Methods for increasing the bioavailability and exposure of voltage-gated potassium channel openers

Abstract

This invention provides a method for increasing the bioavailability and exposure of voltage-gated potassium channel openers. [Solution] In one embodiment, the present disclosure provides a method and use for treating a paroxysmal disorder in humans, comprising administering a therapeutically effective amount of the voltage-gated potassium channel allosteric modulator, N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (compound A) orally to a person in need, for example, after a meal. Furthermore, various improved methods of treatment and administration of compound A are provided.

Description

[Technical Field]

[0001] The present invention relates to a method for improving the bioavailability and exposure of voltage-gated potassium channel openers. [Background technology]

[0002] Epilepsy is a common neurological disorder with an estimated global prevalence of 0.7% of the population (50 million people) (see Hirtz, D. et al., Neurology (2007), 68:326-337). Epilepsy is characterized by abnormal electrical activity in the brain that leads to seizures. For epidemiological purposes, the definition requires multiple unprovoked seizures of any type.

[0003] Patients with epilepsy have a higher mortality risk compared to the general population, primarily due to the etiology of the disease. However, in patients with uncontrolled epilepsy, the greatest seizure-related mortality risk is due to sudden unexpected death (SUDEP) in epilepsy (see Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376). Patients participating in clinical trials of investigational antiepileptic drugs (AEDs) generally have had epilepsy for more than 10 years and have experienced failure in multiple AED therapies.

[0004] While the pathophysiology of most forms of epilepsy remains poorly understood, it is known that epileptic seizures result from the excessive, synchronized, and sustained firing of a group of neurons. This sustained increase in neuronal excitability is common to all epileptic syndromes. Treatment strategies for epilepsy involve reducing neuronal excitability through various mechanistic pathways. Over the past 20 years, several new AEDs have been developed and marketed to broaden the therapeutic spectrum by targeting different mechanisms of action and to improve the risk / benefit profile. Currently available AEDs are thought to act by inhibiting synaptic vesicle glycoproteins, enhancing inhibitory GABAergic neurotransmission, reducing glutamate-mediated excitatory neurotransmission, or inhibiting voltage-gated sodium or calcium channels. Despite this, less than 30% of patients remain resistant to conventional treatments and continue to experience uncontrolled seizures (see Brown, DA et al., Nature (1980), 283:673-676, and Elger, CE et al., Epilepsy Behav. (2008), 12:501-539). Patients with refractory epilepsy have a low quality of life; they are unable to drive and have difficulty working or living independently. In addition, many patients develop behavioral, neurological, and / or intellectual disabilities as complications of their seizure disorder. Despite the fact that potassium-dependent channels play a major role in regulating neuronal excitability, current drugs have little effect on these channels. Therefore, to address the critical and unmet clinical need for seizure control in patients with treatment-resistant epilepsy, there is a need for drugs with novel mechanisms of action or improvements on already marketed AEDs.

[0005] N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (hereinafter referred to as "Compound A") is a small molecule currently under development for the treatment of paroxysmal disorders. Compound A and its use as a potassium channel modulator are disclosed in U.S. Patent No. 8,293,911 and U.S. Patent No. 8,993,593, which are incorporated herein by reference in their entirety.

[0006] Voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3) are important in regulating neuronal excitability. Kv7.2 / Kv7.3 underlie the neuronal "M current," named according to early characterizations, because the neuronal current decreases in response to muscarinic / cholinergic agonists (see Brown, DA et al., Nature (1980), 283:673-676). The M current is a non-inactivating, hyperpolarizing current known to act as a brake on neuronal hyperexcitability. Consequently, a decrease in Kv7.2-mediated M current, for example through genetic loss of function, can lead to neuronal depolarization and increased membrane and neuronal excitability, which can result in action potential bursts that manifest as epileptic seizures. In contrast, an increase in Kv7.2-mediated M current hyperpolarizes the cell membrane, thereby reducing neuronal excitability and preventing the initiation and propagation of action potential bursts, as well as the resulting seizures. Enhancing the open state of Kv7.2 / Kv7.3 channels in neurons is favorable to a hyperpolarized resting state, which reduces rapid action potential spikes (i.e., burst firings). Such enhancement can provide a stabilizing effect on easily excitable, especially hyperexcitable, neurons and may therefore be useful in treating certain seizure disorders. This enhancement has been clinically proven effective in treating seizure disorders such as partial initial seizures in adults with epilepsy using retigabine (ezogabine), known as a Kv7.2 / Kv7.3 opener.

[0007] Retigavin has the following structure. [ka]

[0008] Retigabine was first identified in the late 1980s as an analogue of the analgesic compound flupirtin. Retigabine demonstrated broad-spectrum activity in a study designed to identify novel anticonvulsants using a series of rodent seizure models (see Kupferberg, H., Epilepsia (1989), 30(Suppl.1):S51-S56). Retigabin was approved in 2011 for partial initial seizures, but was withdrawn from the market in 2017 for commercial reasons following a black-frame warning related to skin, lip, and nail discoloration and retinal pigment changes that appeared to be associated with the formation of retigabine dimers, which become chromophores after long-term use (Prescott, JS and Evans, CA, "Pigmentary abnormalities (discoloration) associated with ezogabine / retigabine treatment: nonclinical aspects," Poster 2.324, presented at the 68th Annual Meeting of the American Epilepsy Society (AES), Seattle, Washington, USA, December 5-9, 2014). [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 8,293,911 [Patent Document 2] U.S. Patent No. 8,993,593 [Non-patent literature]

[0010] [Non-Patent Document 1] Hirtz, D. et al., Neurology (2007), 68:326-337 [Non-Patent Document 2] Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376. [Non-Patent Document 3] Brown, D.A. et al., Nature (1980), 283:673-676. [Non-Patent Document 4] Elger, CE et al., Epilepsy Behav. (2008), 12:501-539 [Non-Patent Document 5] Kupferberg, H., Epilepsia (1989), 30(Suppl.1):S51-S56 [Non-Patent Document 6] Prescott, JS and Evans, CA, "Pigmentary abnormalities (discoloration) associated with ezogabine / retigabine treatment: nonclinical aspects," Poster 2.324, presented at the 68th Annual Meeting of the American Epilepsy Society (AES), Seattle, Washington, USA, December 5-9, 2014. [Overview of the project] [Problems that the invention aims to solve]

[0011] While significant progress has been made in this field, particularly with respect to compound A and its use in treating seizure disorders, there remains a substantial need for improved methods to increase the bioavailability and exposure of compound A when administered orally to individuals with seizure disorders such as epilepsy. [Means for solving the problem]

[0012] In some embodiments, the present disclosure relates to a method for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need, comprising the step of orally administering a therapeutically effective amount of compound A to that person in a postprandial state or between 30 minutes before and 2 hours after feeding. In specific examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder such as focal epilepsy.

[0013] In some embodiments, the present disclosure relates to a compound for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need, wherein the compound is compound A, and a therapeutically effective amount of the compound is administered orally to the person in a postprandial state or between 30 minutes before and 2 hours after feeding. In specific examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder such as focal epilepsy.

[0014] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A to the person in a postprandial state or between 30 minutes before and 2 hours after eating, wherein the amount of compound A is sufficient to treat the paroxysmal disorder in the person.

[0015] In one embodiment, the present disclosure provides a compound for use in treating a paroxysmal disorder in a person in need, the compound being compound A, which is administered orally to the person after a meal or between 30 minutes before and 2 hours after a meal.

[0016] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A to the person in a postprandial state or between 30 minutes before and 2 hours after eating, wherein the amount of compound A is 2 to 200 mg.

[0017] In one embodiment, the present disclosure provides a method for increasing one or more of C inf , max , AUC inf , T max , or t1 / 2 λz of compound A in a human subject receiving oral administration of compound A, comprising orally administering to the human subject an amount of compound A in a postprandial state or between 30 minutes before a meal and 2 hours after a meal, wherein this method results in an increase in one or more of C max , AUC inf , T max , or t1 / 2 λz compared to when the same amount of compound A is orally administered to the human subject in a fasting state.

[0018] In one embodiment, the present disclosure provides a compound for use in increasing one or more of C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, or t1 / 2 λz A process of informing the person above to increase one or more of the following, (b) A step in which compound A is orally administered in a postprandial state, or between 30 minutes before and 2 hours after eating, relying on step (a). This provides a method for providing this.

[0020] In certain such embodiments, the probability that (b) occurs (i.e., the administration is performed postprandially or between 30 minutes before feeding and 2 hours after feeding) is higher than in the method without step (a).

[0021] In one embodiment, the present disclosure provides a method for orally administering compound A to a person in need, comprising the step of orally administering compound A to the person in a postprandial state or between 30 minutes before and 2 hours after a meal, wherein the C of compound A is compared to when the same amount of compound A is orally administered to the person in a fasting state. max AUC inf , T max , or t1 / 2 λz This provides a method to increase one or more of the values.

[0022] In one embodiment, the present disclosure provides a method for reducing the dose of compound A to be orally administered to a person as required as part of a treatment plan, comprising the steps of orally administering the reduced dose of compound A to the person in a postprandial state or between 30 minutes before and 2 hours after a meal, wherein the reduced dose is equal to the same C as compound A when orally administered to the person in a fasted state. max AUC inf , T max , or t1 / 2 λz The present invention provides a method that uses a dose lower than the dose required to achieve one or more of the following:

[0023] In one embodiment, the present disclosure relates to a compound for use, which is used to reduce the dose of the compound orally administered to a person as required as part of a treatment plan, wherein the compound is compound A, and the compound is orally administered to the person in a postprandial state or between 30 minutes before and 2 hours after a meal, wherein the reduced dose is the same as compound C when orally administered to the person in a fasted state. max AUC inf , T max , or t1 / 2 λz The present invention provides a compound for use that is in a dose lower than the dose required to achieve one or more of the following:

[0024] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a therapeutically effective amount of compound A to the person. In one embodiment, the method relates to compound A, At least 40 ng / mL of C max , AUC of at least 2500 h·ng / mL inf , At least 3.25h T max , or at least 130h t1 / 2 λz It results in one or more of the following.

[0025] In one embodiment, the present disclosure provides a compound for use in treating a paroxysmal disorder in a person in need, wherein the compound is compound A, and the compound is administered orally to the person. In one embodiment, this oral administration is of compound A, At least 40 ng / mL of C max , AUC of at least 2500 h·ng / mL inf , At least 3.25h T max , or at least 130h t1 / 2 λz It results in one or more of the following.

[0026] In one embodiment, the present disclosure provides a method for increasing the resting motor threshold (RMT) or active motor threshold (AMT) in a person in need, comprising the step of orally administering a certain amount of compound A to the person, optionally after a meal or between 30 minutes before and 2 hours after a meal, wherein the amount of compound A is sufficient to increase the RMT or AMT in the person, or the amount of compound A is 2 to 200 mg.

[0027] In one embodiment, the present disclosure provides a compound for use in raising RMT or AMT in a person in need, wherein the compound is compound A, and a certain amount of the compound is administered orally to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding, wherein the amount of compound A is sufficient to raise RMT or AMT in the person, or the amount of compound A is 2 to 200 mg.

[0028] In one embodiment, the present disclosure provides a method for reducing corticospinal excitability or cortical excitability in a person in need, comprising the step of orally administering a certain amount of compound A to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding, wherein the amount of compound A is sufficient to increase corticospinal excitability or cortical excitability in the person, or the amount of compound A is 2 to 200 mg.

[0029] In one embodiment, the present disclosure provides a compound for use in reducing corticospinal excitability or cortical excitability in a person in need, wherein the compound is compound A, and a certain amount of the compound is administered orally to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding, wherein the amount of compound A is sufficient to increase corticospinal excitability or cortical excitability in the person, or the amount of compound A is 2 to 200 mg.

[0030] In one embodiment, the disclosure provides, as a whole, a method for increasing the bioavailability and exposure of compound A when administered orally.

[0031] Accordingly, one aspect of the present disclosure is a method for treating a paroxysmal disorder in a human, comprising the step of orally administering a therapeutically effective amount of compound A to the human in need in a postprandial state.

[0032] Another aspect of the present disclosure is a method for increasing the bioavailability and exposure of compound A in a person receiving an orally administered therapeutically effective amount of compound A for the treatment of a paroxysmal disorder, the method comprising the step of orally administering a therapeutically effective amount of compound A to the person in a postprandial state.

[0033] Another aspect of the present disclosure is a method for increasing the degree of absorption and exposure of compound A in a human after oral administration of compound A to that human, the method comprising the step of orally administering a therapeutically effective amount of compound A to the human in a postprandial state.

[0034] These and other aspects of the present disclosure will become apparent from the following detailed description. For this purpose, various references that provide more detailed information and procedures are given herein, each incorporated by reference in its entirety. [Brief explanation of the drawing]

[0035] [Figure 1] Figure 1 illustrates the average plasma concentration levels of compound A in a food effect study in cynomolgus monkeys, as described later in Table 5 of Example 1, showing the time course (time) (x axis) and compound A concentration (ng / mL) (y axis). [Figure 2] Figure 2 illustrates the average plasma concentration level of compound A in a human food effect study, as described later in Example 2, showing the time (time) (x axis) and compound A concentration (ng / mL) (y axis). [Figure 3]Figure 3 includes graph (A) illustrating the modification of the resting exercise threshold induced by compound A, showing the post-pre-RMT (y-axis) for three doses (10 mg, 15 mg, and 20 mg) (x-axis) at 2 and 4 hours after drug ingestion, and graph (B) illustrating the modification of the active exercise threshold induced by compound A, showing the post-pre-AMT (y-axis) for three doses (10 mg, 15 mg, and 20 mg) (x-axis) at 2 and 4 hours after drug ingestion. [Figure 4] Figure 4 includes graphs depicting spatiotemporal profiles of TEP after treatment with placebo and compound A. Panel A shows the ground mean (n=16) butterfly plots of placebo (left) and compound A (right) before and after ingestion (Pre). Each line represents TEP recorded in a single EEG channel. The topographic scalp distribution of amplitude (μV) of major TEP components (N15-P25, N45, N100, and P180) before and after drug ingestion is shown in Panels B and C, respectively. Panel D shows a t-statistic map of TEP amplitude showing the difference between post-administration and pre-administration. "ns" represents non-significant results, and the open "x" on the topographic scalp distribution indicates areas of positive amplitude and t-statistic, while the dark areas without "x" indicate negative amplitude and t-statistic. [Figure 5] Figure 5 includes a graph illustrating the modulation of TEP amplitude by compound A at the highest concentration. TEP was ground-averaged across channels showing a significant drug effect. Compared to baseline, compound A induced suppression of components N15-P25, N45, and P180. TEP data were averaged across 16 participants with post-administration conditions selected for the highest drug exposure during TMS evaluation. White "x" on the scalp topography distribution indicates areas of positive t-statistics, while dark areas without "x" indicate negative t-statistics. [Figure 6] Figure 6 is a graph showing the TEP amplitude (μV) (y axis) at time points (x axis) N15-P25, N45, and P180 after TMS pulse, with TEP after treatment using compound A and placebo. [Figure 7]Figure 7 includes a graph illustrating the effect of compound A on TEP at 2, 4, and 6 hours post-administration. The ground-averaged TEP recorded before administration (Pre) and at 2 hours (2hr), 4 hours (4hr), and 6 hours (6hr) post-administration is shown. The compound A fingerprint, including decreases in the N15-P25, N45, and P180 components, reflects the increase in plasma exposure over time. [Figure 8] Figure 8 illustrates the drug-induced modulation of spontaneous brain oscillatory before and after treatment with compound A. Panel A shows the ground-averaged power spectra (n=16) before (Pre) and after (Post) ingestion of compound A. Significant increases in delta, theta, and beta power are indicated by asterisks and are shown in the lower panels A1, A2, and A3, respectively, for each specific frequency band. [Figure 9] Figure 9 illustrates the drug-induced modulation of spontaneous brain oscillatory over time after ingestion of compound A. Panel A shows the ground-averaged (n=16) power spectra (n=16) before (Pre), 2 hours after (Post2hr), and 4 hours after (Post4hr) ingestion of compound A. Significant increases in delta, theta, and beta power are indicated by asterisks and are shown in the lower panels A1, A2, and A3, respectively, for each specific frequency band. [Figure 10] Figure 10 is a graph illustrating the time-dependent effect of compound A on the resting exercise threshold, showing the change from baseline RMT (% maximum stimulus intensity [%MSO]) (left y-axis) and compound A concentration (ng / mL) (right y-axis) over time (time) (x-axis). For compound A, n=19, 20, and 16 were observed at 2, 4, and 6 hours after administration, respectively. For placebo, n=20, 20, and 16 were observed at 2, 4, and 6 hours after administration, respectively. The mean ± standard error of the mean (SEM) is shown. [Figure 11] Figure 11 is a graph illustrating the effect of compound A concentration on RMT adjustment, showing RMT delta (post-pre; %MSO) (y-axis) and compound A and placebo (x-axis). The average high concentration of compound A = 45 ng / mL. [Figure 12]Figure 12 includes graph (A) showing the concentration effect before administration (Pre) versus after administration of compound A, with (seconds) (x axis) (uv2) (y axis) over time, and graph (B) showing the time effect before administration (Pre) versus 2 hours and 4 hours after administration of compound A, with (seconds) (x axis) (uv2) (y axis) over time. The average high concentration of compound A = 45 ng / mL. [Modes for carrying out the invention]

[0036] The effects of food on drugs can significantly impact patient outcomes by affecting the pharmacokinetics and pharmacodynamics of those drugs. This interaction may potentially lead to decreased drug absorption and reduced efficacy, or increased drug absorption and enhanced efficacy. Food may also have either a positive or negative effect on the incidence and severity of adverse events associated with drug use. Whether drug bioavailability and / or patient exposure is affected by food intake is unpredictable without extensive testing. See, for example, Heimbach, T et al., "Case Studies for Practical Food Effect Assessments across BCS / BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data," The AAPS Journal (2012), Vol. 15, No. 1, pp. 143-158.

