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

Abstract

To provide compounds and administration methods for treating seizure disorders in a human.SOLUTION: The present invention provides methods comprising orally administering a therapeutically effective amount of the voltage-gated potassium channel allosteric modulator, N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (Compound A), to the human in need thereof, for example, under fed conditions. The present invention further provides various improved methods related to administration of Compound A.SELECTED DRAWING: Figure 2

Description

[Technical Field]

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

[0002] Epilepsy is a common neurological disorder with an estimated worldwide 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 an elevated risk of death compared to the general population, primarily due to the etiology of their disease. However, in patients with uncontrolled epilepsy, the greatest risk of seizure-related death is due to sudden unexpected death in epilepsy (SUDEP) (see Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376). Patients participating in investigational antiepileptic drug (AED) clinical trials generally have had epilepsy for more than 10 years and have failed multiple AED therapies.

[0004] Although the pathophysiology of most forms of epilepsy remains poorly understood, it is known that epileptic seizures result from excessive, synchronized, and sustained firing of a group of neurons. A sustained increase in neuronal excitability is common to all epilepsy syndromes. Therapeutic strategies for treating epilepsy involve reducing neuronal excitability through various mechanistic pathways. Over the past two decades, several new AEDs have been developed and marketed to broaden the therapeutic spectrum by targeting different mechanisms of action and 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, up to 30% of patients remain refractory to conventional treatments and continue to suffer from uncontrolled seizures (see Brown, DA et al., Nature (1980), 283:673-676, and Elger, CE et al., Epilepsy Behav. (2008), 12:501-539). The quality of life in refractory patients is poor, they are unable to drive, and they have difficulty working or living independently. In addition, many patients suffer from behavioral, neurological, and / or intellectual disabilities as a sequelae of their seizure disorder. Despite the fact that potassium-gated channels play a key role in regulating neuronal excitability, current drugs have little effect on potassium-gated channels in neurons. Therefore, drugs with novel mechanisms of action or that improve upon currently available AEDs are needed to address the significant unmet clinical need for seizure control in patients with treatment-resistant epilepsy.

[0005] N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (herein referred to as "Compound A") is a small molecule currently being developed for the treatment of seizure disorders. Compound A and its use as a potassium channel modulator are disclosed in U.S. Pat. Nos. 8,293,911 and 8,993,593, the disclosures of which are incorporated herein by reference in their entireties.

[0006] The 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 after its early characterization because it is reduced 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, reduction of Kv7.2-mediated M-current, for example through genetic loss of function, can cause neuronal depolarization and increased membrane and neuronal excitability, which can lead to action potential bursts manifesting as epileptic seizures. In contrast, increasing Kv7.2-mediated M-current hyperpolarizes the cell membrane, thereby reducing neuronal excitability and preventing the initiation and propagation of action potential bursts and resulting seizures. Enhancing the open state of Kv7.2 / Kv7.3 channels in neurons favors a hyperpolarized resting state, which reduces rapid action potential spikes (i.e., burst firing). Such enhancement can provide a stabilizing effect on excitable, particularly 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-onset seizures in adults with epilepsy, using retigabine (ezogabine), a known Kv7.2 / Kv7.3 opener.

[0007] Retigabine has the following structure: [ka]

[0008] Retigabine was first identified in the late 1980s as an analogue of the analgesic compound flupirtine. Retigabine demonstrated broad-spectrum activity in studies designed to identify novel anticonvulsant agents using a series of rodent seizure models (see Kupferberg, H., Epilepsia (1989), 30(Suppl. 1):S51-S56). Retigabine was approved for partial-onset seizures in 2011 but was withdrawn from the market in 2017 for commercial reasons after a black box warning was issued related to discoloration of the skin, lips, and nails and retinal pigment changes that appear to be related to the formation of the chromophore retigabine dimer 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, WA, 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, DA 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, WA, USA, December 5-9, 2014. Summary of the Invention [Problem to be solved by the invention]

[0011] Although 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 for increasing the bioavailability and exposure of Compound A when administered orally to humans with seizure disorders such as epilepsy. [Means for solving the problem]

[0012] In some embodiments, the present disclosure relates to a method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human in need thereof, comprising orally administering to the human in the postprandial state, or between 30 minutes before and 2 hours after a meal, a therapeutically effective amount of Compound A. In a particular example, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal-onset 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 human in need thereof, wherein the compound is Compound A, and a therapeutically effective amount of the compound is orally administered to the human in the postprandial state, or between 30 minutes before and 2 hours after a meal. In certain examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal-onset epilepsy.

[0014] In one embodiment, the disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human an amount of Compound A in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to treat the seizure disorder in the human.

[0015] In one embodiment, the disclosure provides a compound for use in treating a seizure disorder in a human in need thereof, wherein the compound is Compound A, and the compound is orally administered to the human in the postprandial state, or between 30 minutes before and 2 hours after a meal.

[0016] In one embodiment, the disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human an amount of Compound A in the postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is between 2 and 200 mg.

[0017] In one embodiment, the present disclosure provides a method for the treatment of C18 of Compound A in a human receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λz orally administering to said human an amount of Compound A in a postprandial state or between 30 minutes before and 2 hours after a meal, said method comprising: max , AUC inf , T max , or t1 / 2 λz The present invention provides a method for increasing one or more of the following:

[0018] In one embodiment, the present disclosure provides a compound for use in a method for treating atopic dermatitis, comprising administering to a subject a compound having a C C of the compound in a human receiving oral administration of the compound. max , AUC inf , T max , or t1 / 2 λz or (iii) a compound for use in increasing one or more of the following: max , AUC inf , T max , or t1 / 2 λz The present invention provides a compound for use in increasing one or more of:

[0019] In certain embodiments, the present disclosure provides a method for measuring the bioavailability or C of Compound A in humans receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λz A method for increasing one or more of (a) Oral administration of Compound A in the postprandial state or between 30 minutes before and 2 hours after a meal improves the bioavailability or C of Compound A. max , AUC inf , T max, or t1 / 2 λz Informing the human that the test will increase one or more of: (b) relying on step (a), orally administering compound A in a postprandial state or between 30 minutes before and 2 hours after a meal; A method comprising:

[0020] In certain such embodiments, the probability that (b) occurs (i.e., the administration occurs in a postprandial state or between 30 minutes before and 2 hours after a meal) is increased relative to the method without step (a).

[0021] In one embodiment, the disclosure provides a method of orally administering Compound A to a human in need thereof, comprising orally administering Compound A to the human in a fed state or between 30 minutes before and 2 hours after a meal, wherein the method results in a C of Compound A compared to the same amount of Compound A administered orally to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The present invention provides a method for increasing one or more of the following:

[0022] In one embodiment, the disclosure provides a method of orally administering a dose of Compound A to a human in need thereof as part of a treatment regimen, comprising orally administering a reduced dose of Compound A to the human in a fed state or between 30 minutes before and 2 hours after a meal, wherein the reduced dose does not exceed the same C of Compound A when orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The present invention provides a method in which the dose is lower than the dose required to achieve one or more of the following:

[0023] In one embodiment, the disclosure provides a compound for use in reducing the dose of said compound orally administered to a human in need thereof as part of a treatment regimen, said compound being Compound A, said compound being orally administered to said human in a fed state or between 30 minutes before and 2 hours after a meal, said reduced dose having the same C value as Compound A when orally administered to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The present invention provides a compound for use in a dosage that is lower than the dosage required to achieve one or more of the following:

[0024] In one embodiment, the disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human a therapeutically effective amount of Compound A. In certain embodiments, the method comprises, for Compound A: C of at least 40 ng / mL max , AUC of at least 2500 h·ng / mL inf , T at least 3.25h max , or t1 / 2 of at least 130h λz This results in one or more of the following:

[0025] In one embodiment, the disclosure provides a compound for use in treating a seizure disorder in a human in need thereof, wherein the compound is Compound A, and the compound is orally administered to the human. In certain embodiments, the oral administration is such that, for Compound A: C of at least 40 ng / mL max , AUC of at least 2500 h·ng / mL inf , T at least 3.25h max , or t1 / 2 of at least 130h λz This results in one or more of the following:

[0026] In one embodiment, the disclosure provides a method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human being in need thereof, comprising orally administering to the human an amount of Compound A, optionally in a fed state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to increase RMT or AMT in the human being, or wherein the amount of Compound A is between 2 and 200 mg.

[0027] In one embodiment, the disclosure provides a compound for use in increasing RMT or AMT in a human being in need thereof, wherein the compound is Compound A, and an amount of the compound is orally administered to the human being, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to increase RMT or AMT in the human being, or wherein the amount of Compound A is between 2 and 200 mg.

[0028] In one embodiment, the disclosure provides a method of decreasing corticospinal or cortical excitability in a human being in need thereof, comprising orally administering to the human an amount of Compound A, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to increase corticospinal or cortical excitability in the human being, or wherein the amount of Compound A is between 2 and 200 mg.

[0029] In one embodiment, the disclosure provides a compound for use in decreasing corticospinal or cortical excitability in a human being in need thereof, wherein the compound is Compound A, and an amount of the compound is orally administered to the human being, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to increase corticospinal or cortical excitability in the human being, or wherein the amount of Compound A is between 2 and 200 mg.

[0030] In certain embodiments, the disclosure generally provides methods 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 seizure disorder in a human, comprising orally administering a therapeutically effective amount of Compound A to said human in need thereof in the postprandial state.

[0032] Another aspect of the present disclosure is a method of increasing the bioavailability and exposure of Compound A in a human receiving oral administration of a therapeutically effective amount of Compound A for the treatment of a seizure disorder, the method comprising orally administering a therapeutically effective amount of Compound A to the human in a fed state.

[0033] Another aspect of the present disclosure is a method of increasing the extent of absorption and exposure of Compound A in a human following oral administration of Compound A to the human, the method comprising orally administering to the human a therapeutically effective amount of Compound A in a fed state.

