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.

Migraine therapeutics in adolescents: a systematic analysis and historic perspectives of triptan trials in adolescents.

OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics.

Dynamic course of intracortical TMS paired-pulse responses during recovery of motor function after stroke.

BACKGROUND: Recovery of motor function after stroke may be associated with changes in inhibitory and facilitatory circuits within the motor cortex. OBJECTIVE: We explored such changes longitudinally after stroke, using transcranial magnetic stimulation (TMS). METHODS: Subjects (N = 27) with a single cerebral infarction affecting movement of either hand were studied at <10 days poststroke, 1 month, and 6 months. Age-matched control subjects (N = 9) were studied at 2 times. RESULTS: In contrast to previous studies, paired-pulse inhibition was increased in patients with a subcortical stroke compared to control subjects. After a cortical stroke, paired-pulse facilitation was also increased. Stroke location affected the time course of inhibition. Subcortical stroke resulted in increased inhibition initially that decreased over time, whereas cortical stroke had no significant effect on inhibition and a more immediate and lasting effect on facilitation. CONCLUSIONS: The time course of a decline in inhibition based on TMS after subcortical stroke followed the gain in motor recovery. Increased facilitation in cortical stroke patients is more likely to represent the effect of early cortical circuit disruption and may not play a role in subacute changes in motor function.

Functional relevance of abnormal fMRI activation pattern after unilateral schizencephaly.

Brain plasticity was investigated in a child with a hemiplegia due to unilateral schizencephaly involving the sensorimotor cortex. This focal lesion led to a dramatic functional reorganization of the undamaged hemisphere, as evidenced by the unusual pattern of fMRI activation during paretic finger movements. The functional relevance of the activation in the undamaged motor cortex was supported by the finding that TMS of this area yielded a response in the paretic hand, indicating that it controls both hands. However, this reorganization was not restricted to the primary motor cortex, but also concerned other structures involved in the control of movements, as shown by the activation of contralesional SMA and thalamus. In contrast, the fMRI activation in the damaged sensorimotor cortex during paretic hand movements appears functionally irrelevant.

Hand motor recovery after stroke: a transcranial magnetic stimulation mapping study of motor output areas and their relation to functional status.

The respective contributions of the stroke and undamaged hemispheres to motor recovery after stroke remains controversial. The aim of this article is to evaluate the relationship between location and size of cortical motor areas and outcome after stroke. Twelve controls and 12 stroke patients were studied. Hand cortical motor output areas were determined using transcranial magnetic stimulation. Motor-evoked potentials were recorded simultaneouslyfrom both hands. Functional motor abilities were evaluated using well-validated measures. Surface area, weighted surface area, and center of gravity of motor output areas were calculated. Different patterns of motor output areas to the paretic band were observed; there was no motor output from the stroke hemisphere in patients with poor outcome, contrasting to large motor output area in the stroke hemisphere in patients with good outcome, regardless of infarct size or location. A significant correlation was found between measures of motor outcome in the stroke-affected upper extremity and both the surface area and weight of the central motor output area in the stroke hemisphere. No ipsilateral motor response was obtained after stimulation of either hemisphere. These data support an association between preservation of cortical motor output area to the paretic hand in the stroke hemisphere and good motor outcome.