[0037] In one embodiment, the Disclosure provides an improved method of treatment and administration based on the application of an unexpected finding that oral administration of compound A to humans in a postprandial state (i.e., with food or immediately after food ingestion) significantly increases the bioavailability and exposure of compound A compared to oral administration of compound A to humans in a fasting state (i.e., without food or immediately after food ingestion). This finding is unexpected considering the results of non-human primate studies that showed no increase in bioavailability and exposure of compound A when administered orally in a postprandial state compared to a fasting state.

[0038] This finding is unexpected, even considering the lack of food effects on bioavailability and exposure after oral administration of another potassium channel opener, retigabine, as described above (see, for example, page 2 of the United States Food and Drug Administration (FDA) Approved Labeling Text dated March 15, 2012, for Potiga, the trademark name for retigabine; and Harris, JA and Murphy, JA, "Retigabine (ezogabine) as add-on therapy for partial onset seizures: an update for clinicians," Therapeutic Advances in Chronic Disease (2011), 2(6), pp. 371-376).

[0039] Furthermore, compound A cannot form a chromophore dimer similar to that formed by retigabine. Therefore, it is expected that the blue-gray discoloration of the skin, lips, or nails and the changes in retinal pigmentation that occur in human patients after long-term use of retigabine will not occur after long-term use of compound A.

[0040] The following disclosure provides certain specific details to give a full understanding of the various embodiments. However, those skilled in the art will understand that the methods and uses described herein may be carried out without these details. In other instances, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Throughout this specification and the appended claims, unless inconsistent with the context, the phrase “comprise” and its derivatives, e.g., “comprises” and “comprising,” should be interpreted in an open, inclusive sense, that is, “including, but not limited to….” Furthermore, the subheadings presented herein are for convenience only and do not imply any scope or meaning of the claimed invention.

[0041] Throughout this specification, any reference to “one embodiment” or “one embodiment” means that any particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, the phrases “in one embodiment” or “in one embodiment” appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a, an” and “the” refer to multiple subjects unless it is clearly evident from the context. It should also be noted that the term “or” generally means “and / or” unless it is clearly evident from the context. Furthermore, as used herein, the term “about” means ±20% of the stated value, and in more specific embodiments, ±10%, ±5%, ±2%, and ±1% of the stated value.

[0042] definition As used herein and in the appended claims, unless otherwise specified, the following terms and abbreviations have the meanings indicated.

[0043] "Compound A" refers to a compound having the following formula and the compound name N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. [ka] The preparation of compound A and its use as a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener are disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593. The mechanism of action of compound A differs from most known AEDs in that it involves enhanced or increased opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), and this enhanced or increased opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3) is important for controlling neuronal excitability. Compound A is used in the methods and uses described herein.

[0044] "AUC" refers to the area under the plasma concentration versus time curve. AUC reflects the actual systemic exposure to compound A after extravascular administration of a dose of compound A and is expressed as a time multiple of the plasma concentration of compound A. For the purposes of this disclosure, AUC is expressed as a time multiple of ng / mL.

[0045] AUC inf " refers to AUC from zero to infinity.

[0046] AUC infobs " refers to the AUC from zero to infinity during the observed time.

[0047] AUC last " refers to the AUC from time zero to the last detectable plasma concentration.

[0048] "%AUCext This refers to the AUC extrapolated as a percentage of the total AUC from time zero to infinity.

[0049] "Bioavailability" refers to the rate and extent to which compound A is absorbed and made available throughout the body for further distribution to the site of action.

[0050] "C max " refers to the maximum plasma concentration observed.

[0051] "h" refers to time (one or more).

[0052] A "high-fat diet" refers to any solid or liquid food in which approximately 50 percent of the total calorie content comes from fat.

[0053] A "high-calorie diet" refers to any meal containing approximately 800-1000 calories. A typical high-fat, high-calorie diet should have approximately 150 calories, 250 calories, and 500-600 calories coming from protein, carbohydrates, and fat, respectively.

[0054] "SD" refers to the standard deviation.

[0055] "Seizure disorders" include partial initial (focal) seizures, photosensitive epilepsy (photosensitive seizures), self-induced syncope, refractory epilepsy, Angelman syndrome, benign Rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, glucose transporter 1 (Glut1) deficiency, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), and myoclonic deficiency. This refers to seizures and seizure-related disorders such as psychiatric epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. In some embodiments, the term “paroxysmal disorder” refers to focal epilepsy, also known as partial-onset (focal) epilepsy.

[0056] "t1 / 2 λz " refers to the elimination half-life of compound A from plasma (i.e., the time required for the plasma concentration of compound A to decrease by half during the elimination phase).

[0057] "T max " refers to the time it takes for compound A to reach its peak plasma concentration after extravascular administration.

[0058] As used herein, “therapeutic dose” refers to a sufficient amount of compound A to treat the indicated disease, disorder, or condition, or to obtain the desired described effect, including improving or preventing the disease, disorder, or condition or one or more underlying mechanisms. In some embodiments, when compound A is administered for the treatment of a paroxysmal disorder, the therapeutic dose refers to the range of amounts of compound A administered to a person that treats, improves, or prevents the paroxysmal disorder in that person, or that produces a detectable therapeutic or preventive effect in a person with a paroxysmal disorder. This effect is detected, for example, by a reduction (frequency) or severity (quality) of seizures. The exact therapeutic dose for a given person will depend on the person's size and health condition, the nature and severity of the paroxysmal disorder, the presence of any concomitant drug therapies, and other variable factors known to those skilled in the art. The therapeutic dose for a given situation can be determined by routine experimentation and is within the scope of a clinician's expertise.

[0059] As used herein, “treatment” refers to a therapeutic application of Compound A that improves or prevents one or more of the indicated disease, disorder, or pathology or the underlying mechanisms of such disease, disorder, or pathology, including slowing or halting the progression of one or more of the indicated disease, disorder, or pathology or the underlying mechanisms of such disease, disorder, or pathology. In some embodiments, when Compound A is administered for the treatment of a paroxysmal disorder, treatment refers to a therapeutic application to slow or halt the progression of the paroxysmal disorder, a prophylactic application to prevent the onset of the paroxysmal disorder, and / or reversal of the paroxysmal disorder. Reversal of a paroxysmal disorder differs from a therapeutic application to slow or halt the paroxysmal disorder in that, when the reversal method is used, the progression of the paroxysmal disorder is not only completely halted, but cellular behavior is moved to some extent toward the normal state that would be observed in the absence of the paroxysmal disorder.

[0060] "Postprandial state" refers to the state in which food has been consumed during the period from approximately 4 hours before oral administration of an effective dose (e.g., within the therapeutically effective dose range described above) of compound A to approximately 4 hours after administration of compound A. The food may be solid, liquid, or a mixture of solid and liquid foods, as long as it has sufficient bulk and fat content to prevent rapid dissolution and absorption in the stomach. In some examples, this food may be a meal such as breakfast, lunch, or dinner, or baby food (e.g., formula or breast milk). A therapeutically effective dose of compound A may be administered orally to the subject, for example, from approximately 30 minutes before eating a meal to approximately 2 hours after eating a meal, and most advantageously, the dosage unit of compound A may be administered orally during or within 15 minutes after eating a meal.

[0061] "Fasting" refers to a state in which no food has been consumed from at least 4 hours before oral administration of a therapeutically effective dose of compound A until approximately 4 hours after administration of compound A.

[0062] Embodiment In some embodiments, the present disclosure relates to a method for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person requiring treatment, comprising the step of orally administering a therapeutically effective amount of compound A to the person in a postprandial state. In specific examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder such as focal epilepsy.

[0063] In one embodiment, the present disclosure relates to a method for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person requiring treatment, comprising the step of orally administering a therapeutically effective amount of compound A to the person between 30 minutes before feeding and 2 hours after feeding. In a specific example, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder such as focal epilepsy.

[0064] In some embodiments, the present disclosure relates to a compound for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need, wherein the compound is compound A, and a therapeutically effective amount of the compound is administered orally to the person in a postprandial state. In a specific example, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder such as focal epilepsy.

[0065] In one embodiment, the present disclosure relates to a compound for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need, wherein the compound is compound A, and a therapeutically effective amount of the compound is administered orally to the person between 30 minutes before and 2 hours after feeding. In a specific example, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder such as focal epilepsy.

[0066] In embodiments relating to diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction, in some examples, the method increases the opening of Kv7 potassium channels such as one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. In certain examples, the method or use is selective to increase the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 rather than Kv7.1. In some embodiments, the method or use is optionally selective for Kv7.2 rather than Kv7.1. In other embodiments, the method or use is optionally selective for Kv7.3 rather than Kv7.1. In yet another embodiment, the method or use is optionally selective for Kv7.4 rather than Kv7.1. In yet another embodiment, the method or use is optionally selective for Kv7.5 rather than Kv7.1. In some embodiments, the above method or use is optionally selective for Kv7.2 and Kv7.3 over Kv7.1.

[0067] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A to the person in a postprandial state, wherein the amount of compound A is sufficient to treat the paroxysmal disorder in the person. In one embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both.

[0068] In one embodiment, the present disclosure provides a compound for use in treating a paroxysmal disorder in a person in need, wherein the compound is compound A, and the compound is administered orally to the person in a postprandial state. In one embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both.

[0069] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A to the person between 30 minutes before feeding and 2 hours after feeding, wherein the amount of compound A is sufficient to treat the paroxysmal disorder in the person. In one embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both.

[0070] In one embodiment, the present disclosure provides a compound for use in treating a paroxysmal disorder in a person in need, wherein the compound is compound A, and the compound is for use to be administered orally to the person between 30 minutes before and 2 hours after eating. In one embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both.

[0071] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A to the person in a postprandial state, wherein the amount of compound A is 2 to 200 mg.

[0072] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A to the person between 30 minutes before feeding and 2 hours after feeding, wherein the amount of compound A is 2 to 200 mg.

[0073] In one embodiment, the present disclosure describes how compound A is administered orally to a human being and the C max AUC inf , T max , or t1 / 2 λz A method for increasing one or more of the following is provided, comprising the step of orally administering a certain amount of compound A to the person in a postprandial state. In one embodiment, the method is compared to when the same amount of compound A is orally administered to the person in a fasting state with respect to C max AUC inf , T max , or t1 / 2 λz Increase one or more of them.

[0074] In one embodiment, the present disclosure relates to a compound for use, wherein the compound is administered orally to a human being, and the C of the compound is used in the human being. max AUC inf , T max , or t1 / 2 λz The present invention provides a compound for use in which one or more of the following are increased, wherein the compound is compound A, and the compound is administered orally to the human in a postprandial state. In one embodiment, this oral administration is compared to when the same amount of compound A is administered orally to the human in a fasting state. max AUC inf , T max , or t1 / 2 λz Increase one or more of them.

[0075] In one embodiment, the present disclosure describes how compound A is administered orally to a human being and the C max AUC inf , T max , or t1 / 2 λzA method for increasing one or more of the following, comprising the step of orally administering a certain amount of Compound A to the human within 30 minutes before a meal to 2 hours after a meal. In certain embodiments, the method results in an increase in C as compared to when the same amount of Compound A is orally administered to the human in a fasting state max , AUC inf , T max or t1 / 2 λz of one or more of them.

[0076] In one embodiment, the present disclosure provides a compound for use, which is a compound that increases one or more of C max , AUC inf , T max or t1 / 2 λz in a human receiving oral administration of the compound, wherein the compound is Compound A and the compound is orally administered to the human between 30 minutes before a meal and 2 hours after a meal. In certain embodiments, this oral administration results in an increase in C max , AUC inf , T max or t1 / 2 λz of one or more of them.

[0077] In certain embodiments, the present disclosure provides a method for increasing the bioavailability or C max , AUC inf , T max or t1 / 2 λz of Compound A in a human receiving oral administration of Compound A, comprising (a) informing the human that administering Compound A orally, in a post - meal state or between 30 minutes before a meal and 2 hours after a meal, increases the bioavailability or C max , AUC inf , T max or t1 / 2 λz of one or more of them; (b) Trust step (a) and orally administer Compound A to the human subject in a postprandial state or within 30 minutes before to 2 hours after a meal, and A method is provided. In certain such embodiments, the probability that (b) occurs (i.e., the administration is performed in a postprandial state or within 30 minutes before to 2 hours after a meal) is increased compared to the method without step (a).

[0078] In one embodiment, the present disclosure provides a method of orally administering Compound A to a human subject in need thereof, the method comprising orally administering Compound A to the human subject in a postprandial state. In certain embodiments, the method results in an increase in one or more of C max , AUC inf , T max , or t1 / 2 λz of Compound A compared to when the same amount of Compound A is orally administered to the human subject in a fasting state.

[0079] In one embodiment, the present disclosure provides a method of orally administering Compound A to a human subject in need thereof, the method comprising orally administering Compound A to the human subject within 30 minutes before to 2 hours after a meal. In certain embodiments, the method results in an increase in one or more of C max , AUC inf , T max , or t1 / 2 λz of Compound A compared to when the same amount of Compound A is orally administered to the human subject in a fasting state.

[0080] In one embodiment, the present disclosure provides a method of reducing the dosage of Compound A to be orally administered to a human subject as part of a treatment regimen, the method comprising orally administering a reduced dosage of Compound A to the human subject in a postprandial state. In certain embodiments, the reduced dosage is lower than the dosage required to achieve one or more of the same C max , AUC inf , T max , or t1 / 2 λz of Compound A when orally administered to the human subject in a fasting state.