[0034] These and other aspects of the present disclosure will become apparent upon reference to the following detailed description, and to this end, various references are set forth herein which describe in more detail certain background information and procedures, each of which is incorporated by reference in its entirety. [Brief explanation of the drawings]

[0035] [Figure 1] FIG. 1 illustrates the mean plasma concentration levels of Compound A in a food effect study in cynomolgus monkeys, showing Compound A concentration (ng / mL) (y-axis) over time (hours) (x-axis), as described below in Table 5 of Example 1. [Figure 2] FIG. 2 illustrates the mean plasma concentration levels of Compound A in a food effect study in humans, as described below in Example 2, showing Compound A concentration (ng / mL) (y-axis) over time (hours) (x-axis). [Figure 3]FIG. 3 includes a graph depicting Compound A-induced modulation of resting motor threshold (A), showing post-to-pre RMT (y-axis) across three doses (10 mg, 15 mg, and 20 mg) (x-axis) at 2 and 4 hours after drug ingestion, and a graph depicting Compound A-induced modulation of active motor threshold (B), showing post-to-pre AMT (y-axis) across three doses (10 mg, 15 mg, and 20 mg) (x-axis) at 2 and 4 hours after drug ingestion. [Figure 4] Figure 4 includes graphical illustrations depicting the spatiotemporal profiles of TEPs after placebo and Compound A treatment. Panel A shows grand-averaged (n = 16) butterfly plots before (Pre) and after (Post) ingestion of placebo (left) and Compound A (right). Each line represents TEPs recorded on a single EEG channel. Topographic scalp distributions of the amplitudes (μV) of the major TEP components (N15-P25, N45, N100, and P180) before and after drug ingestion are shown in Panels B and C, respectively. Panel D shows t-statistic maps of TEP amplitudes showing the difference between post- and pre-administration. "ns" indicates a non-significant result, and open "x"s on the topographic scalp distributions indicate areas of positive amplitude and t-statistic, while dark areas without "x"s indicate negative amplitude and t-statistic. [Figure 5] Figure 5 includes a graph depicting the modulation of TEP amplitude by Compound A at the highest concentration. TEPs were grand-averaged across channels that showed significant drug effects. Compared to pre-administration, Compound A induced suppression of the N15-P25, N45, and P180 components. TEP data were averaged across 16 participants with the post-administration condition selected at the highest drug exposure during TMS assessment. Open "x"s on the topographic scalp distributions indicate areas of positive t-statistics, while dark areas without "x"s indicate negative t-statistics. [Figure 6] FIG. 6 is a graphical representation of TEPs after treatment with Compound A and placebo showing TEP amplitudes (μV) (y-axis) at N15-P25, N45, and P180 time points (x-axis) after a TMS pulse. [Figure 7]Figure 7 includes a graphical representation depicting the effect of Compound A on TEP at 2, 4, and 6 hours post-dose. Grand-averaged TEP recorded before dosing (Pre) and 2 hours (2 hr), 4 hours (4 hr), and 6 hours (6 hr) post-dose are shown. The Compound A fingerprint, which includes decreases in N15-P25, N45, and P180 components, reflects increased plasma exposure over time. [Figure 8] Figure 8 illustrates drug-induced modulation of spontaneous brain oscillations before and after treatment with Compound A. Panel A shows the grand-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 oscillations over time after ingestion of Compound A. Panel A shows the grand-averaged (n=16) power spectra (n=16) before (Pre), 2 hours (Post2hr), and 4 hours (Post4hr) after 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 depicting the Compound A time effect on resting motor threshold, showing the change from baseline RMT (% maximal stimulus intensity [%MSO]) (left y-axis) and Compound A concentration (ng / mL) (right y-axis) over time (hours) (x-axis). For Compound A, n = 19, 20, and 16 at 2, 4, and 6 hours post-dose, respectively. For placebo, n = 20, 20, and 16 at 2, 4, and 6 hours post-dose, respectively. Mean ± standard error of the mean (SEM) is shown. [Figure 11] 11 is a graph depicting the effect of Compound A concentration on RMT modulation showing RMT delta (post-pre; %MSO) (y-axis) and Compound A and placebo (x-axis). Mean high concentration of Compound A = 45 ng / mL. [Figure 12]12 includes a graph (A) depicting the concentration effect before administration (Pre) versus after administration of Compound A, showing Global Mean Field Power (GMFP) (uv2) (y-axis) over time (seconds) (x-axis), and a graph (B) depicting the time effect before administration (Pre) versus 2 and 4 hours after administration of Compound A, showing GMFP (uv2) (y-axis) over time (seconds) (x-axis). The mean high concentration of Compound A = 45 ng / mL. DETAILED DESCRIPTION OF THE INVENTION

[0036] The effect of food on a drug can significantly impact patient outcomes by affecting the drug's pharmacokinetics and pharmacodynamics. This interaction can potentially lead to decreased drug absorption and reduced efficacy or increased drug absorption and increased efficacy. Food can also have either positive or negative effects on the incidence and severity of adverse events associated with drug use. Whether drug bioavailability and / or patient exposure are 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 certain embodiments, the present disclosure provides improved methods of treatment and administration based on the unexpected finding that oral administration of Compound A to humans in the fed state (i.e., with food or immediately after ingestion of food) significantly increases the bioavailability and exposure of Compound A compared to oral administration of Compound A to humans in the fasted state (i.e., in the absence of food or immediately after ingestion of food). This finding is unexpected in view of the results of studies in non-human primates in which oral administration of Compound A in the fed state did not increase the bioavailability and exposure of Compound A compared to the fasted state.

[0038] This finding is unexpected given the lack of a food effect on the bioavailability and exposure of another potassium channel opener, retigabine, following oral administration, as noted above (see, e.g., page 2 of the United States Food and Drug Administration (FDA) Approved Labeling Text for Potiga, the trade name for retigabine, dated March 15, 2012; 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] In addition, Compound A is unable to form chromophore dimers similar to those formed by retigabine. Therefore, the blue-gray discoloration of the skin, lips, or nails and changes in retinal pigmentation in human patients that appear after long-term use of retigabine would not be expected to occur after long-term use of Compound A.

[0040] In the following disclosure, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Except where contradictory in context, throughout this specification and the appended claims, the word "comprise" and its derivatives, such as "comprises" and "comprising," should be construed in an open, inclusive sense, i.e., "including, but not limited to." Furthermore, the subheadings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0041] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" generally includes "and / or" unless the context clearly dictates otherwise. 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 in this specification and the appended claims, unless specifically stated to the contrary, the following terms and abbreviations have the meanings indicated.

[0043] "Compound A" refers to a compound having the formula below and the compound name N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-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 Compound A involves the enhancement or increased opening of the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), which are important in controlling neuronal excitability. Compound A is used in the methods and uses described herein.

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

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

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

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

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

[0049] "Bioavailability" refers to the rate and extent to which Compound A is absorbed and becomes systemically available for further distribution to the site of action.

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

[0051] "h" refers to hour(s).

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

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

[0054] "SD" refers to standard deviation.

[0055] "Seizure disorders" include partial onset (focal) seizures, photosensitive epilepsy (photosensitive seizures), self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorders, 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 absence epilepsy. "Seizure disorder" refers to seizures and disorders associated with seizures, such as 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 one embodiment, the term "seizure disorder" refers to focal onset 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 to reach the maximum (peak) plasma concentration after extravascular administration of Compound A.

[0058] As used herein, a "therapeutically effective amount" refers to an amount of Compound A sufficient to treat the indicated disease, disorder, or condition, or to achieve the desired, described effect, including ameliorating or preventing the disease, disorder, or condition or one or more mechanisms underlying the disease, disorder, or condition. In one embodiment, when Compound A is administered to treat a seizure disorder, a therapeutically effective amount refers to the range of amounts of Compound A that, upon administration to a human, will treat, ameliorate, or prevent the seizure disorder in that human, or produce a detectable therapeutic or preventive effect in that human with a seizure disorder. This effect is detected, for example, by a reduction in seizure frequency or the severity (quality) of seizures. The precise therapeutically effective amount for a given human will depend on that human's size and health, the nature and extent of the seizure disorder, the presence of any concomitant medications, and other variables known to those skilled in the art. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the ability of the clinician.

[0059] As used herein, "treatment" refers to a therapeutic application involving the administration of Compound A to ameliorate or prevent the indicated disease, disorder, or condition or one or more underlying mechanisms thereof, including slowing or halting the progression of the indicated disease, disorder, or condition or one or more underlying mechanisms thereof. In certain embodiments, when Compound A is administered for the treatment of a seizure disorder, treatment refers to a therapeutic application to slow or halt the progression of the seizure disorder, a prophylactic application to prevent the onset of the seizure disorder, and / or a reversal of the seizure disorder. Reversal of a seizure disorder differs from a therapeutic application that slows or halts the seizure disorder in that the reversal method not only halts the progression of the seizure disorder entirely, but also shifts some cellular behavior toward the normal state that would be observed in the absence of the seizure disorder.

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

[0061] "Fasted state" refers to the state in which food has not been consumed for at least 4 hours prior to oral administration of a therapeutically effective amount of Compound A until about 4 hours after administration of Compound A.

[0062] Embodiment In some embodiments, the present disclosure relates to a method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human in need thereof, comprising orally administering to the human, in a postprandial state, a therapeutically effective amount of Compound A. In certain examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal-onset epilepsy.

[0063] In certain embodiments, the present disclosure relates to a method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human in need thereof, comprising orally administering to the human between 30 minutes before and 2 hours after a meal a therapeutically effective amount of Compound A. In a particular example, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal-onset 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 human in need thereof, wherein the compound is Compound A, and a therapeutically effective amount of the compound is orally administered to the human in a postprandial state. In particular examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal-onset epilepsy.

[0065] In certain 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 human in need thereof, wherein the compound is Compound A, and a therapeutically effective amount of the compound is orally administered to the human between 30 minutes before and 2 hours after a meal. In particular examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal-onset epilepsy.

[0066] In embodiments relating to diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction, in some instances, the method enhances the opening of Kv7 potassium channels, such as one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. In particular instances, the method or use is selective for enhancing the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 over Kv7.1. In some embodiments, the method or use is optionally selective for Kv7.2 over Kv7.1. In other embodiments, the method or use is optionally selective for Kv7.3 over Kv7.1. In still other embodiments, the method or use is optionally selective for Kv7.4 over Kv7.1. In still further embodiments, the method or use is optionally selective for Kv7.5 over Kv7.1. In one embodiment, the 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 of treating a seizure disorder in a human in need thereof, comprising orally administering to the human in a postprandial state an amount of Compound A, wherein the amount of Compound A is sufficient to treat the seizure disorder in the human. In certain embodiments, the amount is sufficient to reduce seizure severity, seizure frequency, or both.

[0068] In one embodiment, the disclosure provides a compound for use in treating a seizure disorder in a human in need thereof, wherein the compound is Compound A, and the compound is orally administered to the human in a fed state. In certain embodiments, the amount is sufficient to reduce seizure severity, seizure frequency, or both.

[0069] In one embodiment, the disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human an amount of Compound A between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to treat the seizure disorder in the human. In an embodiment, the amount is sufficient to reduce seizure severity, seizure frequency, or both.

[0070] In one embodiment, the disclosure provides a compound for use in treating a seizure disorder in a human in need thereof, wherein the compound is Compound A, and the compound is orally administered to the human between 30 minutes before and 2 hours after a meal. In an embodiment, the amount is sufficient to reduce seizure severity, seizure frequency, or both.

[0071] In one embodiment, the present disclosure provides a method of treating a seizure disorder in a human being in need thereof, comprising orally administering to the human an amount of Compound A in a fed state, wherein the amount of Compound A is between 2 and 200 mg.

[0072] In one embodiment, the disclosure provides a method of treating a seizure disorder in a human in need thereof, the method comprising orally administering to the human an amount of Compound A between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is between 2 and 200 mg.

[0073] In one embodiment, the present disclosure provides a method for the treatment of C18 of Compound A in a human receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λz orally administering to said human an amount of Compound A in a fed state. In one embodiment, the method provides a method for increasing one or more of C compared to when the same amount of Compound A is administered orally to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz Increase one or more of the following.

[0074] In one embodiment, the present disclosure provides a compound for use in a method for treating atopic dermatitis, comprising administering to a subject a compound having a C C of the compound in a human receiving oral administration of the compound. max , AUC inf , T max , or t1 / 2 λz and / or C, wherein the compound is Compound A, and the compound is orally administered to the human in a fed state. In one embodiment, the oral administration results in a decrease in C compared to when the same amount of Compound A is orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz Increase one or more of the following.

