channels
• Sodium channels

• CGP35348
• Drug resistant
• Epilepsy
• Estradiol
• Replication
• Seizure
• VX-765

• Animals
• Anticonvulsants/therapeutic use
• Dipeptides/therapeutic use
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Doxorubicin/toxicity
• Drug Evaluation, Preclinical/methods
• Estradiol/therapeutic use
• GABA Antagonists/therapeutic use
• Humans
• Infant
• Lipopolysaccharides/toxicity
• Male
• Organophosphorus Compounds/therapeutic use
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Spasms, Infantile/chemically induced
• Spasms, Infantile/drug therapy
• Spasms, Infantile/physiopathology
• Treatment Outcome
• para-Aminobenzoates/therapeutic use

• U54 NS100064 NINDS NIH HHS
• U01 NS045911 NINDS NIH HHS
• R01 NS020253 NINDS NIH HHS
• R01 NS091170 NINDS NIH HHS
• R01 NS043209 NINDS NIH HHS
• R37 NS043209 NINDS NIH HHS
• R56 NS020253 NINDS NIH HHS

• Adult
• Compliance
• Mental health
• Pediatric
• Transition
• Treatment

In children many antiepileptic drugs (AEDs) are prescribed off‐label due to a lack of well‐designed randomized controlled trials (RCTs). We conducted a multicenter RCT in the Netherlands to compare levetiracetam and valproic acid as monotherapy in children with newly diagnosed epilepsy. After 2 years, we had to stop this investigator‐initiated trial prematurely because the inclusion rate was too low. We analyzed the reasons for this failure, assessed the various issues involved in performing RCTs in children, and now give recommendations for future studies.

A questionnaire was completed by all investigators involved in the study. It included questions about the motivation to participate and the perceived reasons for recruitment failure. We also studied literature about financial, logistic, legal, and ethical aspects of RCTs in children.

Main reasons for recruitment failure were overestimation of the number of eligible AED‐naive children referred by general pediatricians; personal preferences of investigators for specific antiepileptic drugs; and the extensive administrative load due to extra regulations and guidelines for children. Fundraising for investigator‐initiated trials is difficult and the majority of RCTs concerning AEDs are sponsored by pharmaceutical companies. Involving children requires balancing between protection and participation; the randomization procedure and obtaining informed consent are complex for both children and parents.

Performing RCTs with AEDs in children is important but complicated by logistic, regulatory, legal, and ethical restrictions. Based on our recent experience, our advice to colleagues who are planning a similar trial would be to perform a feasibility pilot study; to set up intensive collaboration with referring pediatricians; to arrange support of a clinical trials unit and a local research nurse during the complete trial period; and to incorporate the possibility of extending the recruitment period. Major investments, both financially from governmental organizations and in time, are imperative for independent RCTs in children.

• Antiepileptic drugs
• Feasibility
• Off‐label

• Anticonvulsants/therapeutic use
• Clinical Trials as Topic
• Drug Discovery/methods
• Epilepsies, Partial/drug therapy
• Humans

• CDF-2010-03-16 Department of Health
• MR/J014079/1 Medical Research Council
• MR/M013510/1 Medical Research Council
• National Institute for Health Research

• Behavioral
• Epilepsy
• Levetiracetam
• Oxcarbazepine
• Sleepiness

Preclinical studies have produced numerous drugs with antiseizure properties that currently are the standard of care. One third of the human population with epilepsy still continues to have seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease‐modifying treatments, and treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to reevaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may affect the quality, interpretation, and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design; research practices that affect rigor (such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs, and preclinical‐clinical studies); the need to harmonize research methods and outcome assessment; and the importance of improving translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in future success.

• Antiepileptogenesis
• animal model
• antiseizure
• drug resistance
• efficacy endpoint
• preclinical trial
• seizure

• Antiepileptic drug
• Effectiveness
• Mechanisms of action
• Pediatric epilepsy
• Refractory epilepsy

• Acetamides/therapeutic use
• Adolescent
• Age Factors
• Age of Onset
• Anticonvulsants/therapeutic use
• Child
• Child, Preschool
• Cohort Studies
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Epilepsy/drug therapy
• Epilepsy/etiology
• Epilepsy/genetics
• Female
• Humans
• Infant
• Kaplan-Meier Estimate
• Lacosamide
• Male
• Sodium Channel Blockers/therapeutic use
• Treatment Failure
• Young Adult

• Antiepileptic drugs
• childhood absence epilepsy
• cognitive side effect
• ethosuximide
• perampanel
• polytherapy
• zonisamide

• Anticonvulsants/therapeutic use
• Child
• Disease Management
• Drug Therapy, Combination
• Drug-Related Side Effects and Adverse Reactions/diagnosis
• Drug-Related Side Effects and Adverse Reactions/prevention & control
• Epilepsy/diagnosis
• Epilepsy/drug therapy
• Humans
• Randomized Controlled Trials as Topic/methods
• Seizures/diagnosis
• Seizures/drug therapy
• Treatment Outcome

• Antiepileptic drugs
• dose rationale
• epilepsy
• epileptic seizures
• modelling and simulation
• paediatrics
• personalised medicine
• pharmacokinetic-pharmacodynamic relationships
• pharmacokinetics
• translational pharmacology