[0081] In one embodiment, the present disclosure provides a compound for use, which is a compound for use in which the dose of the compound is reduced when orally administered to a person as required as part of a treatment plan, wherein the compound is compound A, and the compound is for use when orally administered to the person in a postprandial state. In one embodiment, the reduced dose is the same C as compound A when orally administered to the person in a fasted state. max AUC inf , T max , or t1 / 2 λz This is a dose lower than the dose required to achieve one or more of the following:

[0082] In one embodiment, the Disclosure provides a method for reducing the dose of compound A to be orally administered to a person as required as part of a treatment plan, comprising the step of orally administering the reduced dose of compound A to the person between 30 minutes before feeding and 2 hours after feeding. In one embodiment, the reduced dose is the same C as compound A when orally administered to the person in a fasted state. max AUC inf , T max , or t1 / 2 λz This is a dose lower than the dose required to achieve one or more of the following:

[0083] In one embodiment, the present disclosure provides a compound for use, which is used to reduce the dose of the compound orally administered to a person as required as part of a treatment plan, wherein the compound is compound A, and the compound is used to be orally administered to the person between 30 minutes before feeding and 2 hours after feeding. In one embodiment, the reduced dose is the same C as compound A when orally administered to the person in a fasted state. max AUC inf , T max , or t1 / 2 λz This is a dose lower than the dose required to achieve one or more of the following:

[0084] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a therapeutically effective amount of compound A to the person. In one embodiment, the method relates to compound A, C at least 40 ng / mL, for example, at least 45 ng / mL, at least 50 ng / mL, at least 55 ng / mL, at least 60 ng / mL, at least 65 ng / mL, at least 70 ng / mL, at least 75 ng / mL, or at least 80 ng / mL max , AUC of at least 2500 h·ng / mL, for example, at least 2600 h·ng / mL, at least 2700 h·ng / mL, at least 2800 h·ng / mL, at least 2900 h·ng / mL, at least 3000 h·ng / mL, at least 3100 h·ng / mL, at least 3300 h·ng / mL, at least 3500 h·ng / mL, at least 3700 h·ng / mL, or at least 4000 h·ng / mL inf , T max , or t1 / 2 of at least 130h, for example, at least 150h, at least 170h, at least 190h or at least 210h λz It results in one or more of the following.

[0085] In one embodiment, the present disclosure provides a compound for use in treating a paroxysmal disorder in a person in need, wherein the compound is compound A, and the compound is administered orally to the person. In one embodiment, this oral administration is of compound A, C at least 40 ng / mL, for example, at least 45 ng / mL, at least 50 ng / mL, at least 55 ng / mL, at least 60 ng / mL, at least 65 ng / mL, at least 70 ng / mL, at least 75 ng / mL, or at least 80 ng / mLmax , AUC of at least 2500 h·ng / mL, for example, at least 2600 h·ng / mL, at least 2700 h·ng / mL, at least 2800 h·ng / mL, at least 2900 h·ng / mL, at least 3000 h·ng / mL, at least 3100 h·ng / mL, at least 3300 h·ng / mL, at least 3500 h·ng / mL, at least 3700 h·ng / mL, or at least 4000 h·ng / mL inf , T max , or t1 / 2 of at least 130h, for example, at least 150h, at least 170h, at least 190h or at least 210h λz It results in one or more of the following.

[0086] In one embodiment, the C of compound A obtained by the method and use max AUC inf , T max , or t1 / 2 λz An increase of one or more of these factors does not depend on the type of food consumed by the person described above; for example, the food may or may not include a high-fat or high-calorie diet.

[0087] In one embodiment, the disclosure provides a method for increasing the resting motor threshold (RMT) or active motor threshold (AMT) in a person in need, comprising the step of orally administering a certain amount of compound A to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding. In one embodiment, the amount of compound A is sufficient to increase the RMT or AMT in the person.

[0088] In one embodiment, the present disclosure provides a compound for use in raising the resting motor threshold (RMT) or active motor threshold (AMT) in a person in need, wherein a certain amount of the compound is administered orally to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding. In one embodiment, the amount of compound A is sufficient to raise the RMT or AMT in the person. In one embodiment, the amount of compound A is 2 to 200 mg.

[0089] In one embodiment, the present disclosure provides a method for increasing the resting motor threshold (RMT) or active motor threshold (AMT) in a person in need, comprising the step of orally administering a certain amount of compound A to the person, optionally after a meal or between 30 minutes before and 2 hours after a meal. In one embodiment, the amount of compound A is 2 to 200 mg.

[0090] In one embodiment, the present disclosure provides a method for reducing corticospinal excitability or cortical excitability in a person in need, comprising the step of orally administering a certain amount of compound A to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding, wherein the amount of compound A is sufficient to increase corticospinal excitability or cortical excitability in the person.

[0091] In one embodiment, the present disclosure provides a compound for use in reducing corticospinal excitability or cortical excitability in a person in need, wherein the compound is compound A, and a certain amount of the compound is administered orally to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding, wherein the amount of compound A is sufficient to increase corticospinal excitability or cortical excitability in the person. In one embodiment, the amount of compound A is 2 to 200 mg.

[0092] In one embodiment, the present disclosure provides a method for reducing corticospinal excitability or cortical excitability in a person in need, comprising the step of orally administering a certain amount of compound A to the person, optionally postprandially, or between 30 minutes before and 2 hours after feeding, wherein the amount of compound A is 2 to 200 mg.

[0093] In one embodiment of this disclosure, orally administering compound A to a human in a postprandial state enhances the bioavailability and exposure of compound A at the time of oral administration. It has been surprisingly found that such conditions significantly increase the bioavailability and exposure of compound A in humans at the time of oral administration. In a more specific embodiment, “postprandial state” includes the consumption of food at the same time as, or very soon after, the oral administration of compound A.

[0094] In some, but not all, embodiments of this disclosure, the food is a high-fat, high-calorie diet. A typical high-fat diet has approximately 50 percent of its total calorie content coming from fat, and a typical high-calorie diet has approximately 800–1000 calories. A typical diet should have approximately 150 calories, 250 calories, and 500–600 calories coming from protein, carbohydrates, and fat, respectively. The amount of food consumed with or in close time to the oral administration of compound A should be sufficient to achieve increased bioavailability and exposure to compound A.

[0095] In some embodiments, oral administration of compound A to a person requiring it, according to the methods and uses described herein, takes place between 30 minutes before and 2 hours after eating. In some embodiments, oral administration can be performed from approximately 60, 45, 30, 25, 20, 15, 10, or 5 minutes before eating, or approximately 5, 10, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, or 240 minutes after eating. In some embodiments, compound A can be administered simultaneously with food intake or within 15 minutes after food intake.

[0096] In some embodiments, oral administration of compound A to a human being according to the method described herein results in a C of compound A compared to oral administration of the same amount of compound A to the same human being in a fasted state. max AUC inf , T max , or t1 / 2 λz It increases one or more of the following. In some embodiments, oral administration of compound A to a human being increases the C of compound A compared to oral administration of the same amount of compound A to that fasted human being. max This increases the AUC. In some embodiments, this oral administration is more effective than in a fasted state. inf It increases T max It increases t1 / 2 compared to a fasted state. In some embodiments, this oral administration increases t1 / 2 λz It increases C max and AUC inf It increases C max and T max It increases C max and t1 / 2 λz This increases the AUC. In some embodiments, this oral administration is more effective than in a fasted state. inf and T maxThis increases the AUC. In some embodiments, this oral administration is more effective than in a fasted state. inf and t1 / 2 λz It increases T max and t1 / 2 λz It increases C max AUC inf , and T max It increases C max AUC inf , and t1 / 2 λz It increases C max , T max , and t1 / 2 λz This increases the AUC. In some embodiments, this oral administration is more effective than in a fasted state. inf , T max , and t1 / 2 λz It increases C max AUC inf , T max , and t1 / 2 λz To increase.

[0097] In some embodiments, oral administration of compound A to a person as needed, according to the method described herein, results in a C of compound A compared to oral administration of the same amount of compound A to that person in a fasted state. max To increase C max The increase is at least 50%, for example, at least 60%, at least 75%, at least 85%, at least 100%, at least 125%, at least 150%, at least 200%, at least 250%, or at least 300%. In some embodiments, C max The increase is at least 100%, at least 150%, or at least 200%, for example, at least 100%. In some embodiments, C maxThe increase can range from approximately 50% to approximately 500%, for example, approximately 50% to approximately 400%, approximately 60% to approximately 350%, approximately 70% to approximately 300%, approximately 80% to approximately 250%, or approximately 100% to approximately 200%, for example, approximately 50%, 60%, 70%, 80%, 90%, or 100% to approximately 200%, 250%, 300%, 350%, 400%, 450%, or 500%, which include approximately or at least approximately 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

[0098] In one embodiment of the present disclosure, C after oral administration of compound A in a fasted state. max C after oral administration of compound A in a postprandial state max The ratio is greater than 1.2. In certain embodiments, this ratio is greater than 1.3, greater than 1.5, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, greater than 5.5, greater than 6.0, or greater than 6.5.

[0099] In some embodiments, compound A is C max The concentration rises to at least 40 ng / mL. In some embodiments, the concentration of compound A is increased to C maxThis ranges from 20 ng / mL to approximately 200 ng / mL, for example, approximately 25 to approximately 200 ng / mL, approximately 30 to approximately 200 ng / mL, approximately 35 to approximately 200 ng / mL, approximately 40 to approximately 175 ng / mL, approximately 40 to approximately 150 ng / mL, approximately 40 to approximately 125 ng / mL, approximately 40 to approximately 100 ng / mL, approximately 40 to approximately 90 ng / mL, approximately 40 to approximately 80 ng / mL, approximately 40 to approximately 70 ng / mL, approximately 40 to approximately 60 ng / mL. Or in the range of approximately 40 to 50 ng / mL, for example, approximately 40 ng / mL, 41 ng / mL, 42 ng / mL, 43 ng / mL, 44 ng / mL, 45 ng / mL, 46 ng / mL, 47 ng / mL, 48 ng / mL, 49 ng / mL, 50 ng / mL, 51 ng / mL, 52 ng / mL, 53 ng / mL, 54 ng / mL, 55 ng / mL, 56 ng / mL, 57 ng / mL, 58 ng / mL , 59ng / mL, 60ng / mL, 61ng / mL, 62ng / mL, 63ng / mL, 64ng / mL, 65ng / mL, 66ng / mL, 67ng / mL, 68ng / mL, 69ng / m L, 70ng / mL, 71ng / mL, 72ng / mL, 73ng / mL, 74ng / mL, 75ng / mL, 76ng / mL, 77ng / mL, 78ng / mL, 79ng / mL, 80ng / m It can increase to L, 81 ng / mL, 82 ng / mL, 83 ng / mL, 84 ng / mL, 85 ng / mL, 86 ng / mL, 87 ng / mL, 88 ng / mL, 89 ng / mL, 90 ng / mL, 91 ng / mL, 92 ng / mL, 93 ng / mL, 94 ng / mL, 95 ng / mL, 96 ng / mL, 97 ng / mL, 98 ng / mL, 99 ng / mL, or up to 100 ng / mL.

[0100] In some embodiments, oral administration of compound A to a human being according to the method disclosed herein results in a higher AUC of compound A compared to oral administration of the same amount of compound A to the same human being in a fasted state. inf This increases the AUC. In some embodiments, inf The increase is at least 50%, for example, at least 60%, at least 75%, at least 85%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%. In some embodiments, AUC infThe increase is at least 75% or at least 100%. In some embodiments, AUC inf The increase can range from approximately 50% to approximately 500%, for example, approximately 50% to approximately 400%, approximately 60% to approximately 350%, approximately 70% to approximately 300%, approximately 80% to approximately 250%, or approximately 100% to approximately 200%, for example, approximately 50%, 60%, 70%, 80%, 90%, or 100% to approximately 200%, 250%, 300%, 350%, 400%, 450%, or 500%, which include approximately or at least approximately 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

[0101] In some embodiments, the AUC after oral administration of compound A in a fasted state is shown. inf AUC of compound A after oral administration in a postprandial state inf The ratio is greater than 1.2. In certain embodiments, this ratio is greater than 1.3, greater than 1.5, greater than 1.8, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, greater than 5.5, greater than 6.0, or greater than 6.5.

[0102] In one embodiment of the present disclosure, the ratio of the AUC of compound A after oral administration in a fed state to the AUC of compound A after oral administration in a fasted state is greater than 1.2. In certain embodiments, this ratio is greater than 1.3, greater than 1.5, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, greater than 5.5, greater than 6.0, or greater than 6.5.

[0103] In some embodiments, the AUC of compound A inf It rises to at least 2500 h·ng / mL. In some embodiments, the AUC of compound A infThis ranges from 2000 h·ng / mL to approximately 5000 h·ng / mL, for example, approximately 2500 to approximately 5000 h·ng / mL, approximately 2500 to approximately 4500 h·ng / mL, approximately 2500 to approximately 4250 h·ng / mL, approximately 2500 to approximately 4000 h·ng / mL, approximately 2500 to approximately 3750 h·ng / mL, approximately 2500 to approximately 3500 h·ng / mL, approximately 2500 to approximately 3250 h·ng / mL, approximately 2500 to approximately 3000 h·ng / mL, or up to the range of approximately 2500 to approximately 2750 h·ng / mL, for example, approximately 2500 h·ng / mL, 2600 h·ng / mL, 2700 h·ng / mL, 2800 h·ng / mL, 2900 h·ng / mL, 3000h ng / mL, 3100h ng / mL, 3200h ng / mL, 3300h ng / mL, 3400h ng / mL, 3500h ng / mL, 3600h ng / mL, 3700h ng / mL, 3800h ng / mL, 3900h ng / mL, 4000h ng / mL, It is possible to increase to 4100h ng / mL, 4200h ng / mL, 4300h ng / mL, 4400h ng / mL, 4500h ng / mL, 4600h ng / mL, 4700h ng / mL, 4800h ng / mL, 4900h ng / mL, or 5000h ng / mL.

[0104] In some embodiments, oral administration of compound A to a person as needed, according to the method disclosed herein, results in a T of compound A compared to oral administration of the same amount of compound A to that person in a fasted state. max To increase. In some embodiments, T max The increase is at least 50%, for example, at least 60%, at least 75%, at least 85%, at least 100%, at least 125%, at least 150%, at least 200%, or at least 250%. In some embodiments, T max The increase is at least 75% or at least 100%. In some embodiments, T maxThe increase can be in the range of approximately 50% to approximately 500%, for example, approximately 50% to approximately 400%, approximately 60% to approximately 350%, approximately 70% to approximately 300%, approximately 80% to approximately 250%, or approximately 100% to approximately 200%, for example, approximately 50%, 60%, 70%, 80%, 90%, or 100% to approximately 200%, 250%, 300%, 350%, 400%, 450%, or 500%, which include approximately or at least approximately 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

[0105] In some embodiments, T after oral administration of compound A in a fasted state max T after oral administration of compound A in a postprandial state max The ratio is greater than 1.2. In certain embodiments, this ratio is greater than 1.3, greater than 1.5, greater than 1.8, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, greater than 5.5, greater than 6.0, or greater than 6.5.

[0106] In some embodiments, T of compound A max It rises to at least 3.25hr. In some embodiments, the T of compound A maxThis ranges from 3 hours to approximately 15 hours, for example, approximately 3.25 hours to approximately 15 hours, approximately 3.25 hours to approximately 14.5 hours, approximately 3.25 hours to approximately 14 hours, approximately 3.25 hours to approximately 13.5 hours, approximately 3.25 hours to approximately 13 hours, approximately 3.25 hours to approximately 12.5 hours, approximately 3.25 hours to approximately 12 hours, approximately 3.25 hours to approximately 11.5 hours, approximately 3.25 hours to approximately 11 hours, approximately 3.25 hours to approximately 10.5 hours, approximately 3.25 hours to approximately 10 hours, approximately 3.25 hours to approximately 9.5 hours, approximately 3.25 hours to approximately 9 hours, approximately 3.25 hours to approximately 8.5 hours, approximately 3.25 hours to approximately 8 hours, approximately 3.25 hours to approximately 7.5 hours, approximately 3.25 hours to approximately 7 hours, approximately It is possible to increase the time to approximately 3.25hr to 6.5hr, approximately 3.25hr to 6hr, approximately 3.25hr to 5.5hr, approximately 3.25hr to 5hr, or approximately 3.25hr to 4.5hr, for example, to approximately 3.25hr, 3.5hr, 3.75hr, 4hr, 4.25hr, 4.5hr, 4.75hr, 5hr, 5.25hr, 5.5hr, 5.75hr, 6hr, 6.25hr, 6.5hr, 6.75hr, 7hr, 7.25hr, 7.5hr, 7.75hr, 8hr, 8.25hr, 8.5hr, 8.75hr, 9hr, 9.25hr, 9.5hr, 9.75hr, or up to 10hr.