[0075] In one embodiment, the present disclosure provides a method for the treatment of C18 of Compound A in a human receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λzor C, the method comprising orally administering to the human an amount of Compound A between 30 minutes before and 2 hours after a meal. In one embodiment, the method provides a method for increasing one or more of C compared to when the same amount of Compound A is orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz Increase one or more of the following.

[0076] In one embodiment, the present disclosure provides a compound for use in a method for treating atopic dermatitis, comprising administering to a subject a compound having a C C of the compound in a human receiving oral administration of the compound. max , AUC inf , T max , or t1 / 2 λz and / or a compound for use in increasing one or more of C, ... max , AUC inf , T max , or t1 / 2 λz Increase one or more of the following.

[0077] In certain embodiments, the present disclosure provides a method for measuring the bioavailability or C of Compound A in humans receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λz A method for increasing one or more of (a) Oral administration of Compound A in the postprandial state or between 30 minutes before and 2 hours after a meal improves the bioavailability or C of Compound A. max , AUC inf , T max , or t1 / 2 λz Informing the human that the test will increase one or more of: (b) relying on step (a), orally administering compound A in a postprandial state or between 30 minutes before and 2 hours after a meal; In certain such embodiments, the probability that (b) occurs (i.e., the administration occurs in a postprandial state or between 30 minutes before and 2 hours after a meal) is increased relative to the method without step (a).

[0078] In one embodiment, the disclosure provides a method of orally administering Compound A to a human in need thereof, comprising orally administering Compound A to the human in a fed state. In certain embodiments, the method results in a C of Compound A of 0.05g compared to when the same amount of Compound A is orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz Increase one or more of the following.

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

[0080] In one embodiment, the present disclosure provides a method of reducing the dose of Compound A administered orally to a human in need thereof as part of a treatment regimen, comprising orally administering a reduced dose of Compound A to the human in a fed state. In certain embodiments, the reduced dose is less than or equal to the same C of Compound A when administered orally to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The dose is lower than that required to achieve one or more of the following:

[0081] In one embodiment, the disclosure provides a compound for use in reducing the dose of a compound orally administered to a human in need thereof as part of a treatment regimen, wherein the compound is Compound A, and the compound is orally administered to the human in a fed state. In one embodiment, the reduced dose is the same C of Compound A when orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The dose is lower than that required to achieve one or more of the following:

[0082] In one embodiment, the present disclosure provides a method of reducing the dose of Compound A administered orally to a human in need thereof as part of a treatment regimen, comprising orally administering a reduced dose of Compound A to the human between 30 minutes before and 2 hours after a meal. In certain embodiments, the reduced dose is greater than or equal to the same C of Compound A when administered orally to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The dose is lower than that required to achieve one or more of the following:

[0083] In one embodiment, the disclosure provides a compound for use in reducing the dose of a compound orally administered to a human in need thereof as part of a treatment regimen, 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 an embodiment, the reduced dose is the same C of Compound A when orally administered to the human in the fasted state. max , AUC inf , T max , or t1 / 2 λz The dose is lower than that required to achieve one or more of the following:

[0084] In one embodiment, the disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human a therapeutically effective amount of Compound A. In certain embodiments, the method comprises, for Compound A: C of at least 40 ng / mL, e.g., 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 , an AUC of at least 2500 h·ng / mL, e.g., 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 of at least 3.25 h, e.g., at least 3.5 h, at least 3.75 h, at least 4 h, at least 4.25 h, or at least 4.5 h max , or a t of at least 130 hours, e.g., at least 150 hours, at least 170 hours, at least 190 hours, or at least 210 hours λz This results in one or more of the following:

[0085] In one embodiment, the disclosure provides a compound for use in treating a seizure disorder in a human in need thereof, wherein the compound is Compound A, and the compound is orally administered to the human. In certain embodiments, the oral administration is such that, for Compound A: C of at least 40 ng / mL, e.g., 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 , an AUC of at least 2500 h·ng / mL, e.g., 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 of at least 3.25 h, e.g., at least 3.5 h, at least 3.75 h, at least 4 h, at least 4.25 h, or at least 4.5 h max , or a t of at least 130 hours, e.g., at least 150 hours, at least 170 hours, at least 190 hours, or at least 210 hours λz This results in one or more of the following:

[0086] In one embodiment, the C of compound A provided by the method and use max , AUC inf , T max , or t1 / 2 λz The increase in one or more of is independent of the type of food ingested by the person, 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 of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human in need thereof, comprising orally administering to the human an amount of Compound A, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal. In certain embodiments, the amount of Compound A is sufficient to increase RMT or AMT in the human.

[0088] In one embodiment, the disclosure provides a compound for use in increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human in need thereof, wherein the compound is Compound A, and an amount of the compound is orally administered to the human, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal. In some embodiments, the amount of Compound A is sufficient to increase RMT or AMT in the human. In some embodiments, the amount of Compound A is between 2 and 200 mg.

[0089] In one embodiment, the disclosure provides a method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human in need thereof, comprising orally administering to the human an amount of Compound A, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal. In one embodiment, the amount of Compound A is between 2 and 200 mg.

[0090] In one embodiment, the disclosure provides a method of decreasing corticospinal or cortical excitability in a human in need thereof, comprising orally administering to the human an amount of Compound A, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to increase corticospinal or cortical excitability in the human.

[0091] In one embodiment, the disclosure provides a compound for use in decreasing corticospinal or cortical excitability in a human being in need thereof, wherein the compound is Compound A, and an amount of the compound is orally administered to the human being, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is sufficient to increase corticospinal or cortical excitability in the human being. In one embodiment, the amount of Compound A is between 2 and 200 mg.

[0092] In one embodiment, the disclosure provides a method of decreasing corticospinal or cortical excitability in a human in need thereof, comprising orally administering to the human an amount of Compound A, optionally in a postprandial state, or between 30 minutes before and 2 hours after a meal, wherein the amount of Compound A is between 2 and 200 mg.

[0093] In one embodiment of the present disclosure, oral administration of Compound A to humans in a fed state increases the bioavailability and exposure of Compound A upon oral administration. Such conditions have surprisingly been found to significantly increase the bioavailability and exposure of Compound A in humans upon oral administration. In a more specific embodiment, "in a fed state" includes the ingestion of food concurrently with or in close proximity to oral administration of Compound A.

[0094] In some, but not all, embodiments of the present disclosure, the food is a high-fat, high-calorie meal. A typical high-fat meal will have approximately 50 percent of the meal's total caloric content derived from fat, and a typical high-calorie meal will have approximately 800-1000 calories. A typical meal should have approximately 150 calories, 250 calories, and 500-600 calories derived from protein, carbohydrates, and fat, respectively. The amount of food ingested with or in close temporal proximity to oral administration of Compound A should be sufficient to achieve enhanced bioavailability and exposure of Compound A.

[0095] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods and uses described herein is between 30 minutes before and 2 hours after a meal. In some aspects, oral administration can occur between about 60, 45, 30, 25, 20, 15, 10, or 5 minutes before a meal and about 5, 10, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, or 240 minutes after a meal. In some aspects, Compound A can be administered simultaneously with or within 15 minutes of ingesting food.

[0096] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods described herein may result in a decrease in C of Compound A compared to when the same amount of Compound A is administered orally to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz In some embodiments, oral administration of Compound A to a human increases one or more of the C of Compound A compared to when the same amount of Compound A is administered orally to the human in a fasted state. max In some embodiments, the oral administration increases AUC inf In some embodiments, this oral administration increases T compared to the fasted state. max In some embodiments, the oral administration increases the t1 / 2 compared to the fasted state. λz In some embodiments, this oral administration increases C compared to the fasted state. max and AUC inf In some embodiments, this oral administration increases C compared to the fasted state. max and T max In some embodiments, this oral administration increases C compared to the fasted state. max and t1 / 2 λz In some embodiments, the oral administration increases AUC inf and T maxIn some embodiments, the oral administration increases AUC inf and t1 / 2 λz In some embodiments, this oral administration increases T compared to the fasted state. max and t1 / 2 λz In some embodiments, this oral administration increases C compared to the fasted state. max , AUC inf , and T max In some embodiments, this oral administration increases C compared to the fasted state. max , AUC inf , and t1 / 2 λz In some embodiments, this oral administration increases C compared to the fasted state. max , T max , and t1 / 2 λz In some embodiments, the oral administration increases AUC inf , T max , and t1 / 2 λz In some embodiments, this oral administration increases C compared to the fasted state. max , AUC inf , T max , and t1 / 2 λz Increases.

[0097] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods described herein results in a Cmax of Compound A compared to when the same amount of Compound A is administered orally to the human in a fasted state. max In some embodiments, C max The increase in C is at least 50%, e.g., 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%. max The increase in C is at least 100%, at least 150%, or at least 200%, e.g., at least 100%. maxThe increase can range from about 50% to about 500%, e.g., from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80% to about 250%, or from about 100% to about 200%, e.g., from about 50%, 60%, 70%, 80%, 90% or 100% to about 200%, 250%, 300%, 350%, 400%, 450% or 500%, including about or at least about 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 the fasted state max C after oral administration of Compound A in the postprandial state max is greater than 1.2. In certain embodiments, the 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, C of compound A max In some embodiments, the C of Compound A is increased to at least 40 ng / mL. maxis 20 ng / mL to about 200 ng / mL, for example, about 25 to about 200 ng / mL, about 30 to about 200 ng / mL, about 35 to about 200 ng / mL, about 40 to about 175 ng / mL, about 40 to about 150 ng / mL, about 40 to about 125 ng / mL, about 40 to about 100 ng / mL, about 40 to about 90 ng / mL, about 40 to about 80 ng / mL, about 40 to about 70 ng / mL, about 40 to about 60 ng / mL, or in the range of about 40 to about 50 ng / mL, for example, about 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 L, and can rise to 81ng / mL, 82ng / mL, 83ng / mL, 84ng / mL, 85ng / mL, 86ng / mL, 87ng / mL, 88ng / mL, 89ng / mL, 90ng / mL, 91ng / mL, 92ng / mL, 93ng / mL, 94ng / mL, 95ng / mL, 96ng / mL, 97ng / mL, 98ng / mL, 99ng / mL, or 100ng / mL.

