Extrapolation of Efficacy from Adults to Pediatric Patients of Drugs for Treatment of Partial Onset Seizures: A Regulatory Perspective.

The US Food and Drug Administration (FDA) has concluded that the efficacy of drugs approved for the treatment of partial onset seizures (POS) in adults can be extrapolated to pediatric patients 1 month of age and above and that independent efficacy trials in this pediatric population are no longer needed. This paper focuses on the dosing, pharmacokinetic (PK), exposure-response, and clinical information that were leveraged from the approved drugs for the treatment of POS to conduct analyses that supported extrapolation of efficacy in pediatric patients. Clinical data from trials for eight drugs (levetiracetam, oxcarbazepine, topiramate, lamotrigine, gabapentin, perampanel, tiagabine, and vigabatrin) approved in both adults and pediatric patients for the treatment of POS were analyzed. Comparisons of exposures at approved doses, placebo response, and model-based exposure-response relationships were performed. Based on disease similarity, similar response to intervention, and similar exposure-response relationships in adults and pediatric patients, it was concluded that extrapolation of efficacy in pediatric patients aged 1 month and above is acceptable. PK analysis to determine pediatric dose and regimens that provide drug exposure similar to that known to be effective in adult patients with POS will be required, along with long-term open-label safety data in pediatric patients.

Model-Informed Drug Development in Pediatric Dose Selection.

Model-informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic-based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age-dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure-response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit-risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model-based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.

Role of Model-Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling.

The unique challenges in pediatric drug development require efficient and innovative tools. Model-informed drug development (MIDD) offers many powerful tools that have been frequently applied in pediatric drug development. MIDD refers to the application of quantitative models to integrate and leverage existing knowledge to bridge knowledge gaps and facilitate development and decision-making processes. This article discusses the current practices and visions of applying MIDD in pediatric drug development, regulatory evaluation, and labeling, with detailed examples. The application of MIDD in pediatric drug development can be broadly classified into 3 categories: leveraging knowledge for bridging the gap, dose selection and optimization, and informing clinical trial design. In particular, MIDD can provide evidence for the assumption of exposure-response similarity in bridging existing knowledge from reference to target population, support the dose selection and optimization based on the "exposure-matching" principle in the pediatric population, and increase the efficiency and success rate of pediatric trials. In addition, the role of physiologically based pharmacokinetics in drug-drug interaction in children and adolescents and in utilizing ontogeny data to predict pharmacokinetics in neonates and infants has also been illustrated. Moving forward, MIDD should be incorporated into all pediatric drug development programs at every stage to inform clinical trial design and dose selection, with both its strengths and limitations clearly laid out. The accumulated experience and knowledge of MIDD has and will continue to drive regulatory policy development and refinement, which will ultimately improve the consistency and efficiency of pediatric drug development.

Electroencephalogram effects of armodafinil: comparison with behavioral alertness.

Development of central nervous system-acting drugs would be enhanced by suitable biomarkers that reflect the targeted pathophysiologic brain state. The electroencephalogram (EEG) has several characteristics of an ideal biomarker and can be promptly adapted to pre-clinical and clinical testing. The aim of this study was to evaluate EEG as a measure of the wakefulness-promoting effect of armodafinil in sleep deprived healthy subjects. Armodafinil pharmacodynamics were simultaneously assessed by EEG- and behavioral-based measures including a well-established measure of alertness. Using two quantitative EEG-based measures-power spectral and event-related brain activity analyses-we observed that armodafinil mitigated the slowing of brain activity and the decrease of the event-related brain activity caused by sleep deprivation. Armodafinil-induced changes in EEG are in agreement and explain up to 73.1% of the armodafinil-induced changes in alertness. Our findings suggest that EEG can serve as a marker of the wakefulness-promoting drug effect.

Electroencephalogram-based pharmacodynamic measures: a review.

Pharmacokinetics and pharmacodynamics can provide a useful modeling framework for predicting drug activity and can serve as a basis for dose optimization. Determining a suitable biomarker or surrogate measure of drug effect for pharmacodynamic models can be challenging. The electroencephalograph is a widely-available and non-invasive tool for recording brainwave activity simultaneously from multiple brain regions. Certain drug classes (such as drugs that act on the central nervous system) also generate a reproducible electroencephalogram (EEG) effect. Characterization of such a drug-induced EEG effect can produce pharmacokinetic/pharmacodynamic models useful for titrating drug levels and expediting development of chemically-similar drug analogs. This paper reviews the relevant concepts involved in pharmacokinetic/pharmacodynamic modeling using EEG-based pharmacodynamic measures. In addition, examples of such models for various drugs are organized by drug activity as well as chemical structure and presented.

Thromboelastographic and pharmacokinetic profiles of micro- and macro-emulsions of propofol in swine.

PURPOSE: Compared with traditional macroemulsion propofol formulations currently in clinical use, microemulsion formulations of this common intravenous anesthetic may offer advantages. The pharmacokinetics and coagulation effects as assessed by thromboelastography of these formulations were characterized in swine. METHODS: Yorkshire swine (20-30 kg, either sex, n=15) were sedated, anesthetized with isoflurane, and instrumented to obtain a tracheostomy, internal jugular access and carotid artery catheterization. Propofol (2 mg/kg, 30 s) was administered as a macroemulsion (10 mg/ml; Diprivan; n=7) or a custom (2 mg/kg, 30 s) microemulsion (10 mg/ml; n=8). Arterial blood specimens acquired pre- and post-injection (1 and 45 min) were used for thromboelastography. Arterial blood specimens (n=12 samples/subject, 60 min) were serially collected, centrifuged and analysed with solid-phase extraction with UPLC to determine propofol plasma concentrations. Non-compartmental pharmacokinetic analysis was applied to plasma concentrations. RESULTS: No changes were noted in the thromboelastographic R time (p=0.74), K time (p=0.41), alpha angle (p=0.97), or maximal amplitude (p=0.71) for either propofol preparation. Pharmacokinetic parameters k (p=0.45), t(1/2) (p=0.26), C(o) (p=0.89), AUC(0-infinity) (p=0.23), CL (p=0.14), MRT (p=0.47), V(ss) (p=0.11) of the two formulations were not significantly different. CONCLUSION: The microemulsion and macroemulsion propofol formulations had similar pharmacokinetics and did not modify thromboelastographic parameters in swine.