[0107] In some embodiments, oral administration of compound A to a person as needed, according to the method disclosed herein, results in a t1 / 2 ratio of compound A compared to oral administration of the same amount of compound A to that person in a fasted state. λz This increases by at least 40% or at least 50%, for example, at least 60%, at least 75%, or at least 100%. In some embodiments, t1 / 2 λz The increase is at least 75%. In some embodiments, t1 / 2 λzThe increase can be in the range of approximately 50% to approximately 500%, for example, approximately 50% to approximately 400%, approximately 60% to approximately 350%, approximately 70% to approximately 300%, approximately 80% to approximately 250%, or approximately 100% to approximately 200%, for example, approximately 50%, 60%, 70%, 80%, 90%, or 100% to approximately 200%, 250%, 300%, 350%, 400%, 450%, or 500%, which include approximately or at least approximately 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

[0108] In some embodiments, t1 / 2 after oral administration of compound A in a fasted state λz t1 / 2 after oral administration of compound A in a postprandial state λz The ratio is greater than 1.2. In certain embodiments, this ratio is greater than 1.3, greater than 1.5, greater than 1.8, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, greater than 5.5, greater than 6.0, or greater than 6.5.

[0109] In some embodiments, t1 / 2 of compound A λz It rises to at least 130hr. In some embodiments, t1 / 2 of compound A λzThis ranges from 100hr to approximately 500hr, for example, approximately 110hr to approximately 500hr, approximately 120hr to approximately 500hr, approximately 130hr to approximately 500hr, approximately 130hr to approximately 490hr, approximately 130hr to approximately 480hr, approximately 130hr to approximately 470hr, approximately 130hr to approximately 460hr, approximately 130hr to approximately 450hr, approximately 130hr to approximately 440hr, approximately 130hr to approximately 430hr, and approximately 130hr to approximately 42 0hr, about 130hr to about 410hr, about 130hr to about 400hr, about 130hr to about 390hr, about 130hr to about 380hr, about 130hr to about 370hr, about 130hr to about 36 0hr, about 130hr to about 350hr, about 130hr to about 340hr, about 130hr to about 330hr, about 130hr to about 320hr, about 130hr to about 310hr, about 130hr to about 300 hr, approximately 130hr to 290hr, approximately 130hr to 280hr, approximately 130hr to 270hr, approximately 130hr to 260hr, approximately 130hr to 250hr, approximately 130hr to 240hr, approximately 130hr to 230hr, approximately 130hr to 220hr, approximately 130hr to 210hr, or up to the range of approximately 130hr to 200hr, for example, approximately 130hr, 140hr, 150 It is possible to increase the hours up to 160hr, 170hr, 180hr, 190hr, 200hr, 210hr, 220hr, 230hr, 240hr, 250hr, 260hr, 270hr, 280hr, 290hr, 300hr, 310hr, 320hr, 330hr, 340hr, 350hr, 360hr, 370hr, 380hr, 390hr, or 400hr.

[0110] In one embodiment, compound A is provided in a dosage unit form suitable for oral administration. Compound A exists in this dosage unit form at levels ranging from about 0.05 mg / kg to about 2.0 mg / kg. More specific representative levels include 0.05 mg / kg, 0.10 mg / kg, 0.20 mg / kg, 0.30 mg / kg, 0.40 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.80 mg / kg, 0.90 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, and 2.0 mg / kg. In some embodiments, the above method comprises a step of orally administering compound A in an amount of 0.1 to 1.0 mg / kg. In some embodiments, the above method comprises the step of orally administering compound A at a dose of 0.2 to 0.5 mg / kg.

[0111] In some embodiments, the methods and uses described herein, for example, the methods and uses in treating or treating a paroxysmal disorder in a human being as required by the methods and uses described herein, are achieved by orally administering 2 to 200 mg of compound A. For example, the above methods may be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39mg, approximately 40mg, approximately 41mg, approximately 42mg, approximately 43mg, approximately 44mg, approximately 45mg, approximately 46mg, approximately 47mg, approximately 48mg, approximately 49mg, approximately 50mg, approximately 51mg, approximately 52mg, approximately 53mg, approximately 54mg, approximately 55mg, approximately 56mg, approximately 57mg, approximately 58mg, approximately 59mg, approximately 60mg, approximately 61mg, approximately 62mg, approximately 63mg, approximately 64mg, approximately 65mg, approximately 66mg, approximately 67mg, approximately 68mg, approximately 69mg, approximately 70mg, approximately 71mg, approximately 72mg, approximately 73mg, approximately 74mg, approximately 75mg Approximately 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg mg, about 111mg, about 112mg, about 113mg, about 114mg, about 115mg, about 116mg, about 117mg, about 118mg, about 119mg, about 120mg, about 121mg, about 122mg, about 123mg, about 124mg, about 125mg, about 1 26mg, about 127mg, about 129mg, about 130mg, about 131mg, about 132mg, about 133mg, about 134mg, about 135mg, about 136mg, about 137mg, about 138mg, about 139mg, about 140mg, about 141mg, about 142mg,Approximately 143mg, approximately 144mg, approximately 145mg, approximately 146mg, approximately 147mg, approximately 148mg, approximately 149mg, approximately 150mg, approximately 151mg, approximately 152mg, approximately 153mg, approximately 154mg, approximately 155mg, approximately 156mg, approximately 157mg, approximately 158mg, approximately 159mg, approximately 160mg, approximately 161mg, approximately 162mg, approximately 163mg, approximately 164mg, approximately 165mg, approximately 166mg, approximately 167mg, approximately 168mg, approximately 169mg, approximately 170mg, approximately 171mg, approximately 172mg, approximately 17 The method may include a step of orally administering 3 mg, approximately 174 mg, approximately 175 mg, approximately 176 mg, approximately 177 mg, approximately 178 mg, approximately 179 mg, approximately 180 mg, approximately 181 mg, approximately 182 mg, approximately 183 mg, approximately 184 mg, approximately 185 mg, approximately 186 mg, approximately 187 mg, approximately 188 mg, approximately 189 mg, approximately 190 mg, approximately 191 mg, approximately 192 mg, approximately 193 mg, approximately 194 mg, approximately 195 mg, approximately 196 mg, approximately 197 mg, approximately 198 mg, approximately 199 mg, or approximately 200 mg. In some embodiments, this oral administration contains 5 to 50 mg of compound A. In some embodiments, this oral administration contains 10 mg, 20 mg, or 25 mg of compound A. In some embodiments, this oral administration contains 20 mg of compound A. In some embodiments, this oral administration contains at least 20 mg of compound A.

[0112] In some embodiments, the methods and uses described herein, for example, the methods or uses in treating a paroxysmal disorder in a human being as required according to the methods and uses described herein, are achieved by orally administering 5 to 1000 mg of compound A per day, for example, 5 to 500 mg or 5 to 250 mg of compound A per day. For example, the above methods can be performed with approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg per day. mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 20 0mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 26 5mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 3 30mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 3 The system may include a step for orally administering 95 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, approximately 500 mg, or approximately 1000 mg.In some embodiments, this oral administration comprises the step of orally administering 10 to 200 mg of compound A per day, for example 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg to 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of compound A per day, for example 20 to 150 mg per day. In some embodiments, this oral administration includes 50 mg, 75 mg, 100 mg, or 125 mg of compound A per day, for example 100 mg of compound A per day.

[0113] In certain cases, the above daily dose of compound A may be administered orally as multiple daily doses, for example, two, three, four, or five doses per day. For example, a daily dose of 100 mg may be administered as four 25 mg doses throughout the day.

[0114] In some embodiments, the above daily dose of compound A is administered orally as a single dose. For example, compound A can be administered orally as a single dose in amounts ranging from approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day to approximately 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, or 150 mg per day, including single doses of 10-25 mg, 10-30 mg, and 10-40 mg per day, for example, 10-25 mg per day as a single dose.

[0115] In one embodiment, the methods and uses described herein, when using the daily dosage disclosed herein, achieve a steady state for compound A within 6 to 9 days, for example, within about one week.

[0116] In some embodiments, the Disclosure provides a method for increasing serum levels of compound A in a person in need, comprising the step of orally administering compound A to the person in a postprandial state or between 30 minutes before and 2 hours after feeding. In similar embodiments, the Disclosure provides compound A for use in increasing serum levels of compound A in a person in need, compound A being administered to the person in a postprandial state or between 30 minutes before and 2 hours after feeding.

[0117] In one embodiment of the present disclosure, the administration of compound A is for the treatment of a paroxysmal disorder in which the patient is thought to benefit from the opening of the Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channel. Compound A is a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener. In one embodiment, the present disclosure provides a method for opening the Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channel in a person in need, comprising the step of administering a certain amount of compound A. In a similar embodiment, the present disclosure provides compound A for use in opening the Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channel in a person in need.

[0118] In some embodiments, the Disclosure provides a method for treating, improving, or preventing in a person in need a disease, disorder, or condition affected by the modulation of at least one potassium channel selected from Kv7.2, Kv7.3, Kv7.4 (KCNQ4), and Kv7.5 (KCNQ5), for example, by opening one or more of the potassium channels, comprising the step of orally administering compound A to the person optionally postprandially, or between 30 minutes before and 2 hours after feeding. In similar embodiments, the Disclosure provides compound A for use in treating, improving, or preventing in a person in need a disease, disorder, or condition affected by the modulation of at least one potassium channel selected from Kv7.2, Kv7.3, Kv7.4, and Kv7.5, for example, by opening one or more of the potassium channels, wherein compound A is orally administered to the person optionally postprandially, or between 30 minutes before and 2 hours after feeding. In one embodiment, oral administration of compound A does not open potassium channel Kv7.1 (KCNQ1). In other words, in certain examples, compound A is more selective than Kv7.1 for one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0119] In some embodiments, oral administration of compound A to a person requiring it, according to the method described herein, increases the resting motor threshold (RMT) or active motor threshold (AMT). In some embodiments, the increase in RMT or AMT is proportional to the plasma concentration of compound A. In some embodiments, oral administration of compound A to a person requiring it decreases corticospinal excitability or cortical excitability as measured using transcranial magnetic stimulation (TMS).

[0120] In one embodiment, the present disclosure provides a method for orally administering compound A to a person exhibiting a lower-than-average RMT or AMT, comprising the step of orally administering compound A optionally after a meal or between 30 minutes before and 2 hours after a meal, thereby increasing the RMT or AMT in the person exhibiting the lower-than-average RMT or AMT.

[0121] In some embodiments, oral administration of compound A according to the methods and uses described herein can modulate TMS-guided electroencephalography (EEG) potentials (TEPs) and reduce cortical excitability. In some embodiments, at specific plasma concentrations (e.g., ≥50 ng / mL), compound A reduces the amplitude of one or more initial TEP components, including 15–35 ms (N15-P25), 45 ms (N45), or 180 ms (P180) after the TMS pulse, by (e.g., ≥50%) compared to placebo. In some embodiments, at 2, 4, and 6 hours post-administration, compound A reduces the amplitude of one or more initial TEP components, including 15–35 ms (N15-P25), 45 ms (N45), or 180 ms (P180) after the TMS pulse, by (e.g., ≥30%) compared to placebo.

[0122] In some embodiments, oral administration of compound A according to the methods and uses described herein can modulate TMS-induced oscillations and ongoing oscillation activity. In some embodiments, at specific plasma concentrations (e.g., 50 ng / mL or higher), compound A reduces initial theta (4-7 Hz) TMS-induced oscillations (30-390 ms) or alpha (8-12 Hz) TMS-induced oscillations (220-400 ms) compared to placebo (e.g., by 40%) and / or increases beta (13-30 Hz) TMS-induced power (220-310 ms) after TMS pulses compared to placebo (e.g., by 40%). In some embodiments, at 2 hours post-administration, compound A reduces initial theta TMS-induced oscillations after TMS pulses compared to placebo (e.g., by 30%). In some embodiments, at 4 hours post-administration, compound A reduces alpha TMS-induced oscillations after TMS pulses compared to placebo (e.g., by 30%). In some embodiments, compound A reduces theta TMS-induced oscillations after TMS pulse by (e.g., 30% or more) compared to placebo, at 6 hours post-administration.

[0123] In some embodiments, oral administration of compound A according to the methods and uses described herein can modulate resting EEG. In some embodiments, at specific plasma concentrations (e.g., 50 ng / mL or higher), compound A increases the power of one or more delta, theta, or beta bands compared to placebo (e.g., by 50% or more). In some embodiments, at 2, 4, and 6 hours post-administration, compound A increases the power of one or more delta, theta, delta, beta, or alpha bands compared to placebo (e.g., by 40% or more).

[0124] In some embodiments, the methods and uses described herein involve administering compound A in the form of a pharmaceutically acceptable oral composition comprising compound A and one or more pharmaceutically acceptable carriers or excipients. The amount of compound A contained in these compositions corresponds to one or more of the amounts described herein. In some embodiments, this composition is a unit dose.

[0125] Examples of pharmaceutically acceptable oral compositions containing compound A include solid formulations (tablets, capsules, lozenges, sugars, granules, powders, microparticles, and films, etc.) and liquid formulations (aqueous solutions, elixirs, tinctures, suspensions, and dispersions). In one embodiment, a pharmaceutically acceptable oral composition of compound A is a suspension or granule for pediatric use. All of the above amounts of compound A may be contained in such formulations, for example, capsules containing 5 mg, 10 mg, 15 mg, 10 mg, 25 mg, 30 mg, or 35 mg of compound A.

[0126] In another embodiment, a kit for oral administration of compound A in a postprandial state is provided to enhance the bioavailability and exposure of compound A during oral administration. Such a kit includes multiple oral dosing unit forms of compound A, combined with instructions for oral administration of compound A in a postprandial state.

[0127] In one embodiment of the present disclosure, oral administration of a therapeutically effective amount of compound A results in the maximum plasma concentration (C) of compound A when administered orally in a fasted state. max ) and compared to the exposure (AUC) of compound A, the C of compound A max This results in an increase in both the AUC of compound A and the AUC of compound A.

[0128] In one embodiment of the present disclosure, C is administered orally in a therapeutically effective amount of compound A while the patient is fasting. max C after oral administration of a therapeutically effective amount of compound A for postprandial conditions max The ratio is greater than 1.3.

[0129] In one embodiment of the present disclosure, the ratio of the AUC after oral administration of a therapeutically effective amount of compound A in a fasted state to the AUC after oral administration of a therapeutically effective amount of compound A in a fed state is greater than 1.3.

[0130] In one embodiment of this disclosure, the therapeutically effective dose of compound A is approximately 0.05 mg / kg to approximately 2.0 mg / kg.

[0131] In one embodiment of the present invention, in which comparisons are made involving humans who have been orally administered compound A while fasting, similar comparisons can be made involving humans who have not ingested food during the period from approximately 4 hours before oral administration of compound A to approximately 4 hours after oral administration of compound A, for example, from approximately 4 hours, 3 hours, 2 hours, 1.5 hours, 1 hour, or from approximately 0.5 hours before oral administration of compound A to approximately 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, or 4 hours after oral administration of compound A.

[0132] In one embodiment, when a seizure disorder is treated with the present invention, the seizure disorder may include partial initial (focal) seizures, photosensitive epilepsy (photosensitive seizures), self-induced syncope, refractory epilepsy, Angelman syndrome, benign Rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, glucose transporter 1 deficiency, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, and Lennox-Gastaut syndrome. The following are selected from (LGS), myoclonic absence epilepsy, Ohtahara syndrome, Panaetopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. In some embodiments, the paroxysmal disorder is focal epilepsy, also known as partial (focal) epilepsy.

[0133] Further embodiments and examples of the present disclosure are described herein. These embodiments and examples are for illustrative purposes only and should not be construed as limiting the scope of the claimed invention.

[0134] Numbered Embodiments Embodiment 1. A method for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person requiring treatment, comprising the step of orally administering a therapeutic dose of compound A to the person after a meal, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

[0135] Embodiment 2. A method for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person requiring treatment, comprising the step of orally administering a therapeutic dose of compound A to the person between 30 minutes before feeding and 2 hours after feeding, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

[0136] Embodiment 3. The method described above, which increases the opening of the Kv7 potassium channel, as described in Embodiment 1 or Embodiment 2.

[0137] Embodiment 4. The method according to Embodiment 3, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0138] Embodiment 5. The method according to Embodiment 4, wherein the method is selective to increase the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5, rather than Kv7.1.

[0139] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the disease, disorder, or pathological condition is a paroxysmal disorder.

[0140] Embodiment 7. The method according to Embodiment 6, wherein the paroxysmal disorder is focal epilepsy.