[0100] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods disclosed herein results in a decrease in the AUC of Compound A compared to when the same amount of Compound A is administered orally to said human in a fasted state. inf In some embodiments, the AUC inf The increase in AUC is at least 50%, e.g., 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%. infThe increase in AUC is at least 75% or at least 100%. inf The increase can range from about 50% to about 500%, e.g., from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80% to about 250%, or from about 100% to about 200%, e.g., from about 50%, 60%, 70%, 80%, 90% or 100% to about 200%, 250%, 300%, 350%, 400%, 450% or 500%, including about or at least about 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 the fasted state inf AUC after oral administration of Compound A in the postprandial state inf is greater than 1.2. In certain embodiments, the 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 AUC after oral administration of Compound A in the fed state to AUC after oral administration of Compound A in the 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 inf In some embodiments, the AUC of Compound A is increased to at least 2500 h·ng / mL. infis in the range of 2000 h·ng / mL to about 5000 h·ng / mL, for example, about 2500 to about 5000 h·ng / mL, about 2500 to about 4500 h·ng / mL, about 2500 to about 4250 h·ng / mL, about 2500 to about 4000 h·ng / mL, about 2500 to about 3750 h·ng / mL, about 2500 to about 3500 h·ng / mL, about 2500 to about 3250 h·ng / mL, about 2500 to about 3000 h·ng / mL, or about 2500 to about 2750 h·ng / mL, for example, about 2500 h·ng / mL, 2600 h·ng / mL, 2700 h·ng / mL, 2800 h·ng / mL, 2900 h·ng / mL, 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 human in need thereof according to the methods disclosed herein may result in a decrease in the T value of Compound A compared to when the same amount of Compound A is administered orally to the human in a fasted state. max In some embodiments, T max The increase in T is at least 50%, e.g., 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%. max The increase in T is at least 75% or at least 100%. maxThe increase can range from about 50% to about 500%, e.g., from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80% to about 250%, or from about 100% to about 200%, e.g., from about 50%, 60%, 70%, 80%, 90%, or 100% to about 200%, 250%, 300%, 350%, 400%, 450%, or 500%, including about or at least about 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

[0105] In some embodiments, the T after oral administration of Compound A in the fasted state max T after oral administration of Compound A in the postprandial state max is greater than 1.2. In certain embodiments, the 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, the T max In some embodiments, the T of Compound A is increased to at least 3.25 hours. maxis 3 hours to about 15 hours, for example, about 3.25 hours to about 15 hours, about 3.25 hours to about 14.5 hours, about 3.25 hours to about 14 hours, about 3.25 hours to about 13.5 hours, about 3.25 hours to about 13 hours, about 3.25 hours to about 12.5 hours, about 3.25 hours to about 12 hours, about 3.25 hours to about 11.5 hours, about 3.25 hours to about 11 hours, about 3.25 hours to about 10.5 hours, about 3.25 hours to about 10 hours, about 3.25 hours to about 9.5 hours, about 3.25 hours to about 9 hours, about 3.25 hours to about 8.5 hours, about 3.25 hours to about 8 hours, about 3.25 hours to about 7.5 hours, about 3.25 hours to about 7 hours, about It is possible to increase the time to a range of 3.25 hours to about 6.5 hours, about 3.25 hours to about 6 hours, about 3.25 hours to about 5.5 hours, about 3.25 hours to about 5 hours, or about 3.25 hours to about 4.5 hours, for example, about 3.25 hours, 3.5 hours, 3.75 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5.25 hours, 5.5 hours, 5.75 hours, 6 hours, 6.25 hours, 6.5 hours, 6.75 hours, 7 hours, 7.25 hours, 7.5 hours, 7.75 hours, 8 hours, 8.25 hours, 8.5 hours, 8.75 hours, 9 hours, 9.25 hours, 9.5 hours, 9.75 hours, or 10 hours.

[0107] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods disclosed herein reduces the t½ of Compound A compared to when the same amount of Compound A is administered orally to the human in a fasted state. λz In some embodiments, the t is increased by at least 40% or at least 50%, e.g., at least 60%, at least 75%, or at least 100%. λz In some embodiments, the increase in t is at least 75%. λzThe increase can range from about 50% to about 500%, e.g., from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80% to about 250%, or from about 100% to about 200%, e.g., from about 50%, 60%, 70%, 80%, 90%, or 100% to about 200%, 250%, 300%, 350%, 400%, 450% or 500%, including about or at least about 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%.

[0108] In some embodiments, the t1 / 2 following oral administration of Compound A in the fasted state λz t1 / 2 after oral administration of Compound A in the postprandial state λz is greater than 1.2. In certain embodiments, the 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, the t λz In some embodiments, the t1 / 2 of Compound A is increased to at least 130 hours. λzis 100 hours to about 500 hours, for example, about 110 hours to about 500 hours, about 120 hours to about 500 hours, about 130 hours to about 500 hours, about 130 hours to about 490 hours, about 130 hours to about 480 hours, about 130 hours to about 470 hours, about 130 hours to about 460 hours, about 130 hours to about 450 hours, about 130 hours to about 440 hours, about 130 hours to about 430 hours, about 130 hours to about 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, about 130 hr to about 290 hr, about 130 hr to about 280 hr, about 130 hr to about 270 hr, about 130 hr to about 260 hr, about 130 hr to about 250 hr, about 130 hr to about 240 hr, about 130 hr to about 230 hr, about 130 hr to about 220 hr, about 130 hr to about 210 hr, or about 130 hr to about 200 hr, for example, about 130 hr, 140 hr, 150 hr hr, 160 hr, 170 hr, 180 hr, 190 hr, 200 hr, 210 hr, 220 hr, 230 hr, 240 hr, 250 hr, 260 hr, 270 hr, 280 hr, 290 hr, 300 hr, 310 hr, 320 hr, 330 hr, 340 hr, 350 hr, 360 hr, 370 hr, 380 hr, 390 hr, or 400 hr.

[0110] In one embodiment, Compound A is provided in a dosage unit form suitable for oral administration. Compound A is present in the dosage unit form at a level 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 aspects, the method comprises orally administering 0.1 to 1.0 mg / kg of Compound A. In some embodiments, the method comprises orally administering 0.2 to 0.5 mg / kg of Compound A.

[0111] In some embodiments, the methods and uses described herein, e.g., methods of treating or using in treating a seizure disorder in a human in need thereof according to the methods and uses described herein, are accomplished by oral administration of 2 to 200 mg of Compound A. For example, the methods can be administered in the presence of 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 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 61mg, about 62mg, about 63mg, about 64mg, about 65mg, about 66mg, about 67mg, about 68mg, about 69mg, about 70mg, about 71mg, about 72mg, about 73mg, about 74mg, about 75mg , about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 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,About 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 ​​mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg The method may include orally administering about 3 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, or about 200 mg of Compound A. In some embodiments, the oral administration comprises 5-50 mg of Compound A. In some embodiments, the oral administration comprises 10 mg, 20 mg, or 25 mg of Compound A. In some embodiments, the oral administration comprises 20 mg of Compound A. In some embodiments, the oral administration comprises at least 20 mg of Compound A.

[0112] In some embodiments, the methods and uses described herein, e.g., methods of treating or using in treating a seizure disorder in a human in need thereof according to the methods and uses described herein, are accomplished by oral administration of 5 to 1000 mg of Compound A per day, e.g., 5 to 500 mg or 5 to 250 mg of Compound A per day. For example, the methods can be administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 250 mg, about 260 mg, about 265 mg, about 270 mg, about 280 mg, about 285 mg, about 290 mg, about 300 mg, about 315 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 3 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 method can include orally administering 95 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, or about 1000 mg.In some embodiments, the oral administration comprises orally administering 10-200 mg of Compound A per day, e.g., 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, e.g., 20-150 mg per day. In some embodiments, the oral administration comprises 50 mg, 75 mg, 100 mg, or 125 mg of Compound A per day, e.g., 100 mg of Compound A per day.

[0113] In certain instances, the daily dose of Compound A is administered orally as multiple doses per day, for example, 2, 3, 4, or 5 doses per day. For example, a 100 mg daily dose may be administered in four 25 mg doses throughout the day.

[0114] In some embodiments, the above daily doses of Compound A are administered orally as a single dose. For example, from about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg to about 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, or 150 mg of Compound A per day can be administered orally as a single dose, including 10-25 mg, 10-30 mg, and 10-40 mg per day as a single dose, e.g., 10-25 mg per day as a single dose.

[0115] In one embodiment, the methods and uses described herein achieve steady state for Compound A within 6 to 9 days, for example, within about 1 week, when using the daily dosing regimens disclosed herein.

[0116] In some examples, the disclosure provides a method of increasing serum levels of Compound A in a human in need thereof, the method comprising orally administering Compound A to the human in a postprandial state, or between 30 minutes before and 2 hours after a meal. In a similar embodiment, the disclosure provides Compound A for use in increasing serum levels of Compound A in a human in need thereof, wherein Compound A is administered to the human in a postprandial state, or between 30 minutes before and 2 hours after a meal.

[0117] In one embodiment of the present disclosure, administration of Compound A is for treating a seizure disorder that would benefit from opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels. Compound A is a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener. In an embodiment, the present disclosure provides a method of opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels in a human in need thereof, comprising administering an amount of Compound A. In a similar embodiment, the present disclosure provides Compound A for use in opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels in a human in need thereof.

[0118] In some embodiments, the disclosure provides a method of treating, ameliorating, or preventing a disease, disorder, or condition affected by modulation of at least one potassium channel selected from Kv7.2, Kv7.3, Kv7.4 (KCNQ4), and Kv7.5 (KCNQ5) in a human in need thereof, e.g., by opening one or more of said potassium channels, comprising orally administering Compound A to said human, optionally in a postprandial state or between 30 minutes before and 2 hours after a meal. In a similar embodiment, the disclosure provides Compound A for use in treating, ameliorating, or preventing a disease, disorder, or condition affected by modulation of at least one potassium channel selected from Kv7.2, Kv7.3, Kv7.4, and Kv7.5 in a human in need thereof, e.g., by opening one or more of said potassium channels, wherein Compound A is orally administered to said human, optionally in a postprandial state or between 30 minutes before and 2 hours after a meal. In certain embodiments, oral administration of Compound A does not open the potassium channel Kv7.1 (KCNQ1), i.e., in certain instances, Compound A is selective for one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 over Kv7.1.

[0119] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods described herein increases the resting motor threshold (RMT) or the 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 human in need thereof decreases corticospinal or cortical excitability as measured using transcranial magnetic stimulation (TMS).

[0120] In certain embodiments, the present disclosure provides a method of orally administering Compound A to a human exhibiting a reduced RMT or AMT compared to the average human, the method comprising orally administering Compound A, optionally in a postprandial state or between 30 minutes before and 2 hours after a meal, thereby increasing the RMT or AMT in the human exhibiting a reduced RMT or AMT.

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

[0122] In some embodiments, oral administration of Compound A according to the methods and uses described herein can modulate TMS-induced oscillations and ongoing oscillatory activity. In some aspects, at certain plasma concentrations (e.g., 50 ng / mL or greater), 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) relative to placebo (e.g., by 40% or greater) and / or increases beta (13-30 Hz) TMS-induced power (220-310 ms) following a TMS pulse relative to placebo (e.g., by 40% or greater). In some aspects, at 2 hours post-administration, Compound A reduces initial theta TMS-induced oscillations following a TMS pulse relative to placebo (e.g., by 30% or greater). In some aspects, at 4 hours post-administration, Compound A reduces alpha TMS-induced oscillations following a TMS pulse relative to placebo (e.g., by 30% or greater). In some embodiments, Compound A reduces theta TMS-induced oscillations following a TMS pulse relative to placebo (eg, by 30% or more) 6 hours after administration.

[0123] In some embodiments, oral administration of Compound A according to the methods and uses described herein can modulate resting EEG. In some aspects, at a certain plasma concentration (e.g., 50 ng / mL or higher), Compound A increases the power of one or more of the delta band, theta band, or beta band compared to placebo (e.g., 50% or higher). In some aspects, Compound A increases the power of one or more of the delta band, theta band, delta band, beta band, or alpha band compared to placebo (e.g., 40% or higher) at 2 hours, 4 hours, and 6 hours after administration.

[0124] In some embodiments, the methods and uses described herein administer 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, the composition is a unit dose.

[0125] Examples of pharmaceutically acceptable oral compositions containing Compound A include solid formulations (such as tablets, capsules, lozenges, dragees, granules, powders, multiparticulates, and films) and liquid formulations (such as aqueous solutions, elixirs, tinctures, suspensions, and dispersions). In one embodiment, pharmaceutically acceptable oral compositions of Compound A include pediatric suspensions or granules. All of the above amounts of Compound A may be included in such formulations, including, 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 is provided for oral administration of Compound A in the fed state to enhance the bioavailability and exposure of Compound A upon oral administration. Such a kit includes multiple oral dosage unit forms of Compound A in combination with instructions for oral administration of Compound A in the fed state.

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

[0128] In one embodiment of the present disclosure, the C max C after oral administration of a therapeutically effective amount of Compound A in the postprandial state max The ratio is over 1.3.

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

[0130] In one embodiment of the present disclosure, the therapeutically effective amount of Compound A is from about 0.05 mg / kg to about 2.0 mg / kg.

[0131] In certain embodiments of the invention where a comparison is made involving humans administered oral Compound A in the fasted state, similar comparisons can be made involving humans who have not ingested food from about 4 hours before oral administration of Compound A to about 4 hours after oral administration of Compound A, e.g., from about 4 hours, about 3 hours, about 2 hours, about 1.5 hours, about 1 hour, or about 0.5 hours before oral administration of Compound A to about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 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 is selected from the group consisting of partial onset (focal) seizures, photosensitive epilepsy (light-sensitive seizures), self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorders, 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 seizure disorder is 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 syndrome, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. In one embodiment, the seizure disorder is focal onset epilepsy, also known as partial onset (focal) epilepsy.

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

[0134] Numbered Embodiments Embodiment 1. A method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human being in need thereof, comprising orally administering to said human a therapeutic amount of Compound A in the postprandial state, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

[0135] Embodiment 2. A method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human being in need thereof, comprising orally administering to said human a therapeutic amount of Compound A between 30 minutes before and 2 hours after a meal, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

[0136] Embodiment 3 The method of embodiment 1 or embodiment 2, wherein said method increases the opening of Kv7 potassium channels.

[0137] Embodiment 4. The method of 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 of embodiment 4, wherein said method is selective for enhancing opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 over Kv7.1.

[0139] Embodiment 6 The method of any one of embodiments 1 to 5, wherein the disease, disorder, or condition is a seizure disorder.

[0140] Embodiment 7 The method of embodiment 6, wherein the seizure disorder is focal-onset epilepsy.

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

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

[0143] Embodiment 10. A method of treating a seizure disorder in a human being in need thereof, comprising orally administering to said human being in a postprandial state an amount of Compound A, 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 of treating a seizure disorder in a human being in need thereof, comprising orally administering to said human an amount of Compound A between 30 minutes before and 2 hours after a meal, 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 of treating a seizure disorder in a human in need thereof, comprising orally administering to said human Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the improvement comprising orally administering said Compound A to said human in a postprandial state.

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

[0147] Embodiment 14. A method of orally administering Compound A to a human being in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the improvement comprising orally administering said Compound A to said human being in a fed state.

[0148] Embodiment 15. A method of orally administering Compound A to a human being in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the improvement comprising orally administering said Compound A to said human being between 30 minutes before and 2 hours after a meal.

[0149] Embodiment 16. The method comprises administering to said human a dose of Compound A in a fasted state compared to the same amount of Compound A administered orally to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The method of any one of embodiments 8 to 15, wherein one or more of:

[0150] Embodiment 17. C of Compound A in humans receiving oral administration of Compound A max , AUC inf , T max , or t1 / 2 λz orally administering to the human in a fed state an amount of Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the method increases C compared to when the same amount of Compound A is orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz A method to increase one or more of the above.

[0151] Embodiment 18. C of Compound A in humans receiving oral administration of Compound A max , AUC inf , T max , or t1 / 2 λz orally administering to the human an amount of Compound A between 30 minutes before and 2 hours after a meal, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein the method increases C compared to when the same amount of Compound A is orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz A method to increase one or more of the above.

[0152] Embodiment 19. A method of orally administering Compound A to a human being in need thereof, comprising orally administering Compound A to said human being in a fed state, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein said method results in a C of Compound A compared to when the same amount of Compound A is orally administered to said human being in a fasted state.max , AUC inf , T max , or t1 / 2 λz A method to increase one or more of the above.

[0153] Embodiment 20. A method of orally administering Compound A to a human being in need thereof, comprising orally administering Compound A to said human being between 30 minutes before and 2 hours after a meal, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein said method reduces Cmax of Compound A compared to when the same amount of Compound A is orally administered to said human being in a fasted state. max , AUC inf , T max , or t1 / 2 λz A method to increase one or more of the above.

[0154] Embodiment 21. A method of reducing a dose of Compound A orally administered to a human in need thereof as part of a treatment regimen, comprising orally administering a reduced dose of Compound A to said human in a fed state, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and said reduced dose is greater than or equal to the C of Compound A when orally administered to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz A method in which the dose is lower than the dose required to achieve one or more of the following:

[0155] Embodiment 22. A method of reducing the dose of Compound A orally administered to a human in need thereof as part of a treatment regimen, comprising orally administering a reduced dose of Compound A to said human between 30 minutes before and 2 hours after a meal, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and said reduced dose is equal to or greater than the C of Compound A when orally administered to said human in a fasted state. max, AUC inf , T max , or t1 / 2 λz A method in which the dose is lower than the dose required to achieve one or more of the following:

[0156] Embodiment 23. Oral administration of Compound A to said human results in a Cmax of Compound A compared to when the same amount of Compound A is administered orally to said human in the fasted state. max 23. The method of any one of embodiments 16 to 22, wherein the

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

[0158] Embodiment 25. C after oral administration of Compound A in the fasted state max C after oral administration of Compound A to max 24. The method of embodiment 23, wherein the ratio is greater than 2.

[0159] Embodiment 26. C after oral administration of Compound A in the fasted state max C after oral administration of Compound A to max 24. The method of embodiment 23, wherein the ratio is greater than 3.

[0160] Embodiment 27. Compound A C max 24. The method of embodiment 23, wherein the increase in

[0161] Embodiment 28. Compound A C max 24. The method of embodiment 23, wherein the increase in is at least 100%.

[0162] Embodiment 29. Oral administration of Compound A to said human decreases the AUC of Compound A compared to the same amount of Compound A administered orally to said human in the fasted state. inf The method of any one of embodiments 16 to 28, wherein the

[0163] Embodiment 30. AUC after oral administration of Compound A in the fasted state inf AUC after oral administration of Compound A to inf 30. The method of embodiment 29, wherein the ratio is greater than 1.3.

[0164] Embodiment 31. AUC after oral administration of Compound A in the fasted state inf AUC after oral administration of Compound A to inf 30. The method of embodiment 29, wherein the ratio is greater than 1.5.

[0165] Embodiment 32. AUC after oral administration of Compound A in the fasted state inf AUC after oral administration of Compound A to inf 30. The method of embodiment 29, wherein the ratio is greater than 1.8.

[0166] Embodiment 33. AUC of Compound A inf 30. The method of embodiment 29, wherein the increase in

[0167] Embodiment 34. AUC of Compound A inf 30. The method of embodiment 29, wherein the increase in

[0168] Embodiment 35. Oral administration of Compound A to said human results in an increase in the T value of Compound A compared to when the same amount of Compound A is administered orally to said human in the fasted state. max The method of any one of embodiments 16 to 34, wherein the

[0169] Embodiment 36. T after oral administration of Compound A in the fasted state max T after oral administration of Compound A to max 36. The method of embodiment 35, wherein the ratio is greater than 1.3.

[0170] Embodiment 37. T after oral administration of Compound A in the fasted state max T after oral administration of Compound A to max 36. The method of embodiment 35, wherein the ratio is greater than 1.8.

[0171] Embodiment 38. T after oral administration of Compound A in the fasted state max T after oral administration of Compound A to max 36. The method of embodiment 35, wherein the ratio is greater than 2.

[0172] Embodiment 39. Compound A T max 36. The method of embodiment 35, wherein the increase in

[0173] Embodiment 40. Compound A T max 36. The method of embodiment 35, wherein the increase in

[0174] Embodiment 41. Oral administration of Compound A to said human reduces the t½ of Compound A compared to when the same amount of Compound A is administered orally to said human in the fasted state. λz The method of any one of embodiments 16 to 40, wherein the

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

[0176] Embodiment 43. t1 / 2 after oral administration of Compound A in the fasted state λz t1 / 2 after oral administration of Compound A to λz 42. The method of embodiment 41, wherein the ratio is greater than 1.4.

[0177] Embodiment 44. t1 / 2 of Compound A λz 42. The method of embodiment 41, wherein the increase in

[0178] Embodiment 45. t1 / 2 of Compound A λz 42. The method of embodiment 41, wherein the increase in

[0179] Embodiment 46. A method of treating a seizure disorder in a human in need thereof, comprising orally administering to said human Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein said method comprises, for Compound A: C of at least 40 ng / mL max , AUC of at least 2500 h·ng / mL inf , T of at least 3.25 hours max , or t1 / 2 of at least 130h λz A method that results in one or more of the following:

[0180] Embodiment 47. A method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human being in need thereof, comprising orally administering to the human being an amount of Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein the amount of Compound A is sufficient to increase RMT or AMT in the human being.

[0181] Embodiment 48. A method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human being in need thereof, comprising orally administering to said human being an amount of Compound A, 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.

[0182] Embodiment 49 The method of 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 of decreasing corticospinal or cortical excitability in a human being in need thereof, comprising orally administering to said human an amount of Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein the amount of Compound A is sufficient to decrease corticospinal or cortical excitability in said human being.

[0184] Embodiment 51. A method of decreasing corticospinal or cortical excitability in a human being in need thereof, comprising orally administering to said human an amount of Compound A, 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.

[0185] Embodiment 52 The method of any one of Embodiments 1 to 7 comprising orally administering 2 to 200 mg of Compound A.

[0186] Embodiment 53 The method of any one of Embodiments 8 to 52 comprising orally administering 2 to 100 mg of Compound A.

[0187] Embodiment 54 The method of embodiment 53 comprising orally administering 5 to 50 mg of Compound A.

[0188] Embodiment 55 The method of embodiment 53 comprising orally administering 10 mg, 20 mg, or 25 mg of Compound A.

[0189] Embodiment 56 The method of embodiment 53 comprising orally administering 20 mg of Compound A.

[0190] Embodiment 57 The method of any one of Embodiments 8 to 54 comprising orally administering at least 20 mg of Compound A.

[0191] Embodiment 58 The method of any one of Embodiments 8 to 57 comprising orally administering 5 to 500 mg of Compound A per day.

[0192] Embodiment 59 The method of embodiment 58 comprising orally administering 20 to 150 mg of Compound A per day.

[0193] Embodiment 60 The method of embodiment 58 comprising orally administering 100 mg of Compound A per day.

[0194] Embodiment 61 The method of any one of Embodiments 1 to 60, comprising orally administering 0.05 to 2.0 mg / kg of Compound A.

[0195] Embodiment 62 The method of embodiment 61 comprising orally administering 0.1 to 1.0 mg / kg of Compound A.