[0141] Embodiment 8. A method for treating a seizure disorder in a human subject, comprising the step of orally administering a certain amount of Compound A to the human subject in a postprandial state, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of Compound A is sufficient to treat the seizure disorder in the human subject.

[0142] Embodiment 9. A method for treating a seizure disorder in a human subject, comprising the step of orally administering a certain amount of Compound A to the human subject between 30 minutes before eating and 2 hours after eating, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of Compound A is sufficient to treat the seizure disorder in the human subject.

[0143] Embodiment 10. A method for treating a seizure disorder in a human subject, comprising the step of orally administering a certain amount of Compound A to the human subject in a postprandial state, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of Compound A is 2 to 200 mg.

[0144] Embodiment 11. A method for treating a seizure disorder in a human subject, comprising the step of orally administering a certain amount of Compound A to the human subject between 30 minutes before eating and 2 hours after eating, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of Compound A is 2 to 200 mg.

[0145] Embodiment 12. A method for treating a seizure disorder in a human subject, comprising the step of orally administering compound A to the human subject, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the improvement comprises orally administering the compound A to the human subject in a postprandial state.

[0146] Embodiment 13. A method for treating a seizure disorder in a human subject, comprising the step of orally administering compound A to the human subject, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the improvement comprises orally administering the compound A to the human subject between about 30 minutes before a meal and about 2 hours after a meal.

[0147] Embodiment 14. A method for orally administering compound A to a human subject, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the improvement comprises orally administering the compound A to the human subject in a postprandial state.

[0148] Embodiment 15. A method for orally administering compound A to a human subject, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the improvement comprises orally administering the compound A to the human subject between about 30 minutes before a meal and about 2 hours after a meal.

[0149] Embodiment 16. The method according to any one of Embodiments 8 to 15, wherein the method increases one or more of C max , AUC inf , T max , or t1 / 2 λz of compound A as compared to when the same amount of compound A is orally administered to the human subject in a fasting state.

[0150] Embodiment 17. In a human receiving oral administration of compound A, the C max AUC inf , T max , or t1 / 2 λz A method for increasing one or more of the following, comprising the step of orally administering a certain amount of compound A to the above person in a postprandial state, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the above method is compared to when the same amount of compound A is orally administered to the above person in a fasting state with respect to C max AUC inf , T max , or t1 / 2 λz A method to increase one or more of the values.

[0151] Embodiment 18. In a human receiving oral administration of compound A, the C max AUC inf , T max , or t1 / 2 λz A method for increasing one or more of the following, comprising the step of orally administering a certain amount of compound A to the above person between 30 minutes before feeding and 2 hours after feeding, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the above method is compared to when the same amount of compound A is orally administered to the above person in a fasting state with respect to C max AUC inf , T max , or t1 / 2 λz A method to increase one or more of the values.

[0152] Embodiment 19. A method for orally administering compound A to a person in need, comprising the step of orally administering compound A to the person in a postprandial state, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the above method provides a C of compound A compared to when the same amount of compound A is orally administered to the person in a fasting state.max AUC inf , T max , or t1 / 2 λz A method to increase one or more of the values.

[0153] Embodiment 20. A method for orally administering compound A to a person in need, comprising the step of orally administering compound A to the person between 30 minutes before feeding and 2 hours after feeding, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the above method provides a C of compound A compared to when the same amount of compound A is orally administered to the person in a fasting state. max AUC inf , T max , or t1 / 2 λz A method to increase one or more of the values.

[0154] Embodiment 21. A method for reducing the dose of compound A to be orally administered to a person as required as part of a treatment plan, comprising the step of orally administering the reduced dose of compound A to the person in a postprandial state, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the reduced dose is the same C as when compound A is orally administered to the person in a fasting state. max AUC inf , T max , or t1 / 2 λz A method that uses a dose lower than the dose required to achieve one or more of the following:

[0155] Embodiment 22. A method for reducing the dose of compound A orally administered to a person as required as part of a treatment plan, comprising the step of orally administering the reduced dose of compound A to the person between 30 minutes before feeding and 2 hours after feeding, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the reduced dose is the same C as compound A when orally administered to the person in a fasted state. maxAUC inf , T max , or t1 / 2 λz A method that uses a dose lower than the dose required to achieve one or more of the following:

[0156] Embodiment 23. Oral administration of compound A to the above-mentioned human compared to oral administration of the same amount of compound A to the above-mentioned human in a fasting state, resulting in a C max A method according to any one of Embodiments 16 to 22 for increasing

[0157] Embodiment 24. C after oral administration of compound A in a fasted state. max C after oral administration of compound A to the target max The method according to embodiment 23, wherein the ratio is greater than 1.3.

[0158] Embodiment 25. C after oral administration of compound A in a fasted state. max C after oral administration of compound A to the target max The method according to embodiment 23, wherein the ratio is greater than 2.

[0159] Embodiment 26. C after oral administration of compound A in a fasted state. max C after oral administration of compound A to the target max The method according to embodiment 23, wherein the ratio is greater than 3.

[0160] Embodiment 27. C of compound A max The method according to embodiment 23, wherein the increase is at least 50%.

[0161] Embodiment 28. C of compound A max The method according to embodiment 23, wherein the increase is at least 100%.

[0162] Embodiment 29. Oral administration of compound A to the above-mentioned human compared to oral administration of the same amount of compound A to the above-mentioned fasting human, resulting in a higher AUC of compound A. inf A method according to any one of embodiments 16 to 28 for increasing

[0163] Embodiment 30. The AUC after oral administration of Compound A in a fasting state inf The AUC after oral administration of Compound A relative to inf the method according to Embodiment 29, wherein the ratio is more than 1.3.

[0164] Embodiment 31. The AUC after oral administration of Compound A in a fasting state inf The AUC after oral administration of Compound A relative to inf the method according to Embodiment 29, wherein the ratio is more than 1.5.

[0165] Embodiment 32. The AUC after oral administration of Compound A in a fasting state inf The AUC after oral administration of Compound A relative to inf the method according to Embodiment 29, wherein the ratio is more than 1.8.

[0166] Embodiment 33. The method according to Embodiment 29, wherein the increase in the AUC of Compound A is at least 50%. inf

[0167] Embodiment 34. The method according to Embodiment 29, wherein the increase in the AUC of Compound A is at least 75%. inf

[0168] Embodiment 35. The method according to any one of Embodiments 16 to 34, wherein the oral administration of Compound A to the human increases the T of Compound A as compared with the case where the same amount of Compound A is orally administered to the fasting human. max

[0169] Embodiment 36. The method according to Embodiment 35, wherein the ratio of the T after oral administration of Compound A in a fasting state to the T after oral administration of Compound A is more than 1.3. max The T after oral administration of Compound A relative to<opposite max

[0170] Embodiment 37. The method according to Embodiment 35, wherein the ratio of the T after oral administration of Compound A in a fasting state to the T after oral administration of Compound A is more than 1.8. max The T after oral administration of Compound A relative to max

[0171] Embodiment 38. T after oral administration of compound A in a fasted state max T after oral administration of compound A to the target max The method according to embodiment 35, wherein the ratio is greater than 2.

[0172] Embodiment 39. T of compound A max The method according to embodiment 35, wherein the increase is at least 50%.

[0173] Embodiment 40. T of compound A max The method according to embodiment 35, wherein the increase is at least 75%.

[0174] Embodiment 41. Oral administration of compound A to the above human subject results in a t1 / 2 ratio of compound A compared to oral administration of the same amount of compound A to the above human subject in a fasting state. λz A method according to any one of embodiments 16 to 40 for increasing

[0175] Embodiment 42. t1 / 2 after oral administration of compound A in a fasted state λz t1 / 2 after oral administration of compound A to the target population λz The method according to embodiment 41, wherein the ratio is greater than 1.2.

[0176] Embodiment 43. t1 / 2 after oral administration of compound A in a fasted state λz t1 / 2 after oral administration of compound A to the target population λz The method according to embodiment 41, wherein the ratio is greater than 1.4.

[0177] Embodiment 44. t1 / 2 of compound A λz The method according to embodiment 41, wherein the increase is at least 20%.

[0178] Embodiment 45. t1 / 2 of compound A λz The method according to embodiment 41, wherein the increase is at least 35%.

[0179] Embodiment 46. A method for treating a paroxysmal disorder in a person requiring it, comprising the step of orally administering compound A to the person, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the above method, with respect to compound A, At least 40 ng / mL of C max , AUC of at least 2500 h·ng / mL inf , At least 3.25 hours max , or at least 130h t1 / 2 λz A method that results in one or more of the following.

[0180] Embodiment 47. A method for increasing the resting exercise threshold (RMT) or active exercise threshold (AMT) in a person in need, comprising the step of orally administering a certain amount of compound A to the person, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of compound A is sufficient to increase the RMT or AMT in the person.

[0181] Embodiment 48. A method for increasing the resting exercise threshold (RMT) or active exercise threshold (AMT) in a person in need, comprising the step of orally administering a certain amount of compound A to the person, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of compound A is 2 to 200 mg.

[0182] Embodiment 49. The method according to Embodiment 47 or Embodiment 48, wherein the increase in RMT or AMT is proportional to the plasma concentration of compound A.

[0183] Embodiment 50. A method for reducing corticospinal excitability or cortical excitability in a person in need, comprising the step of orally administering a certain amount of compound A to the person, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of compound A is sufficient to reduce corticospinal excitability or cortical excitability in the person.

[0184] Embodiment 51. A method for reducing corticospinal excitability or cortical excitability in a person in need, comprising the step of orally administering a certain amount of compound A to the person, wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount of compound A is 2 to 200 mg.

[0185] Embodiment 52. The method according to any one of Embodiments 1 to 7, further comprising the step of orally administering 2 to 200 mg of compound A.

[0186] Embodiment 53. The method according to any one of Embodiments 8 to 52, further comprising the step of orally administering 2 to 100 mg of compound A.

[0187] Embodiment 54. The method according to Embodiment 53, further comprising the step of orally administering 5 to 50 mg of compound A.

[0188] Embodiment 55. The method according to Embodiment 53, further comprising the step of orally administering 10 mg, 20 mg, or 25 mg of compound A.

[0189] Embodiment 56. The method according to Embodiment 53, further comprising the step of orally administering 20 mg of compound A.

[0190] Embodiment 57. The method according to any one of Embodiments 8 to 54, further comprising the step of orally administering at least 20 mg of compound A.

[0191] Embodiment 58. The method according to any one of Embodiments 8 to 57, further comprising the step of orally administering 5 to 500 mg of compound A per day.

[0192] Embodiment 59. The method according to Embodiment 58, further comprising the step of orally administering 20 to 150 mg of compound A per day.

[0193] Embodiment 60. The method according to Embodiment 58, further comprising the step of orally administering 100 mg of compound A per day.

[0194] Embodiment 61. The method according to any one of Embodiments 1 to 60, comprising the step of orally administering compound A at a dose of 0.05 to 2.0 mg / kg.

[0195] Embodiment 62. The method according to Embodiment 61, further comprising the step of orally administering compound A at a dose of 0.1 to 1.0 mg / kg.

[0196] Embodiment 63. The method according to Embodiment 61, further comprising the step of orally administering compound A at a dose of 0.2 to 0.5 mg / kg.

[0197] Embodiment 64. A compound for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is for use in which the person is orally administered after a meal.

[0198] Embodiment 65. A compound for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is for use to be orally administered to the person between 30 minutes before and 2 hours after feeding.

[0199] Embodiment 66. The compound for use according to Embodiment 63 or Embodiment 64, wherein the above method increases the opening of the Kv7 potassium channel.

[0200] Embodiment 67. The compound for use according to Embodiment 65, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0201] Embodiment 68. The compound for use according to Embodiment 66, wherein the method described above is selective for increasing the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5, rather than Kv7.1.

[0202] Embodiment 69. The compound for use according to any one of Embodiments 63 to 67, wherein the disease, disorder, or pathology is a paroxysmal disorder.

[0203] Embodiment 70. The compound for use according to Embodiment 68, wherein the above-mentioned seizure disorder is focal primary epilepsy.

[0204] Embodiment 71. A compound for use in treating a paroxysmal disorder in a person in need, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is for use to be administered orally to the person in a postprandial state.

[0205] Embodiment 72. A compound for use in treating a paroxysmal disorder in a person in need, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is for use to be orally administered to the person between 30 minutes before and 2 hours after feeding.

[0206] Embodiment 73. Oral administration of the above compound compared to oral administration of the same amount of the above compound to the above human in a fasting state results in a higher C content of the above compound. max AUC inf , T max , or t1 / 2 λz A compound for use according to Embodiment 56 or Embodiment 57 that increases one or more of the following.

[0207] Embodiment 74. A compound for use, wherein the C of the compound is present in a human being who receives oral administration of the compound. max AUC inf , T max , or t1 / 2 λz A compound for use in increasing one or more of the following, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is administered orally to the person in a postprandial state, and the oral administration of the compound is compared to the case where the same amount of the compound is administered orally to the person in a fasting state. max AUC inf , T max , or t1 / 2 λz A compound for use that increases one or more of the following:

[0208] Embodiment 75. A compound for use, wherein in a person receiving oral administration of the compound, the C of the compound max AUC inf , T max , or t1 / 2 λz A compound for use in increasing one or more of the following, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is administered orally to the person between 30 minutes before feeding and 2 hours after feeding, and the oral administration of the compound is compared to the case where the same amount of the compound is administered orally to the person in a fasting state. max AUC inf , T max , or t1 / 2λz A compound for use that increases one or more of the following:

[0209] Embodiment 76. A compound for use, a compound for use in reducing the dose of the compound orally administered to a person as required as part of a treatment plan, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the reduced dose of the compound is orally administered to the person in a postprandial state, and the reduced dose is the same as the C of the compound when orally administered to the person in a fasting state. max AUC inf , T max , or t1 / 2 λz A compound for use that is in a dose lower than the dose required to achieve one or more of the following:

[0210] Embodiment 77. A compound for use, a compound for use in reducing the dose of the compound orally administered to a person as required as part of a treatment plan, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the reduced dose of the compound is orally administered to the person between 30 minutes before feeding and 2 hours after feeding, wherein the reduced dose is the same C as the compound when orally administered to a fasted person. max AUC inf , T max , or t1 / 2 λz A compound for use that is in a dose lower than the dose required to achieve one or more of the following:

[0211] Embodiment 78. Oral administration of the compound to the human subject compared to oral administration of the same amount of the compound to the human subject in a fasting state. max A compound for use according to any one of embodiments 73 to 77 that increases the

[0212] Embodiment 79. C after oral administration of the above compound in a fasted state max C after oral administration of the above compound to the target of max The compound for use according to Embodiment 78, wherein the ratio is greater than 1.3.

[0213] Embodiment 80. C after oral administration of the above compound in a fasted state max C after oral administration of the above compound to the target of max The compound for use according to Embodiment 78, wherein the ratio is greater than 2.

[0214] Embodiment 81. C after oral administration of the above compound in a fasted state max C after oral administration of the above compound to the target of max The compound for use according to Embodiment 78, wherein the ratio is greater than 3.

[0215] Embodiment 82. The C of the above compound max The compound for use according to Embodiment 78, wherein the increase is at least 50%.

[0216] Embodiment 83. C of the above compound max The compound for use according to Embodiment 78, wherein the increase is at least 100%.

[0217] Embodiment 84. Oral administration of the compound to the human subject compared to oral administration of the same amount of the compound to the fasted human subject with respect to the AUC of the compound. inf A compound for use according to any one of embodiments 73 to 78 that increases the

[0218] Embodiment 85. AUC after oral administration of the above compound in a fasted state inf AUC after oral administration of the above compound to the target population inf The compound for use according to Embodiment 84, wherein the ratio is greater than 1.3.

[0219] Embodiment 86. AUC after oral administration of the above compound in a fasted state inf AUC after oral administration of the above compound to the target population infThe compound for use according to Embodiment 84, wherein the ratio is greater than 1.5.

[0220] Embodiment 87. AUC after oral administration of the above compound in a fasted state. inf AUC after oral administration of the above compound to the target population inf The compound for use according to Embodiment 84, wherein the ratio is greater than 1.8.

[0221] Embodiment 88. AUC of the above compound inf The compound for use according to Embodiment 84, wherein the increase is at least 50%.