[0196] Embodiment 63 The method of embodiment 61 comprising orally administering 0.2 to 0.5 mg / kg of Compound A.

[0197] Embodiment 64. A compound for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human being in need thereof, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is orally administered to the human being in the fed state.

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

[0199] Embodiment 66 A compound for use according to embodiment 63 or embodiment 64, wherein said method increases the opening of Kv7 potassium channels.

[0200] Embodiment 67. The compound for use according to embodiment 65, wherein said 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 said method is selective for enhancing the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 over Kv7.1.

[0202] Embodiment 69. A compound for use according to any one of embodiments 63 to 67, wherein the disease, disorder or condition is a seizure disorder.

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

[0204] Embodiment 71. A compound for use in treating a seizure disorder in a human being in need thereof, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is orally administered to the human being in the fed state.

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

[0206] Embodiment 73. Oral administration of the compound increases the C of the compound compared to the same amount of the compound administered orally to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The compound for use according to embodiment 56 or embodiment 57, which increases one or more of:

[0207] Embodiment 74. A compound for use, comprising: a compound having a C C of the compound in a human receiving oral administration of the compound; max , AUC inf , T max , or t1 / 2 λz wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and wherein the compound is orally administered to the human in a fed state, and wherein the oral administration of the compound increases C compared to the same amount of the compound administered orally to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The compound for use in elevating one or more of the following:

[0208] Embodiment 75. A compound for use, comprising: a C β -reactive protein (C β -reactive protein) of the compound in a human receiving oral administration of the compound; max , AUC inf , T max , or t1 / 2 λz and wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is orally administered to the human between 30 minutes before a meal and 2 hours after a meal, and the oral administration of the compound reduces C compared to the same amount of the compound administered orally to the human in a fasted state. max , AUC inf , T max , or t1 / 2λz The compound for use in elevating one or more of the following:

[0209] Embodiment 76. A compound for use in reducing the dose of said compound orally administered to a human in need thereof as part of a treatment regimen, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the reduced dose of the compound is orally administered to the human in a fed state, and the reduced dose achieves the same C of the compound when orally administered to the human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The compound for use is at a dose lower than that required to achieve one or more of the following:

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

[0211] Embodiment 78. Oral administration of the compound to the human increases the C of the compound compared to the same amount of the compound administered orally to the human in a fasted state. max The compound for use according to any one of embodiments 73 to 77, wherein the compound increases

[0212] Embodiment 79. C after oral administration of the compound in the fasted state max C after oral administration of the above compounds to 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 compound in the fasted state max C after oral administration of the above compounds to max The compound for use according to embodiment 78, wherein the ratio of is greater than 2.

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

[0215] Embodiment 82. C of the above compound max The compound for use according to embodiment 78, wherein the increase in

[0216] Embodiment 83. C of the compound max The compound for use according to embodiment 78, wherein the increase in

[0217] Embodiment 84. Oral administration of the compound to the human reduces the AUC of the compound compared to the same amount of the compound administered orally to the human in the fasted state. inf The compound for use according to any one of embodiments 73 to 78, wherein the compound increases

[0218] Embodiment 85. AUC after oral administration of the compound in the fasted state inf AUC after oral administration of the above compound 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 compound in the fasted state inf AUC after oral administration of the above compound 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 compound in the fasted state inf AUC after oral administration of the above compound inf The compound for use according to embodiment 84, wherein the ratio is greater than 1.8.

[0221] Embodiment 88. AUC of the compound inf The compound for use according to embodiment 84, wherein the increase in

[0222] Embodiment 89. AUC of the compound inf The compound for use according to embodiment 84, wherein the increase in

[0223] Embodiment 90. Oral administration of the compound to the human increases the T of the compound compared to the same amount of the compound administered orally to the human in a fasted state. max 90. The compound for use according to any one of embodiments 73 to 89, which increases

[0224] Embodiment 91. T after oral administration of the compound in the fasted state max T after oral administration of the above compounds to 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 compound in the fasted state max T after oral administration of the above compounds to 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 compound in the fasted state max T after oral administration of the above compounds to max The compound for use according to embodiment 90, wherein the ratio of is greater than 2.

[0227] Embodiment 94. T of the compound max The compound for use according to embodiment 75, wherein the increase in

[0228] Embodiment 95. T of the compound max The compound for use according to embodiment 90, wherein the increase in

[0229] Embodiment 96. Oral administration of the compound to the human increases the t½ of the compound compared to the same amount of the compound administered orally to the human in the fasted state. λz The compound for use according to any one of embodiments 73 to 95, wherein the compound increases

[0230] Embodiment 97. t1 / 2 after oral administration of the compound in the fasted state λz t1 / 2 after oral administration of the above compounds to 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 compound in the fasted state λz t1 / 2 after oral administration of the above compounds to λz The compound for use according to embodiment 96, wherein the ratio is greater than 1.4.

[0232] Embodiment 99. The t1 / 2 of the compound λz The compound for use according to embodiment 96, wherein the increase in

[0233] Embodiment 100. The t1 / 2 of the compound λz The compound for use according to embodiment 96, wherein the increase in

[0234] Embodiment 101. A compound for use in treating a seizure disorder in a human being in need thereof, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is orally administered to the human being, and the oral administration of the compound results in the compound: C of at least 40 ng / mL max , AUC of at least 2500 h·ng / mL inf , T of at least 3.25 hours max , or t1 / 2 of at least 130h λz The compound for use results in one or more of:

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

[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 said compound.

[0237] Embodiment 104. A compound for use in decreasing corticospinal or cortical excitability in a human being in need thereof, wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the compound is orally administered to the human being.

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

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

[0240] Embodiment 107. The compound for use according to embodiment 105, wherein 5 to 50 mg of said 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 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 said 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 said compound is administered per day.

[0245] Embodiment 112. The compound for use according to embodiment 111, wherein 20 to 150 mg of the compound is administered per day.

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

[0247] Embodiment 114. The compound for use according to any one of embodiments 64 to 113, wherein 0.05 to 2.0 mg / kg of said compound is administered.

[0248] Embodiment 115. The compound for use according to embodiment 114, wherein 0.1 to 1.0 mg / kg of said compound is administered.

[0249] Embodiment 116. The compound for use according to embodiment 114, wherein 0.2 to 0.5 mg / kg of said compound is administered.

[0250] Additional Numbered Embodiments Embodiment 1a. A method of treating a seizure disorder in a human, comprising orally administering a therapeutically effective amount of Compound A to said human in need thereof in the postprandial state.

[0251] Embodiment 2a. The method of Embodiment 1a, wherein oral administration of a therapeutically effective amount of Compound A to said human results in increased bioavailability and exposure of Compound A compared to the bioavailability and exposure of Compound A when administered orally in the fasted state.

[0252] Embodiment 3a. Oral administration of a therapeutically effective amount of Compound A results in a maximum plasma concentration of Compound A when administered orally in the fasted state (C max ) and Compound A exposure (AUC) compared to Compound A C max 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 the fasted state max C after oral administration of a therapeutically effective amount of Compound A in the postprandial state max The method of embodiment 3a, wherein the ratio is greater than 1.3.

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

[0255] Embodiment 6a. The method of any one of Embodiments 1a through 5a, wherein said therapeutically effective amount of Compound A is from about 0.05 mg / kg to about 2.0 mg / kg.

[0256] Embodiment 7a. A method of increasing the bioavailability and exposure of Compound A in a human receiving oral administration of a therapeutically effective amount of Compound A for the treatment of a seizure disorder, comprising orally administering said therapeutically effective amount of Compound A to said human in a fed state.

[0257] Embodiment 8a. Oral administration of a therapeutically effective amount of Compound A results in a maximum plasma concentration of Compound A when administered orally in the fasted state (C max ) and Compound A exposure (AUC) compared to Compound A C max 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 the fasted state max C after oral administration of a therapeutically effective amount of Compound A in the postprandial state max The method of embodiment 8a, wherein the ratio is greater than 1.3.

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

[0260] Embodiment 11a. The method of any one of Embodiments 7a through 10a, wherein said therapeutically effective amount of Compound A is from about 0.05 mg / kg to about 2.0 mg / kg. [Example]

[0261] The following study was conducted to determine the effect of food, if any, on the bioavailability and exposure of Compound A when administered orally. Further studies were conducted to assess the effect, if any, of Compound A on cortical excitability using transcranial magnetic stimulation (TMS).

[0262] 1. Example 1. Non-human primate studies The following study was conducted to determine the effect of food when Compound A was orally administered to non-human primates.

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

[0264] A certified primate diet (Teklad® Certified Diet 2050C) was fed during the study. For Group 1, three monkeys were fasted overnight with food returned four hours after dosing. For Group 2, the same three monkeys were fasted overnight and food was provided approximately one hour before dosing with food returned four hours after dosing. Table 1 below provides the food intake for Group 2.

[0265] [Table 1]

[0266] 1.2. Oral Dosage Units The oral dosage unit consisted of approximately 3 mg / kg of Compound A in a capsule. The capsules were filled the morning of dose administration and kept at room temperature until dosing. The remaining capsules were placed in storage at -20°C.

[0267] 1.3. Oral Unit Dosage Administration The capsule was placed as far back in the animal's mouth as possible using a pill gun or modified gavage 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 was dosed twice with a 96-hour washout period between doses. See Table 2 below for details.

[0268] Group 1: All animals were weighed in the afternoon prior to dose administration. Animal number 2 struggled with dosing. After several attempts, the animal was given a break and was finally successfully dosed.

[0269] Group 2: All animals were weighed on the morning of dosing. All animals were dosed without incident.

[0270] [Table 2]

[0271] 1.4. Blood Collection Whole blood (approximately 2.0 mL) was collected from the cephalic or saphenous vein using a syringe and needle, transferred to a vacutainer tube containing K2EDTA, and kept on wet ice until processed for plasma. Blood samples were collected at time of dosing (0.0 h, time zero) and 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose.

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

[0273] All samples were processed according to standard procedures for bioanalytical 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 max No significant food effect was observed on either the mean mean or AUC. Figure 1 presents the data from Table 5 in graphical form.

[0280] 2. Example 2. Human studies To evaluate the effect of food on the bioavailability and exposure of Compound A, an open-label, randomized, two-period, fed / fasted crossover study was conducted in nine healthy adult, non-smoking male and female (non-childbearing potential only) human subjects aged 18 to 55 years.

[0281] The study consisted of two treatment periods, Period 1 and Period 2. Each treatment period consisted of 7 days, with Compound A dosing on Day 1. These two treatment periods were separated by a 10-day washout period. Subjects were randomized into two groups. During Treatment Period 1, one group received an oral dose of Compound A in the fasted state, while the other group received an oral dose of Compound A in the fed state. The group that was fasted during Treatment Period 1 was fed during Treatment Period 2, and the group that was fed during Treatment Period 1 was fasted during Treatment Period 2.

[0282] On day 1 of each treatment period, each subject received 20 mg of Compound A orally (4 capsules of 5 mg Compound A each).

[0283] During the feeding period after at least a 10-hour overnight fast, a standard high-fat, high-calorie breakfast was provided per FDA guidelines. This breakfast was served 30 minutes before the scheduled dosing time and completed 10 minutes before dosing. A typical breakfast included two slices of buttered toast, two fried eggs, two slices of bacon, 4 ounces of hash browns, and 8 ounces of whole milk. Subjects did not eat or drink anything for at least four hours after dosing.

[0284] During the fasting period, dosing occurred after an overnight fast of at least 10 hours. No food was allowed for 4 hours after dosing, whether during the fed or fasted period. Water was allowed as desired, except for 1 hour before and after dosing.

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

[0286] 2.1.Results The plasma concentrations (ng / mL) of Compound A in subjects who received an oral dose of Compound A in the fed state are shown in Table 7 below.

[0287] Plasma concentrations (ng / mL) of Compound A in subjects who received an oral dose of Compound A in the fasted state are shown in Table 8 below.

[0288] The mean plasma concentrations (ng / mL) of Compound A in subjects receiving an oral dose of Compound A in the fed state versus the mean plasma concentrations (ng / mL) of Compound A in subjects receiving an oral dose of Compound A in the fasted state are shown graphically in Figure 2.

[0289] The pharmacokinetic parameters for subjects who received 20 mg of Compound A orally in the fed state are shown in Table 9 below.

[0290] Pharmacokinetic parameters for subjects receiving 20 mg of Compound A orally in the fasted state are shown in Table 10 below.

[0291] [Table 7]

[0292] [Table 8]

[0293] [Table 9]

[0294] [Table 10]

[0295] The pharmacokinetic results of this study demonstrate that the bioavailability and exposure of Compound A when administered orally in the fed state was significantly increased compared to the bioavailability and exposure of Compound A when administered orally in the fasted state. These results were unexpected given the results of the non-human primate study shown in Example 1 above, in which no food effect was observed.

[0296] 3. Example 3. Studies 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 ascending dose and multiple ascending dose (SAD and MAD) studies.

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

[0298] Repeat doses of Compound A (15 mg once daily) were evaluated over 7 and 10 days in the fasted and fed state, respectively. Repeat doses of Compound A (25 mg once daily) were also evaluated over 10 days in the fed state.

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

[0300] Pharmacokinetics Compound A exhibited a PK profile with a low peak-to-trough ratio, suitable for once-daily dosing. Compound A had less than dose-proportional exposure in the fasted state, but absorption was enhanced by food (AUC inf With multiple doses in the postprandial state, exposure increased proportionally with dose. Apparent steady state was achieved by days 6 to 9, based on 90% CIs for successive-day exposure ratios ranging from 0.8 to 1.25.

[0301] [Table 11]

[0302] [Table 12]

[0303] 3.3. Safety Single and multiple doses of Compound A produced individual C values ​​up to 104 ng / mL and 107 ng / mL, respectively. max The study was well tolerated at the 2016 and 2017 levels. The majority of AEs were mild or moderate, self-resolving, and consistent with this class of antiepileptic drug (e.g., dizziness, sedation). There were no significant 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 PK profile, including an effective half-life of greater than 24 hours, supports a once-daily dosing schedule using an immediate-release formulation, with steady state achieved within one week without the need for dose titration.

[0306] 4. Example 4. Transcranial Magnetic Stimulation Pilot Study Transcranial magnetic stimulation (TMS), combined with electromyography (EMG) and electroencephalography (EEG), allows for the measurement of resting and active motor thresholds (RMT / AMT) and TMS-induced EEG potentials (TEP). The RMT / AMT and TMS-induced EEG potentials (TEP) can indicate drug effects on corticospinal and cortical excitability, respectively. Several antiepileptic drugs (AEDs) have been shown to significantly increase RMT and modulate TEP, indicating a shift toward corticospinal / cortical inhibition.

[0307] A pilot study used TMS to noninvasively determine whether Compound A (10 mg, 15 mg, and 20 mg) affected cortical excitability. This TMS pilot study was designed to inform sample size calculations 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, 2 hours, and 4 hours after Compound A administration. Spectral analysis was performed on resting EEG. To determine the effect of Compound A on TEP amplitude, analysis was performed at the single-subject level using multiple independent-samples t-tests. Multiple comparisons were accounted for using cluster-based permutation analysis (permutation analysis).

[0309] 4.2.Results Compound A suppressed TEP amplitude at late latencies (e.g., 1.92 ± 0.03 μV at the 180 ms peak (P180) after TMS, p<0.01, N=3) at 20 mg (Cplasma = 50 ± 10 ng / mL) 4 hours later. The 10 mg (N=2) and 15 mg (N=3) doses did not demonstrate significant robust TEP modulation, with mean Compound A plasma levels of 23.1 ng / mL and 36.3 ng / mL at 4 hours. At 4 hours after 20 mg, RMT increased 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 (but not SICI) assessed using TMS / EMG. Black bars indicate the effect 2 hours after drug administration, and gray bars indicate the effect 4 hours after drug administration (change from baseline as % maximum stimulus intensity, mean ± SEM). N=2 for 10 mg, N=3 for 15 mg and 20 mg. Compound A 10 mg did not change AMT. N=2 for 10 mg, N=3 for 15 mg and 20 mg.

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

[0312] The objectives of the 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 effects of Compound A compared to placebo on measures of cortical excitability assessed by TMS-electroencephalography (EEG) and TMS-electromyography (EMG).

[0313] Twenty healthy, right-handed male subjects were enrolled and randomly assigned (1:1 randomization ratio) to receive a single oral dose of Compound A 20 mg or placebo in a blinded manner on Day 1, followed by crossover to receive a single dose of the other treatment on Day 7.

[0314] Subjects were screened within 27 days prior to study entry on Day 1. For Period 1, subjects were admitted to the research unit, dosed on Day 1, and discharged on Day 2. For Period 2, after a 6-day washout period, the same subjects were again admitted to the research unit, dosed on Day 7, and discharged on Day 8. All subjects returned to the clinical unit for an outpatient visit on Day 14 and received a follow-up phone call on Day 37.

[0315] Subjects were dosed in the postprandial state, but the timing of dosing relative to food varied during the study, varying between a high-fat or standard meal taken 2 hours or 30 minutes before dosing, and a high-fat or standard meal taken 1 hour or 2.5 hours after dosing.

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

[0317] PK variables include maximum plasma concentration (C max ), maximum plasma concentration time (T max ), terminal elimination half-life (t1 / 2 ), elimination rate constant (λz), area under the curve from 0 to 24 hours (AUC 0-24h ), area under the time curve from 0 to the final quantifiable concentration (AUC 0-tlast ), the area under the time curve from 0 to infinity (AUC 0-inf ), the percentage of AUC by extrapolation from tlast to infinity (%AUC extrap ), apparent total body clearance (CL / F) after oral administration, body weight-normalized CL / F, mean residence time from time zero to the final quantifiable concentration (MRT last ), mean residence time (MRT) extrapolated to infinity inf ), apparent volume of distribution during the terminal phase (Vz / F), and Vz / F normalized by body weight.

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

[0319] 5.1. Pharmacokinetic analysis PK parameters for this study were summarized in two ways. First, PK parameters were calculated using PK samples collected during each 24-hour sampling period in Period 1 and Period 2, separately, when possible. Second, PK parameters were determined using samples beyond the 24-hour sampling period (i.e., from Days 7 / 8 and / or 14). For subjects who received Compound A in Period 1, additional PK time points beyond 24 hours were obtained from PK samples collected before placebo treatment. For subjects who received Compound A in Period 2, no PK time points beyond 24 hours were obtained until the inclusion of the PK sample on Day 14. Therefore, subjects randomized to receive Compound A in Period 2 and enrolled before the additional PK sample on Day 14 did not have PK data beyond 24 hours. The complete PK profile dataset consisted of the 16 subjects who had PK samples collected beyond 24 hours after dosing. For the following PK parameter discussion, the complete PK profile dataset was generally used because it allowed for more accurate estimation of PK parameters.

[0320] Initially, subjects were dosed 2 hours after a high-fat meal and then given a relatively high-fat lunch 1 hour after dosing. After blinded review of the PK profiles of the first 8 subjects, T max Reduce the fat content of lunch to shorten the time to C max The timing of the meal relative to dosing was changed from 2 hours to 30 minutes prior to dosing, followed by a reduction in the fat content of the 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 dosing, C max or T max Therefore, PK data are presented without categorization by meal type or relative timing of meals.

[0321] [Table 13]

[0322] 5.1.1. Plasma concentration Compound A plasma concentrations over time were recorded for the complete PK profile. At the 2-, 4-, and 6-hour TMS time points, 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] Average C for each period max or T max No differences were observed in the total time to peak plasma concentration (Table 14). The total time to peak plasma concentration ranged from 1.9 to 12 hours, with a median time of 7.8 hours, indicating that TMS assessments performed at 2, 4, and 6 hours were consistent with TMS in the majority of subjects. max It was shown that this was done before.

[0324] Subjects who received placebo in Period 2 had low but measurable Compound A concentrations at the start of the placebo treatment period and max The mean 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 Other PK parameters are summarized in Table 15. Mean AUC last was 2370 ng·h / mL, which included PK samples taken at follow-up visits when available. AUC from the same dataset inf The mean mean plasma concentration was 3155 ng·h / mL, with a median (range) extrapolated area of ​​19.9% ​​(range 10.6–40.5%). This relatively high level of extrapolated area in several subjects was due to the high λz-derived parameters (half-life, MRT infThis suggests that the drug's drug delivery parameters (e.g., drug release rate, clearance, and volume of distribution) should be analyzed with caution and may have higher inherent variance in their calculations.

[0327] The mean normalized volume of distribution (Vz / F) of 16.3 L / kg well exceeded the total blood volume of the mean body weight of 72.3 kg, indicating that the drug was distributed from the plasma into 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 is the plasma clearance, not the blood clearance. However, this is well below the total hepatic blood flow of 17 mL / min / kg, even after adjusting for hematocrit (Carlisle et al., Gut 1992, 33:92-97), suggesting a poorly extracted drug.

[0329] [Table 15]

[0330] 5.1.3. Pharmacokinetic Conclusions Compound A was slowly absorbed after a 20 mg oral dose, with median peak plasma concentrations occurring approximately 8 hours after administration. Once absorbed, Compound A was distributed from plasma to surrounding tissues and slowly removed from the systemic circulation at a rate significantly below hepatic blood flow, indicating minimal extraction (metabolism) from the liver. 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 underestimate, as some subjects had %AUC values ​​greater than 20% and as high as 40%. extrap Because it had value.

[0331] The washout period between periods was insufficient for Compound A concentrations to fall below the limit of quantitation in subjects receiving placebo in Period 2 (mean 3.1 ng / mL, range 1.3–6.8 ng / mL).

[0332] 5.2. Pharmacodynamic analysis All 20 subjects underwent TMS-EMG and TMS-EEG sessions before dosing and 2 and 4 hours after dosing on days 1 and 7. Due to the prolonged absorption phase for Compound A revealed by pharmacokinetic analysis, an extra measurement was added 6 hours after drug ingestion. For this 6-hour time point, 16 subjects underwent RMT, and 8 subjects underwent AMT, resting EEG, and TMS-EEG.

[0333] Subject 912 did not undergo any PD assessments at the 2 hour time point during the Compound A treatment period due to an adverse reaction (vomiting). Due to technical issues, the TMS procedure for Subject 940 could not be completed during Hour 2 of the placebo treatment period, so this subject only underwent RMT and resting-state EEG procedures during Hour 2.