[0222] Embodiment 89. AUC of the above compound inf The compound for use according to Embodiment 84, wherein the increase is at least 75%.

[0223] Embodiment 90. Oral administration of the compound to the human subject compared to oral administration of the same amount of the compound to the human subject in a fasting state resulted in a higher T of the compound. max A compound for use according to any one of embodiments 73 to 89 that increases the

[0224] Embodiment 91. T after oral administration of the above compound in a fasted state max T after oral administration of the above compound to the target group max The compound for use according to Embodiment 90, wherein the ratio is greater than 1.3.

[0225] Embodiment 92. T after oral administration of the above compound in a fasted state max T after oral administration of the above compound to the target group max The compound for use according to Embodiment 90, wherein the ratio is greater than 1.8.

[0226] Embodiment 93. T after oral administration of the above compound in a fasted state max T after oral administration of the above compound to the target group max The compound for use according to Embodiment 90, wherein the ratio is greater than 2.

[0227] Embodiment 94. The T of the above compound max The compound for use according to Embodiment 75, wherein the increase is at least 50%.

[0228] Embodiment 95. The T of the above compound max The compound for use according to Embodiment 90, wherein the increase is at least 75%.

[0229] Embodiment 96. Oral administration of the compound to the human subject compared to oral administration of the same amount of the compound to the human subject in a fasting state resulted in a compound t1 / 2 λz A compound for use according to any one of embodiments 73 to 95 that increases the

[0230] Embodiment 97. t1 / 2 after oral administration of the above compound in a fasted state λz t1 / 2 after oral administration of the above compound to the target population λz The compound for use according to Embodiment 96, wherein the ratio is greater than 1.2.

[0231] Embodiment 98. t1 / 2 after oral administration of the above compound in a fasted state λz t1 / 2 after oral administration of the above compound to the target population λz The compound for use according to Embodiment 96, wherein the ratio is greater than 1.4.

[0232] Embodiment 99. t1 / 2 of the above compound λz The compound for use according to Embodiment 96, wherein the increase is at least 20%.

[0233] Embodiment 100. t1 / 2 of the above compound λz The compound for use according to Embodiment 96, wherein the increase is at least 35%.

[0234] Embodiment 101. A compound for use in treating paroxysmal disorders in a person in need, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the compound is administered orally to the person, and the oral administration of the compound is effective for the compound. At least 40 ng / mL of C max , AUC of at least 2500 h·ng / mL inf , At least 3.25 hours max , or at least 130h t1 / 2 λz A compound for use that yields one or more of the following.

[0235] Embodiment 102. A compound for use in raising the resting motor threshold (RMT) or active motor threshold (AMT) in a person in need, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is administered orally to the person.

[0236] Embodiment 103. The compound for use according to Embodiment 102, wherein the increase in RMT or AMT is proportional to the plasma concentration of the compound.

[0237] Embodiment 104. A compound for use in reducing corticospinal excitability or cortical excitability in a person requiring it, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is administered orally to the person.

[0238] Embodiment 105. The compound for use according to any one of Embodiments 64 to 89, wherein 2 to 200 mg of the above compound is administered.

[0239] Embodiment 106. The compound for use according to Embodiment 105, wherein 2 to 100 mg of the above compound is administered.

[0240] Embodiment 107. The compound for use according to Embodiment 105, wherein 5 to 50 mg of the above compound is administered.

[0241] Embodiment 108. The compound for use according to Embodiment 105, wherein 10 mg, 20 mg, or 25 mg of the compound is administered.

[0242] Embodiment 109. The compound for use according to Embodiment 105, wherein 20 mg of the above compound is administered.

[0243] Embodiment 110. The compound for use according to any one of Embodiments 64 to 107, wherein at least 20 mg of the compound is administered.

[0244] Embodiment 111. The compound for use according to any one of Embodiments 64 to 110, wherein 5 to 500 mg of the compound is administered per day.

[0245] Embodiment 112. The compound for use according to Embodiment 111, administered at a dose of 20 to 150 mg per day.

[0246] Embodiment 113. The compound for use according to Embodiment 111, wherein 100 mg of the compound is administered per day.

[0247] Embodiment 114. The compound for use according to any one of Embodiments 64 to 113, wherein the compound is administered at a dose of 0.05 to 2.0 mg / kg.

[0248] Embodiment 115. The compound for use as described in Embodiment 114, administered at a dose of 0.1 to 1.0 mg / kg.

[0249] Embodiment 116. The compound for use according to Embodiment 114, administered at a dose of 0.2 to 0.5 mg / kg.

[0250] Additional numbered embodiments Embodiment 1a. A method for treating a paroxysmal disorder in a human, comprising the step of orally administering a therapeutically effective amount of compound A to the human in need, in a postprandial state.

[0251] Embodiment 2a. The method according to Embodiment 1a, wherein oral administration of a therapeutically effective amount of compound A to a human subject results in increased bioavailability and exposure of compound A compared to the bioavailability and exposure of compound A when administered orally under fasting conditions.

[0252] Embodiment 3a. Oral administration of a therapeutically effective amount of compound A results in the maximum plasma concentration of compound A (C) when administered orally in a fasted state. max ) and the C of compound A compared to the exposure (AUC) of compound A max The method according to embodiment 2a, which results in an increase in and an increase in the AUC of compound A.

[0253] Embodiment 4a. C after oral administration of a therapeutically effective amount of compound A in a fasted state. max C after oral administration of a therapeutically effective amount of compound A for postprandial conditions max The method according to embodiment 3a, wherein the ratio is greater than 1.3.

[0254] Embodiment 5a. The method according to Embodiment 3a, wherein the ratio of the AUC after oral administration of a therapeutically effective amount of compound A in a fasted state to the AUC after oral administration of a therapeutically effective amount of compound A in a postprandial state is greater than 1.3.

[0255] Embodiment 6a. The method according to any one of Embodiments 1a to 5a, wherein the therapeutically effective dose of compound A is approximately 0.05 mg / kg to approximately 2.0 mg / kg.

[0256] Embodiment 7a. A method for increasing the bioavailability and exposure of compound A in a person receiving an orally administered therapeutically effective amount of compound A for the treatment of a paroxysmal disorder, comprising the step of orally administering the therapeutically effective amount of compound A to the person in a postprandial state.

[0257] Embodiment 8a. Oral administration of a therapeutically effective amount of compound A results in the maximum plasma concentration of compound A (C) when administered orally in a fasted state. max ) and the C of compound A compared to the exposure (AUC) of compound A max The method according to embodiment 7a, which results in an increase in and an increase in the AUC of compound A.

[0258] Embodiment 9a. C after oral administration of a therapeutically effective amount of compound A in a fasted state. max C after oral administration of a therapeutically effective amount of compound A for postprandial conditions max The method according to embodiment 8a, wherein the ratio is greater than 1.3.

[0259] Embodiment 10a. The method according to Embodiment 8a, wherein the ratio of the AUC after oral administration of a therapeutically effective amount of compound A in a fasted state to the AUC after oral administration of a therapeutically effective amount of compound A in a postprandial state is greater than 1.3.

[0260] Embodiment 11a. The method according to any one of Embodiments 7a to 10a, wherein the therapeutically effective dose of compound A is approximately 0.05 mg / kg to approximately 2.0 mg / kg. [Examples]

[0261] If compound A has a food effect on bioavailability and exposure when administered orally, the following studies were conducted to determine that food effect. If compound A has an effect on cortical excitability, further studies were conducted to evaluate that effect using transcranial magnetic stimulation (TMS).

[0262] 1. Example 1. Non-human primate research The following study was conducted to determine the effects of food on compound A when administered orally to non-human primates.

[0263] 1.1. Research animals This study used three cynomolgus macaques (n=3) native to Vietnam. At the time of the initial dose administration, these monkeys weighed 4.7–5.1 kg and were approximately 4.5 years old.

[0264] During this study, the monkeys were given a certified primate diet (Teklad® Certified Diet 2050C). For Group 1, three monkeys were fasted overnight, and food was returned 4 hours after administration. For Group 2, the same three monkeys were fasted overnight, and food was given approximately 1 hour before administration, and food was returned 4 hours after administration. Table 1 below shows the food intake for Group 2.

[0265] [Table 1]

[0266] 1.2. Oral medication units Each oral dose consisted of approximately 3 mg / kg of compound A in a capsule. The capsule was filled on the morning of the dose and kept at room temperature until administration. The remaining capsules were stored in a -20°C storage chamber.

[0267] 1.3. Administration of oral medication units The capsules were placed as far back as possible in the animal's mouth using a pill gun or a modified gastric feeding tube. Approximately 10 mL of water was administered via syringe to ensure complete delivery of the intended dose. Each animal received one capsule per dose. The same animal received two doses with a 96-hour rest period between doses. See Table 2 below for details.

[0268] Group 1: All animals were weighed in the afternoon before dose administration. Animal number 2 was difficult to administer the medication to. After several attempts, the animal was given a short break and finally the medication was successfully administered.

[0269] Group 2: All animals were weighed on the morning of dose administration. All animals received the medication without any problems.

[0270] [Table 2]

[0271] 1.4. Blood collection Whole blood (approximately 2.0 mL) was collected from the cephalic vein or saphenous vein using a syringe and needle, transferred to a Vacutainer tube containing K2EDTA, and kept on moist ice until processing of the plasma. Blood samples were collected at the time of administration (0.0 hour, time zero) and at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours after administration.

[0272] 1.5. Blood Sample Processing Whole blood samples were placed in K2EDTA tubes and centrifuged at approximately 5°C at 3200 RPM for 10 minutes. The plasma samples were divided into two aliquots, and each aliquot was transferred directly into a separate, appropriately labeled tube containing the study number, collection time point, animal identification number, and sample description. One aliquot was stored in a -20±5°C storage chamber until transport for analysis. The other aliquot was maintained at -20±5°C. Red blood cells were disposed of.

[0273] All samples were processed according to standard procedures for biochemical analysis.

[0274] 1.6.Results

[0275] [Table 3]

[0276] [Table 4]

[0277] [Table 5]

[0278] [Table 6]

[0279] 1.7. Discussion In this study, when compound A was orally administered to non-human primates, the C of compound A max No significant food effect was observed for either AUC. Figure 1 shows the data from Table 5 in graph format.

[0280] 2. Example 2. Human Studies To evaluate the bioavailability of compound A and the effects of food on exposure, an open-label, randomized, two-period, feeding / fasting crossover study was conducted using nine healthy, non-smoking adult males and females (only those not of childbearing potential) aged 18 to 55 years.

[0281] This study consisted of two treatment periods, Period 1 and Period 2. Each treatment period lasted 7 days, with compound A administered on day 1. These two treatment periods were separated by a 10-day drug-free period. Participants were randomized into two groups. During Treatment Period 1, one group received an oral dose of compound A while fasting, while the other group received an oral dose of compound A while eating. The group that fasted during Treatment Period 1 received a meal during Treatment Period 2, and the group that received a meal during Treatment Period 1 fasted during Treatment Period 2.

[0282] On the first day of each treatment period, each subject received 20 mg of compound A (four capsules of compound A, each containing 5 mg) orally.

[0283] During the feeding period following at least 10 hours of overnight fasting, participants were given a standard high-fat, high-calorie breakfast according to FDA guidelines. This breakfast was given 30 minutes before the scheduled administration time and completed 10 minutes before the medication was administered. A typical breakfast included two slices of buttered toast, two scrambled eggs, two slices of bacon, 4 ounces (approximately 113g) of hash browns, and 8 ounces (approximately 227g) of whole milk. Participants refrained from eating or drinking for at least 4 hours after the medication was administered.

[0284] During the fasting period, the medication was administered after at least 10 hours of fasting overnight. Food was not permitted for 4 hours after administration, whether during the feeding period or the fasting period. Water was permitted as desired, except for 1 hour before and after administration.

[0285] For all subjects, blood samples for measuring the plasma concentration of compound A were collected at the time of administration (0.0 hours (time zero)) and at 0.5 hours, 1.0 hours, 1.5 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 12.0 hours, 24.0 hours, 32.0 hours, 48.0 hours, and 144.0 hours after administration.

[0286] 2.1.Results Table 7 below shows the plasma concentrations (ng / mL) of compound A in subjects who received an oral dose of compound A after a meal.

[0287] Table 8 below shows the plasma concentrations (ng / mL) of compound A in subjects who received an oral dose of compound A while fasting.

[0288] Figure 2 shows the mean plasma concentration (ng / mL) of compound A in subjects who received an oral dose of compound A after a meal versus the mean plasma concentration (ng / mL) of compound A in subjects who received an oral dose of compound A in a fasted state.

[0289] The pharmacokinetic parameters of subjects who received 20 mg of compound A orally after a meal are shown in Table 9 below.

[0290] Table 10 below shows the pharmacokinetic parameters of subjects who received 20 mg of compound A orally while fasting.

[0291] [Table 7]

[0292] [Table 8]

[0293] [Table 9]

[0294] [Table 10]

[0295] As the pharmacokinetic results of this study clearly show, the bioavailability and exposure of compound A were significantly higher when administered orally after a meal compared to when administered orally in a fasted state. These results were unexpected considering the results of the study in non-human primates shown in Example 1 above, in which no food effect was observed.

[0296] 3. Example 3. Study of human SAD and MAD A first-in-human study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral compound A in single-dose escalation studies and repeated-dose escalation studies (SAD and MAD).

[0297] 3.1. Method In the SAD phase, 32 healthy volunteers were randomized (3:1) to either compound A (5 mg, 15 mg, 20 mg, 25 mg, or 30 mg) or placebo. This study featured an adaptive design. A crossover food effects cohort (N=10) also completed a single 20 mg dose. A subset of eight male subjects also had their effects on cortical excitability evaluated using transcranial magnetic stimulation (TMS) (see Examples 4 and 5).

[0298] The repeated dose of compound A (15 mg once daily) was evaluated over 7 and 10 days in both fasting and postprandial conditions. The repeated dose of compound A (25 mg once daily) was also evaluated over 10 days in a postprandial condition.

[0299] Compound A was formulated as an immediate-release capsule. A series of plasma PK samples were collected from all cohorts. Safety assessments throughout the study included adverse event (AE) monitoring, laboratory tests, vital signs, ECG, physical examination, and the Columbia-Suicide Severity Rating Scale.

[0300] 3.2. Pharmacokinetics Compound A exhibited a low peak-to-peak ratio and a PK profile suitable for once-daily administration. Compound A had less than dose-proportional exposure in a fasted state, but absorption was enhanced by food (AUC). inf (Approximately 1.8 times). When multiple doses were used in a postprandial state, exposure increased proportionally to the dose. Based on the 90% CI for consecutive day exposure ratios in the range of 0.8 to 1.25, an apparent steady state was achieved between day 6 and day 9.

[0301] [Table 11]

[0302] [Table 12]

[0303] 3.3. Safety The single and multi-dose doses of compound A are up to 104 ng / mL and 107 ng / mL, respectively, for individual C max The drug was well tolerable at this level. Most adverse events (AEs) were mild or moderate, resolved spontaneously, and were consistent with this class of antiepileptic drugs (e.g., dizziness, sedation). There were no serious adverse events (SAEs), deaths, or clinically significant ECG or laboratory findings.

[0304] These results suggest that compound A is safe and well-tolerated up to the doses investigated (single doses up to 30 mg and multiple doses of 25 mg once daily (QD)).

[0305] The above PK profile (including an effective half-life of over 24 hours) supports a once-daily dosing schedule using the immediate-release formulation, achieving a steady state within one week without the need for dose setting.

[0306] 4. Example 4. Pilot study of transcranial magnetic stimulation Transcranial magnetic stimulation (TMS), in combination with electromyography (EMG) and electroencephalography (EEG), enables the measurement of resting and active motor thresholds (RMT / AMT) and TMS-induced EEG potentials (TEP). These, along with TMS-induced EEG potentials (TEP), can indicate pharmacological effects on corticospinal excitability and cortical excitability, respectively. Several antiepileptic drugs (AEDs) have been shown to significantly increase RMT values ​​and modulate TEP, indicating a shift towards corticospinal / cortical inhibition.

[0307] In the pilot study, transcranial magnetic stimulation (TMS) was used to non-invasively determine whether compound A (10 mg, 15 mg, and 20 mg) affected cortical excitability. This TMS pilot study was designed to provide information for sample size calculation for a larger randomized, double-blind, placebo-controlled TMS crossover study (N=20) using compound A.

[0308] 4.1 Method Eight healthy, right-handed male subjects (21–35 years old, 62.4–95.4 kg) from a first-in-human phase 1 study were enrolled in this open-label TMS pilot study. RMT, TEP, and EEG were recorded before compound A administration and at 2 and 4 hours after administration. Spectral analysis was performed on resting EEG. To determine the effect of compound A on TEP amplitude, single-subject analysis was performed using multiple independent sample t-tests. Multiple comparisons were considered using cluster-based permutation analysis.

[0309] 4.2.Results Compound A suppressed TEP amplitude at a slow latency (e.g., 1.92 ± 0.03 μV at a peak (P180) at 180 ms post-TMS, p<0.01, N=3) 4 hours after 20 mg (Cplasma = 50 ± 10 ng / mL). Doses of 10 mg (N=2) and 15 mg (N=3) did not show significant and robust TEP regulation, with mean plasma levels of compound A at 4 hours being 23.1 ng / mL and 36.3 ng / mL, respectively. At 4 hours after 20 mg, RMT increased by 4.3 ± 0.6% from baseline (Poster 3.282), and theta power increased in rEEG. The 20 mg dose of compound A was selected for use in a placebo-controlled, double-blind TMS crossover study.

[0310] Figure 3 shows that compound A increased the motor threshold (excluding SICI) as assessed using TMS / EMG. Black bars represent the effect 2 hours after drug administration, and gray bars represent the effect 4 hours after drug administration (change from baseline as % maximum stimulus intensity, mean ± SEM). N=2 for 10 mg, and N=3 for 15 mg and 20 mg. Compound A 10 mg did not change AMT. N=2 for 10 mg, and N=3 for 15 mg and 20 mg.

[0311] 5. Example 5. Transcranial Magnetic Stimulation Crossover Study The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose of compound A were investigated in a randomized, double-blind, placebo-controlled transcranial magnetic stimulation (TMS) crossover study in healthy, right-handed male subjects.

[0312] The objectives of this study were: 1) to evaluate the safety, tolerability, and pharmacokinetics of a single dose of compound A in healthy male subjects; and 2) to characterize the effect of compound A on cortical excitability measurements assessed by TMS-EEG and TMS-EMG compared to placebo.

[0313] Twenty healthy, right-handed male subjects were enrolled and randomly assigned on day 1 to receive either a single oral dose of compound A 20 mg or a placebo in a blinded manner (randomization rate 1:1). They then crossed over and received a single dose of the other treatment on day 7.

[0314] On day 1, participants underwent screening within 27 days prior to participating in the study. For Period 1, participants were admitted to the research unit, received medication on day 1, and were discharged on day 2. For Period 2, after a 6-day drug-free period, the same participants were admitted to the research unit again, received medication on day 7, and were discharged on day 8. All participants returned to the clinical unit for an outpatient consultation on day 14 and received a follow-up call on day 37.

[0315] The subjects were administered the medication after meals, but the timing of medication administration relative to meals was changed during the study, ranging from a high-fat or standard meal eaten 2 hours or 30 minutes before administration, to a high-fat or standard meal eaten 1 hour or 2.5 hours after administration.

[0316] Safety assessments included adverse events (AEs), laboratory evaluations, vital signs, 12-lead electrocardiogram (ECG), physical examination, and the Columbia Suicide Severity Rating Scale (C-SSRS).

[0317] The PK variable includes the maximum plasma concentration (C max ), maximum plasma concentration time (T max ), terminal disappearance half-life (t1 / 2 ), vanishing rate constant (λz), area under the curve (AUC) from 0 to 24 hours. 0-24h ), Area under the time curve (AUC) from 0 to the final quantifiable concentration 0-tlast ), Area under the time curve from 0 to infinity (AUC 0-inf ), the percentage of AUC obtained by extrapolation from tlast to infinity (%AUC) extrap ), apparent systemic clearance (CL / F) after oral administration, CL / F normalized by body weight, mean residence time (MRT) from time zero to final quantifiable concentration. last ), average dwell time (MRT) extrapolated to infinity inf This included the apparent volume of distribution (Vz / F) in the terminal phase and Vz / F normalized by body weight.

[0318] PD assessment included resting-state electroencephalography (RS-EEG); TMS-EMG measurements including resting-state motor threshold (RMT), activity-state motor threshold (AMT), and short-interval intracortical inhibition (SICI); and TMS-EEG measurements.

[0319] 5.1. Pharmacokinetic Analysis The PK parameters for this study were summarized in two ways. First, PK parameters were calculated using PK samples collected separately during each 24-hour sampling period in Period 1 and Period 2, where possible. Second, PK parameters were determined using samples from beyond the 24-hour sampling period (i.e., from day 7 / 8 and / or day 14). For subjects administered compound A in Period 1, additional PK time points beyond 24 hours were obtained from PK samples collected before the placebo treatment. For subjects administered compound A in Period 2, there were no PK time points beyond 24 hours until the addition of the PK sample from day 14. Therefore, subjects randomly assigned to administer compound A in Period 2 and registered before the administration of the additional PK sample on day 14 did not have PK data beyond 24 hours. The complete PK profile dataset consists of 16 subjects from whom PK samples were collected beyond 24 hours after administration. The complete PK profile dataset was generally used for the following discussion of PK parameters. This is because the complete PK profile dataset allowed for a more accurate estimation of the PK parameters.

[0320] Initially, subjects were administered the drug two hours after a high-fat meal, followed one hour later by a relatively high-fat lunch. After examining the PK profiles of the first eight subjects in a blinded manner, T max To shorten the time until, reduce the fat content of lunch, C max This was done to ensure that it fell within the time frame for TMS measurement. In addition, the timing of meals relative to administration was changed from 2 hours to 30 minutes before administration, followed by a reduction in the fat content of breakfast. All these changes were made to provide higher plasma levels during the TMS evaluation period. The timing and type of meals for each subject are specified in Table 13. Overall, despite the changes in meal composition and timing relative to administration, C max or T max No clear differences were observed. Therefore, PK data is presented without classification by dietary content or relative timing of meals.

[0321] [Table 13]

[0322] 5.1.1. Plasma concentration The plasma concentrations of compound A over time were recorded for the complete PK profile. At TMS time points of 2, 4, and 6 hours, the mean ± SD plasma concentrations were 15.9 ± 21.4 ng / mL, 30.2 ± 21.1 ng / mL, and 42.1 ± 19.1 ng / mL, respectively.

[0323] The average C over each period max or T max No significant difference was observed (Table 14). The total time to peak plasma concentration ranged from 1.9 to 12 hours, with a median time of 7.8 hours. This indicates that TMS assessments performed at 2, 4, and 6 hours showed that the majority of subjects had a T max This indicated that it had taken place before.

[0324] Subjects who received a placebo in period 2 had a low but measurable concentration of compound A at the start of the placebo treatment period, and C max The average value was 5.84 ng / mL (range 3.34~9.61 ng / mL).

[0325] [Table 14]

[0326] 5.1.2. Other pharmacokinetic parameters for the complete PK profile Table 15 provides an overview of other PK parameters. (Average AUC) last The value was 2370 ng·h / mL, which included PK samples collected at follow-up visits, where available. AUC from the same dataset. inf The value was 3155 ng·h / mL, and the median (range) extrapolation area was 19.9% ​​(range 10.6-40.5%). This relatively high level of extrapolation area in several subjects was due to the parameters (half-life, MRT) calculated from λz. infThe clearance and volume of distribution should be analyzed carefully, suggesting that it may be possible to have a higher intrinsic variance in their calculation.

[0327] The mean normalized distribution volume (Vz / F) of 16.3 L / kg was well above the total blood volume of an average body weight of 72.3 kg, indicating that the drug was distributed from the plasma to the surrounding tissues.

[0328] The weight-normalized clearance (CL / F) was 97.5 mL / h / kg (equivalent to approximately 1.6 mL / min / kg). This value represents plasma clearance, not blood clearance. However, even after adjusting for hematocrit, this is far below the total hepatic blood flow of 17 mL / min / kg (Carlisle et al., Gut 1992, 33:92-97), suggesting that it is a drug with a low extraction rate.

[0329] [Table 15]

[0330] 5.1.3. Conclusions regarding pharmacokinetics Compound A was slowly absorbed after an oral dose of 20 mg, with the median peak plasma concentration occurring approximately 8 hours after administration. Upon absorption, Compound A distributed from the plasma to surrounding tissues and was slowly removed from the systemic circulation at a rate considerably lower than hepatic blood flow, indicating very little hepatic extraction (metabolism). Compound A exhibited a mean half-life of 127 hours (range 48.2–306 hours) and a mean residence time of 102 hours (range 33–304 hours). This may be an underestimation, as some subjects reported high %AUC levels exceeding 20% ​​and reaching as high as 40%. extrap Because it had a value.

[0331] The drug-free period between the two periods was not sufficient for compound A concentrations to decrease below the limit of quantification in subjects who received placebo during period 2 (mean 3.1 ng / mL, range 1.3–6.8 ng / mL).

[0332] 5.2. Pharmacodynamic analysis All 20 subjects received TMS-EMG and TMS-EEG sessions before medication on days 1 and 7, and 2 and 4 hours after medication. An additional measurement was added 6 hours after drug ingestion for the long-term absorption phase of compound A, as revealed by pharmacokinetic analysis. At this 6-hour time point, RMT was performed on 16 subjects, and AMT, resting EEG, and TMS-EEG were performed on 8 subjects.

[0333] Subject 912 did not undergo any PD assessments at the 2-hour mark of the compound A treatment period due to an adverse event (vomiting). Due to technical problems, the TMS procedure for subject 940 could not be completed at 2 hours of the placebo treatment period; therefore, this subject only underwent RMT and resting EEG procedures at 2 hours.

[0334] Compound A-induced modulation of the PD marker was evaluated as an effect of time (comparison between baseline and post-administration values ​​at 2, 4, and 6 hours post-administration) and concentration (using post-administration measurements taken at peak drug exposure and baseline values).

[0335] Analysis was performed on all subjects (n=20) and on subjects (n=16) who showed higher drug plasma concentrations than the highest concentration detected as a carryover effect in the placebo group (Table 16).

[0336] [Table 16]

[0337] 5.2.1.TMS-induced EGG potential TMS-induced EEG potential (TEP) was calculated by averaging artifact-free EEG test results under different experimental conditions (Table 17).

[0338] [Table 17]

[0339] The following TEP components (P=positive, N=negative) were studied according to the literature. The values ​​in parentheses are time of interest (TOI): P25 (15–35 ms), N45 (35–70 ms), P70 (70–80 ms), N100 (80–145 ms), and P180 (145–230 ms). TOI was selected based on ground-averaged (all-response sum-average) TEP and was kept identical throughout the analysis of pre- and post-administration measurements, as well as across conditions. To analyze drug-induced modulation of TEP, the inventors selected a region of interest (ROI) consisting of 27 channels above and around the stimulation site (left M1) and the corresponding contralateral site ("FC1", "FC3", "FC5", "C1", "C3", "C5", "CP1", "CP3", "CP5", "P1", "P3", "P5", "Cz", "CPz", "Pz", "FC2", "FC4", "FC6", "C2", "C4", "C6", "CP2", "CP4", "CP6", "P2", "P4", "P6").

[0340] To analyze the significance of TEP amplitude modulation induced by compound A, multiple paired t-test comparisons (post-administration vs. pre-administration) were applied to each TOI at all electrodes within the indicated ROI. To correct for multiple comparisons (i.e., electrode, time point), the inventors performed a non-parametric cluster-based sorting analysis, as performed in FieldTrip.

[0341] The spatiotemporal profiles of TMS-induced EEG potentials are consistent with previous reports in the literature (Figure 4-A). The initial components (N15, P25) are primarily located in the stimulated left M1, followed by a marked negative on the contralateral region corresponding to the N45 potential. Finally, the N100 and P180 components confirm their optimal topographic reproducibility across the left central and central frontal regions, respectively (Figure 4-B). Comparisons between pre-administration conditions (placebo vs. compound A) did not show significant differences (p>0.05). These results apply to datasets of n=20 and n=16. Figure 4 shows that compound A resulted in significant regulation of the initial TEPs (N45 and P180).

[0342] Concentration analysis (N=16): Cluster-based sorting analysis was applied between post-administration and pre-administration conditions to test the effect of compound A at the highest plasma concentration available during the TMS evaluation time point. While the time-matched placebo showed no significant changes, compound A reduced the amplitude of the initial TEP components measured at 15–35 ms (initial composite wave N15-P25 peak vs. peak amplitude: 4.5 vs. 6.0 μV, p<0.05), 45 ms (N45: -2.3 vs. -3.0 μV, p<0.01), and 180 ms (P180: 2.2 vs. 3.0 μV, p<0.01) after the TMS pulse (Figures 4-D, 5). Figure 6 shows that compound A significantly modulates TEP and reduces cortical excitability.

[0343] Time-based analysis (subjects with drug exposure at the time of measurement): Cluster-based sorting analysis was applied between the post-administration and pre-administration conditions to test the effect of compound A at 2 hours (n=15), 4 hours (n=16), and 6 hours (n=7) post-administration in subjects with sufficient exposure to compound A during the first 6 hours. Compared to pre-administration, the initial N15-P25 composite wave decreased at 2 hours (p=0.008) and 4 hours (p=0.02). Furthermore, at 4 hours post-administration, compound A significantly suppressed N45 (p=0.03), N100 (p=0.04), and P180 (p=0.004) (Figure 7).

[0344] Other comparisons were not statistically significant (p>0.05), and the placebo did not induce a significant change (p>0.05).

[0345] Time-based analysis (all available subjects): Cluster-based sorting analysis was applied between the post-administration and pre-administration conditions to test the effect of compound A at 2 hours (n=19), 4 hours (n=20), and 6 hours (n=8) post-administration in all available subjects. Compared to pre-administration, the initial N15-P25 composite wave decreased at 2 hours (p=0.006) and 4 hours (p=0.01). Furthermore, at 4 hours post-administration, compound A significantly suppressed N45 (p=0.03) and P180 (p=0.02). This indicates that compound A modulates TEP and reduces cortical excitability.

[0346] Other comparisons were not statistically significant (p>0.05), and the placebo did not induce a significant change (p>0.05).

[0347] 5.2.2.TMS induced vibration Single-pulse TMS applied to the left motor cortex induced a series of changes in the power of ongoing oscillatory activity. At baseline, prior to drug administration, TMS induced an early increase in theta / alpha power, followed by a decrease in beta power (desynchronicity), and a final, slower response of increased beta power.

[0348] Next, the effect of the active compound on TMS-induced oscillations was analyzed by cluster-based sorting analysis, following the same procedure used in the TEP analysis. Theta (4–7 Hz), alpha (8–12 Hz), and beta (13–30 Hz) TMS-induced oscillations were compared between drug conditions from 30 ms (the first time-frequency point considered artifact-free) to 800 ms. This method was preferred over a predetermined set of time windows, given the lack of consensus on the time windows of interest to be used in TMS-induced oscillation analysis. Furthermore, this cluster-based statistical approach is suitable for exploratory analysis because it minimizes false positives involved in testing at multiple time points.

[0349] Concentration analysis (N=16): Cluster-based sorting analysis was applied between the post-administration and pre-administration conditions to test the effect of compound A at the highest plasma concentration present during TMS evaluation. Compound A suppressed initial theta TMS-induced oscillations (p<0.001; significant effect from 30 ms to 390 ms) and alpha TMS-induced oscillations (p=0.02; significant effect from 220 ms to 400 ms), and increased beta TMS-induced power (p=0.04; significant effect from 220 ms to 310 ms).

[0350] Other comparisons were not statistically significant (p>0.05), and the placebo did not induce a significant change (p>0.05).

[0351] Time analysis (subjects with drug exposure at the time of measurement): Cluster-based sorting analysis was applied between the post-administration and pre-administration conditions to test the effect of compound A at 2 hours (n=15), 4 hours (n=16), and 6 hours (n=7) post-administration. Compared to pre-administration, compound A did not modulate registered oscillations at 2 hours post-administration, but at 4 hours, compound A suppressed initial theta-TMS-induced oscillations (p=0.03; significant effect from 30ms to 180ms) and alpha-TMS-induced oscillations (p=0.03; significant effect from 250ms to 390ms), and increased beta-TMS-induced desync (p=0.04; significant effect from 250ms to 330ms). Finally, at 6 hours post-administration, the results showed a significant decrease in theta-induced oscillations (p<0.001; significant effect from 30ms to 280ms).

[0352] Other comparisons were not statistically significant (p>0.05), and the placebo did not induce a significant change (p>0.05).

[0353] Time analysis (all available subjects): Cluster-based sorting analysis was applied between the post-administration and pre-administration conditions to test the effect of compound A at 2 hours (n=19), 4 hours (n=20), and 6 hours (n=8) post-administration. Compared to pre-administration, compound A showed a tendency to suppress theta TMS-induced oscillations at 2 hours post-administration. At 4 hours, compound A suppressed alpha TMS-induced oscillations (p=0.03; significant effect from 250ms to 400ms). Finally, at 6 hours post-administration, the results showed a significant decrease in theta-induced oscillations (p=0.03; significant effect from 80ms to 300ms) and a tendency to suppress the alpha band (tendency p=0.07; 270ms~390ms).

[0354] Other comparisons were not statistically significant (p>0.05), and the placebo did not induce a significant change (p>0.05).

[0355] 5.2.3. Resting EEG at rest Sensor-level delta (2–4 Hz), theta (4–7 Hz), alpha (8–12 Hz), and beta (13–30 Hz) frequency activity was estimated using a fast Fourier transform (FFT) approach. Power across all frequencies between 2–30 Hz was estimated using a frequency resolution of 0.5 Hz. Differences between drug conditions on all EEG sensors were tested using a nonparametric paired t-test based on a sorting approach (1500 sorts).

[0356] Concentration analysis (N=16): During high plasma exposure to compound A, resting oscillatory activity was significantly regulated, showing increased power in delta (p<0.001), theta (p=0.01), and beta (p=0.005). Placebo induced an increase in theta power (p=0.001), while all other comparisons did not show significant results.

[0357] The difference between the post-administration and pre-administration states within each drug condition was calculated, and then the calculated difference (post-administration minus pre-administration value) between compound A and placebo was statistically compared. Compared to placebo, compound A induced an overall increase in power for delta (p<0.001), theta (p=0.02), and beta (p=0.003) (Figure 8).

[0358] Time analysis (subjects with drug exposure at the time of measurement): Cluster-based sorting analysis was applied between the post-administration and pre-administration conditions to test the effect of compound A at 2 hours (n=15), 4 hours (n=16), and 6 hours (n=7) after administration.

[0359] Compared to the pre-administration state, compound A significantly increased the power of low-frequency oscillations (2 hours after administration vs. pre-administration: delta, p=0.001; theta, p=0.01; 4 hours after administration vs. pre-administration: delta, p<0.001; theta, p=0.01) and beta-band power (2 hours after administration vs. pre-administration: p=0.01; 4 hours after administration vs. pre-administration: p<0.001) (Figure 9).

[0360] The placebo group produced an increase in the theta band 4 hours after drug administration (p=0.003), but all other comparisons were not statistically significant (p>0.05).

[0361] Time analysis (all available subjects): Cluster-based sorting analysis was applied between the post-drug and pre-drug conditions to test the effect of compound A at 2 hours (n=19), 4 hours (n=20), and 6 hours (n=8) post-drug.

[0362] Compared to the pre-administration state, compound A significantly increased the power of low-frequency oscillations (2 hours after administration vs. pre-administration: delta, p<0.001; theta, p=0.006; 4 hours after administration vs. pre-administration: delta, p<0.001; theta, two clusters p=0.008 and p=0.03), as well as the power of the beta band (2 hours after administration vs. pre-administration: p=0.005; 4 hours after administration vs. pre-administration: p<0.001; 6 hours after administration vs. pre-administration: p=0.009).

[0363] Placebo caused increases in power in the delta band (2 hours after administration vs. before administration: two clusters p=0.02 and p=0.04; 4 hours after administration vs. before administration: two clusters p=0.004 and p=0.01; 6 hours after administration vs. before administration: p=0.05), theta band (4 hours after administration vs. before administration: p<0.001; 6 hours after administration vs. before administration: p=0.009), alpha band (6 hours after administration vs. before administration: p=0.04), and beta band (6 hours after administration vs. before administration: p=0.04), but all other comparisons were not statistically significant (p>0.05).

[0364] 5.2.4. TMS-EMG RMT and AMT values ​​are reported as percentages of maximum stimulation intensity (%MSO). Drug-induced modulation of TMS-EMG parameters was evaluated over three time points (2 hours, 4 hours, and 6 hours), as well as at the time point with the highest drug exposure.

[0365] 5.2.4.1. Resting Exercise Threshold Table 18 presents the baseline individual RMT values, mean RMT values, and changes at each time point for all 20 subjects for compound A and placebo. Four subjects (901, 925, 928, and 930) did not experience high drug exposure during TMS measurement. In addition, RMT could not be registered for subject 912 two hours after compound A ingestion.

[0366] [Table 18]

[0367] In all groups, there was no significant difference compared to baseline. Treatment with compound A resulted in a significant increase in RMT, indicating a decrease in corticospinal excitability (Figures 10 and 11). There was a strong relationship between the PD effect and the mean plasma concentration of compound A, with the effect on RMT being >4% 6 hours after administration. Figure 8 shows that RMT increased proportionally to the plasma concentration of compound A, with a mean ± SEM increase of 4.9 ± 0.7% at 6 hours. This significant increase in RMT indicates a decrease in corticospinal excitability and therefore represents a strong PK-PD relationship.

[0368] 5.2.4.2. Activity-related motor thresholds AMT was recorded while subjects compressed a manometer at 20% of their maximum contractile force. Table 19 shows the individual and mean AMT values ​​at each time point for compound A and placebo. For subjects 912 and 940, AMT could not be recorded 2 hours after ingestion of compound A and placebo, respectively.

[0369] In all groups, there was no significant difference from baseline values. AMT increased after treatment with compound A. The change from baseline in AMT for compound A was significantly different from placebo 6 hours after administration (p<0.01).

[0370] [Table 19]

[0371] 5.2.4.3. Short-interval intracortical inhibition Short-interval intracortical inhibition (SICI) was measured using 15 conditioned test stimulus pairs given in a random order with a 2 ms inter-stimulus interval (ISI). These conditioned stimuli were set to 80% of the AMT and 120% of the RMT for above-threshold stimuli.

[0372] SICI was calculated using a custom script to measure the amplitudes of conditioned and unconditioned motor evoked potentials (MEPs) and express SICI as the ratio of the average conditioned MEP to the average unconditioned MEP.

[0373] SICI values ​​(mean conditioned MEP / mean unconditioned MEP) are reported for each individual, experimental session, and compound A dose (Table 20). Mean and standard deviation are also reported for each condition. No significant findings were observed.

[0374] [Table 20]

[0375] 5.2.5. Conclusions on Pharmacodynamics Pharmacodynamic evaluations were performed to determine the acute effects of compound A, a potassium channel opener, on corticospinal excitability and cortical excitability, as measured by TMS-EMG and TMS-EEG, respectively.

[0376] 5.3. TMS-EMG Measurement Since several antiepileptic drugs (AEDs) that act on sodium channels (i.e., lamotrigine, carbamazepine; Ziemann et al., J.Int.Fed.Clin.Neurophys.2015, 126:1847-1868) and several antiepileptic drugs that act on potassium channels (i.e., retigabine; Ossemann et al., Epilepsy Res.2016, 126:78-82) increased the motor threshold (at rest and during muscle contraction), the motor threshold (at rest and during muscle contraction) is associated with ion channel conductivity, and therefore with nerve membrane excitability.

[0377] In addition, intracortical inhibition can be tested by SICI, a well-established TMS versus pulse paradigm. SICI can assess the synaptic excitability of interneurons in the stimulated motor cortex, which is associated with GABA-A receptor-mediated neurotransmission.

[0378] The results showed that compound A significantly affected the motor threshold, which manifested as a decrease in corticospinal excitability. RMT was modulated in a time-dependent and plasma concentration-dependent manner, particularly compared to placebo. At 2, 4, and 6 hours post-administration, a single 20 mg dose of compound A elevated RMT from baseline compared to time-matched placebo. Furthermore, the increase in RMT at each time point correlated with increased systemic exposure to compound A.

[0379] AMT was regulated to a lower degree, with a significant difference from placebo only observed 6 hours after administration. The nature of the discrepancy between RMT and AMT results is unknown, however, it is consistent with other AEDs (Ziemann et al., Ann. Neuro. 1996, 40:367-378). During voluntary muscle activation, the decrease in motor threshold is thought to occur via increased excitability of corticospinal output or spinal motor neurons, or both. Subthreshold activation of the former element is also likely a target of TMS, which explains why drugs acting on membrane ion channels do not elevate AMT as much as RMT. During voluntary muscle activation, many physiological and anatomical elements play a role in addition to those directly activated by TMS, which would explain why drug-induced regulation of AMT is more limited than RMT. Finally, the lack of effect on SICI indicates that compound A does not alter intracortical inhibition via GABA-A receptors. These results are consistent with the TMS-EMG reports for retigabine (Ossemann et al., 2016) and sodium channel blockers (Ziemann et al., 1996).

[0380] 5.4. TMS-EEG Measurement Compound A significantly regulated TMS-EEG output and resting EEG output, exhibiting a unique fingerprint at the highest drug plasma concentration. Furthermore, following this drug-induced regulation, the strongest drug plasma exposure was observed 4 hours after drug ingestion (Table 21).

[0381] [Table 21]

[0382] Additional measurements of cortical excitability, including global mean field power, were similarly affected. Global mean field power (GMFP) represents the total amount of electrical activity induced by TMS. Figure 12 shows that compound A causes a decrease in cortical excitability over time with long-term absorption. Compound A also shifted the power spectrum of resting EEG to the lower frequency side.

[0383] TMS-EEG allows for the measurement of the pharmacological effects of drugs acting in the brain. This aspect is particularly appealing to epilepsy research, where, despite widespread AED use, seizures are refractory to treatment in 30% of cases, making it difficult to predict long-term treatment outcomes (Kwan and Brodie, N.Engl.J.Med. 2000, 342:314-319). Lamotrigine and levetiracetam are two of the most frequently prescribed AEDs and have been previously evaluated using TMS-EEG. Lamotrigine is a voltage-gated Na+ channel blocker, while levetiracetam binds to synaptic vesicle protein 2A (SV2A) and inhibits the release of excitatory neurotransmitters (Rogawski and Loescher, Nat.Rev.Neurosci. 2004, 5:553-564). At the systemic level, both drugs increased the amplitude of N45 and suppressed the P180 component (Premoli et al., Epilepsia 2016, 58:42-50).

[0384] In the TMS-EEG portion of this study, 20 mg of compound A produced a statistically significant modulation of TEP in a manner consistent with a decrease in cortical excitability. At the point of peak plasma levels during TMS evaluation, compared to time-matched placebo, compound A reduced the amplitude of the initial N15-P25 composite wave, and the N45 and P180 potentials provided distinctive fingerprints. The N15 component was generated in the ipsilateral premotor cortex, while the origin of P25 was less clear, but it may reflect activity in the ipsilateral sensorimotor / premotor cortex junction, ipsilateral supracingate wall or supplementary motor area, or contralateral cortex (Maki and Ilmoniemi, Neurosci. Lett. 2010, 478:24-28). The N15-P25 composite wave is inversely correlated with MEP amplitude and therefore provides information about the excitability of the stimulated area. Following this interpretation, the reduction in peak-to-peak amplitude of these initial components may reflect a drug-induced decrease in cortical excitability. Over time, compound A suppressed N45 amplitude, which is linked to GABA-A receptor-mediated neurotransmission, as demonstrated in studies manipulating TEP with benzodiazepines as GABAergic positive modulators (Premoli et al., J. Neurosci.:J.Soc. Neurosci. 2014, 34:5603-5612; Darmani et al., J. Neurosci.:J.Soc. Neurosci. 2016, 36:12312-12320). The decrease in N45 may reflect less GABA-A receptor-mediated inhibition due to activation of presynaptic GABA-A receptors, which reduces GABA release into the synaptic cleft. Another explanation is that the TMS response did not propagate to the contralateral hemisphere, given the overall increase in cortical inhibition, which would explain the decrease in N45 amplitude across distant regions. Finally, the decrease in the P180 component is consistent with observations from other AEDs (Premoli et al., 2016).

[0385] In addition to TEP, brain responses to TMS can be investigated by applying time-frequency analysis at the single-trial level, removing the evoked (i.e., TEP) component from the signal. TMS-induced oscillatory signals are a result of this analytical approach, and they provide phase-asynchronous neural information (Premoli et al., Neuroimage 2017, 163:1-12). The effects of compounds acting on GABAergic neurotransmission on TMS-induced oscillatory signals showed that early α-synchronicity increased with GABA-A agonists and decreased with GABA-B agonists, late α-dissynchronicity increased with GABA-B agonists, and late β-dissynchronicity increased with both GABA-A and GABA-B agonists.

[0386] Compound A exhibited a unique profile of modulation of the induced response, consisting of suppression of theta and alpha TMS-induced power, and a further increase in beta TMS-induced desynchronization. In the absence of TMS stimulation, at rest, spontaneous oscillatory brain activity was modulated, showing increased power in the delta, theta, and beta bands.

[0387] TMS-EMG and TMS-EEG results indicate that 20 mg of compound A, upon crossing the blood-brain barrier, affects cortical excitability, as demonstrated by the modulation of a range of PD markers. Intrinsic properties of the neuronal cell membrane and levels of cortical excitation and inhibition are relevant in epileptic seizures. Therefore, these study endpoints may play a crucial role in determining the therapeutic effect of compound A in epileptic patients. For example, RMT is lower in drug-untreated patients compared to healthy controls, indicating impaired intracortical inhibition. For this particular compound, changes in RMT and other PD markers before and after treatment can be used to assess the therapeutic responsiveness of compound A. *****

[0388] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein, including U.S. Provisional Application No. 62 / 670,354 filed May 11, 2018, are incorporated herein by reference in their entirety.

[0389] Although the compositions, methods, and uses described above have been explained in some detail for the sake of understanding, it will be apparent that certain modifications and variations may be made within the scope of the appended claims. Accordingly, the embodiments described should be considered to be for illustrative purposes only and not to limit, and the claimed inventions should not be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

Claims

1. A drug for use in the treatment of humans who require treatment, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; 10-50 mg of N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide is administered to humans. It is a substance, an agent.

2. An agent for use in the treatment of diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction in humans requiring treatment, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

3. The agent according to claim 2, which increases the opening of the Kv7 potassium channel.

4. The agent according to claim 3, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.

5.

5. The agent according to claim 4, which is selective for increasing the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5, rather than Kv7.

1.

6. A drug for use in the treatment of paroxysmal disorders in humans requiring treatment, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

7. A drug for use in the treatment of humans who require treatment, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

8. An agent for use in raising the resting exercise threshold (RMT) or active exercise threshold (AMT) in humans, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

9. An agent for use in reducing corticospinal excitability or cortical excitability in humans, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

10. An agent for use in increasing the bioavailability of a drug in humans, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

11. An agent for use in increasing the bioavailability and exposure of an agent in humans, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

12. An agent used to increase the degree of absorption and exposure to a drug in humans, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; The aforementioned drug is administered to humans after a meal. It is a substance, an agent.

13. C of agents in humans ｍａｘ AUC ｉｎｆ , T ｍａｘ , or t1 / 2 λｚ An agent for use in raising by 1 or more, The agent comprises N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide; Oral administration of the aforementioned agent, compared to oral administration of the same amount to a fasted person, results in C ｍａｘ AUC ｉｎｆ , T ｍａｘ , or t1 / 2 λｚ Increase by 1 or more. It is a substance, an agent.

14. The agent according to any one of claims 1 to 13, which is administered orally between four hours before and four hours after eating.

15. A kit including compound A and instructions for orally administering compound A to humans after a meal, Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. It is a kit.

16. A kit comprising 10-50 mg of compound A and instructions for orally administering compound A to humans after a meal, Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. It is a kit.

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