[0334] Compound A-induced modulation of PD markers was assessed as an effect of time (2, 4, and 6 hours post-dose compared with pre-dose) and concentration (using post-dose measurements taken at the time of maximum drug exposure versus baseline).

[0335] Analyses were performed for all subjects (n=20) and for subjects (n=16) who had drug plasma concentrations higher than the maximum detected as carryover in the placebo group (Table 16).

[0336] [Table 16]

[0337] 5.2.1.TMS-induced EGG potential TMS-induced EEG potentials (TEPs) were calculated by averaging artifact-free EEG test results in the different experimental conditions (Table 17).

[0338] [Table 17]

[0339] The following TEP components (P = positive, N = negative) were studied according to the literature. Values ​​in parentheses are times of interest (TOI): P25 (15–35 ms), N45 (35–70 ms), P70 (70–80 ms), N100 (80–145 ms), and P180 (145–230 ms). TOIs were selected based on grand-averaged (all-subjects, all-response average) TEPs and were kept identical during analysis of pre- and post-administration measurements, as well as across conditions. To analyze drug-induced modulation of TEPs, we selected a region of interest (ROI) consisting of 27 channels above and surrounding 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- vs. pre-administration) were applied for each TOI at all electrodes within the indicated ROI. To correct for multiple comparisons (i.e., electrodes, time points), we performed a nonparametric cluster-based permutation analysis, as implemented in FieldTrip.

[0341] The spatiotemporal profile of TMS-induced EEG potentials is consistent with previous reports (Figure 4A). Early components (N15, P25) are located primarily in the stimulated left M1, followed by a prominent negativity over the contralateral site corresponding to the N45 potential. Finally, the N100 and P180 components confirm their optimal topographical reproducibility over the left central and central frontal regions, respectively (Figure 4B). Comparison between pre-treatment conditions (placebo vs. Compound A) showed no significant differences (p>0.05). These results apply to data sets of n = 20 and n = 16. Figure 4 shows that Compound A significantly modulated early TEPs (N45 and P180).

[0342] Concentration analysis (N = 16): Cluster-based permutation analysis was applied between the post- and pre-administration conditions to examine the effect of Compound A at the highest plasma concentration available during the TMS assessment time point. While a time-matched placebo did not show any significant changes, Compound A reduced the amplitude of the early TEP component measured at 15–35 ms (peak-to-peak amplitude of the early complex wave N15–P25: 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 4D and 5). Figure 6 shows that Compound A significantly modulates TEPs and reduces cortical excitability.

[0343] Temporal analysis (subjects with drug exposure at the time of measurement): Cluster-based permutation analysis was applied between post-dose and pre-dose conditions to examine the effects of Compound A at 2 hours (n = 15), 4 hours (n = 16), and 6 hours (n = 7) post-dose in subjects with sufficient Compound A exposure during the first 6 hours. Compared to pre-dose, the first N15-P25 complex was reduced at 2 hours (p = 0.008) and 4 hours (p = 0.02). Furthermore, at 4 hours post-dose, Compound A significantly suppressed N45 (p = 0.03), N100 (p = 0.04), and P180 (p = 0.004) (Figure 7).

[0344] No other comparisons were statistically significant (p>0.05) and placebo did not induce any significant changes (p>0.05).

[0345] Temporal analysis (all available subjects): Cluster-based permutation analysis was applied between the post- and pre-dose conditions to examine the effects of Compound A at 2 hours (n = 19), 4 hours (n = 20), and 6 hours (n = 8) post-dose in all available subjects. Compared with pre-dose, the first N15-P25 complex was reduced at 2 hours (p = 0.006) and 4 hours (p = 0.01). Furthermore, at 4 hours post-dose, Compound A significantly suppressed N45 (p = 0.03) and P180 (p = 0.02). This indicates that Compound A modulates TEPs and reduces cortical excitability.

[0346] No other comparisons were statistically significant (p>0.05) and placebo did not induce any significant changes (p>0.05).

[0347] 5.2.2.TMS induced vibration Single-pulse TMS delivered over the left motor cortex produced a series of changes in the power of ongoing oscillatory activity. At baseline, before drug intake, TMS induced an early increase in theta / alpha power, followed by a decrease in beta power (desynchronization), and a final late response of increased beta power.

[0348] The effects of active compounds on TMS-induced oscillations were then analyzed by cluster-based permutation analysis, following the same procedure employed in the analysis of TEPs. TMS-induced oscillations in theta (4-7 Hz), alpha (8-12 Hz), and beta (13-30 Hz) frequencies were compared between drug conditions from 30 ms (the first time-frequency point considered artifact-free) to 800 ms. This method was preferred instead of a set of predetermined time windows, given the lack of consensus on the time window of interest that should be used for TMS-induced oscillation analysis. Furthermore, this cluster-based statistical approach is appropriate for exploratory analyses, as it minimizes false positives associated with testing multiple time points.

[0349] Concentration analysis (N = 16): Cluster-based permutation analysis was applied between post- and pre-treatment conditions to test the effect of Compound A at the highest plasma concentration present during TMS assessment. Compound A suppressed early theta TMS-induced oscillations (p < 0.001; significant effect from 30 ms to 390 ms), 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] No other comparisons were statistically significant (p>0.05) and placebo did not induce any significant changes (p>0.05).

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

[0352] No other comparisons were statistically significant (p>0.05) and placebo did not induce any significant changes (p>0.05).

[0353] Temporal analysis (all available subjects): Cluster-based permutation analysis was applied between the post- and pre-administration conditions to examine the effects 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 trend toward suppressing 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 250 ms to 400 ms). Finally, at 6 hours post-administration, results showed a significant reduction in theta-induced oscillations (p = 0.03; significant effect from 80 ms to 300 ms) and a trend toward suppressing the alpha band (trend p = 0.07; 270 ms to 390 ms).

[0354] No other comparisons were statistically significant (p>0.05) and placebo did not induce any significant changes (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. A frequency resolution of 0.5 Hz was used to estimate power at all frequencies between 2 and 30 Hz. Differences between drug conditions on all EEG sensors were tested using nonparametric, paired t-tests based on a permutation approach (1500 permutations).

[0356] Concentration analysis (N=16): During high plasma exposure to Compound A, resting oscillatory activity was significantly modulated, 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), and all other comparisons were non-significant.

[0357] The difference between post-dose and pre-dose states within each drug condition was calculated, and then the calculated difference (post-dose minus pre-dose) 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] Temporal analysis (subjects with drug exposure at the time of measurement): Cluster-based permutation analysis was applied between post-dose and pre-dose conditions to examine the effects of Compound A at 2 hours (n=15), 4 hours (n=16), and 6 hours (n=7) post-dose.

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

[0360] Placebo caused an increase in the theta band 4 hours after drug intake (p=0.003), but all other comparisons were not statistically significant (p>0.05).

[0361] Temporal analysis (all available subjects): A cluster-based permutation analysis was applied between post-drug and pre-drug conditions to test the effects 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 an increase in power in the delta (2 hours post-dose vs. pre-dose: two clusters p=0.02 and p=0.04; 4 hours post-dose vs. pre-dose: two clusters p=0.004 and p=0.01; 6 hours post-dose vs. pre-dose: p=0.05) and theta bands (4 hours post-dose vs. pre-dose: p<0.001; 6 hours post-dose vs. pre-dose: p=0.009), alpha band (6 hours post-dose vs. pre-dose: p=0.04), and beta band (6 hours post-dose vs. pre-dose: p=0.04), but all other comparisons were not statistically significant (p>0.05).

[0364] TMS-EMG RMT and AMT values ​​are reported as a percentage of maximal stimulation intensity (%MSO). Drug-induced modulation of TMS-EMG parameters was assessed over three time points (2 h, 4 h, and 6 h) and for the time point with the highest drug exposure.

[0365] 5.2.4.1. Resting Motor Threshold For all 20 subjects, the individual and average RMT values ​​at baseline and the change at each time point for Compound A and placebo are presented in Table 18. Four subjects (901, 925, 928, and 930) did not have high drug exposure during TMS measurement. In addition, 2 hours after taking Compound A, RMT could not be recorded for subject 912.

[0366] [Table 18]

[0367] There were no significant differences from baseline in either group. Compound A treatment 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 Compound A plasma concentration, with the effect on RMT being >4% at 6 hours post-dose. Figure 8 shows that RMT increased proportionally with Compound A plasma concentration, 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. Active motor threshold AMT was recorded while subjects pressed the manometer at 20% of their individual maximum contraction force.Table 19 shows the individual AMT values ​​and average AMT values ​​at each time point for Compound A and placebo.For subject 912 and subject 940, AMT could not be recorded 2 hours after taking Compound A and placebo, respectively.

[0369] There was no significant difference between baseline values ​​in either group. AMT increased after treatment with Compound A. The change from baseline in AMT for Compound A was significantly different from placebo at 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 conditioning test stimulus pairs presented in random order with an inter-stimulus interval (ISI) of 2 ms, where the conditioning stimulus was set at 80% of the AMT and the suprathreshold stimulus was set at 120% RMT.

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

[0373] SICI values ​​(mean conditioned MEP / mean unconditioned MEP) are reported for each individual, experimental session, and Compound A dose (Table 20). Means and SDs are also reported for each condition. There were no significant findings.

[0374] [Table 20]

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

[0376] 5.3.TMS-EMG Measurement Motor threshold (at rest and during muscle contraction activity) has been linked to ion channel conductivity and therefore to neuronal membrane excitability, as several antiepileptic drugs (AEDs) acting on sodium channels (i.e., lamotrigine, carbamazepine; Ziemann et al., J. Int. Fed. Clin. Neurophys. 2015, 126:1847-1868) and several AEDs acting on potassium channels (i.e., retigabine; Ossemann et al., Epilepsy Res. 2016, 126:78-82) increased motor threshold (at rest and during muscle contraction activity).

[0377] Additionally, intracortical inhibition can be tested by SICI, a well-established TMS-paired pulse paradigm that can assess synaptic excitability of interneurons within the stimulated motor cortex and has been linked to GABA-A receptor-mediated neurotransmission.

[0378] The results showed that Compound A significantly affected motor threshold, indicating a decrease in corticospinal excitability. RMT was specifically modulated in a time-dependent and plasma concentration-dependent manner compared to placebo. At 2, 4, and 6 hours after administration, a single 20 mg dose of Compound A increased 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 modulated to a lesser extent and was significantly different from placebo only 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, lowering of motor threshold is thought to occur via increased excitability of corticospinal output, spinal motor neurons, or both. Subthreshold activation of the former components, which are likely also targeted by TMS, explains why AMT is less likely to be elevated than RMT by drugs acting on membrane ion channels. During voluntary muscle activation, many physiological and anatomical factors play a role in addition to those directly activated by TMS, which may explain why drug-induced modulation of AMT is more limited than RMT. Finally, the lack of effect on SICI indicates that Compound A does not alter GABA-A receptor-mediated intracortical inhibition. This result is consistent with TMS-EMG reports of retigabine ( Ossemann et al., 2016 ) and sodium channel blockers ( Ziemann et al., 1996 ).

[0380] 5.4.TMS-EEG Measurements Compound A significantly modulated TMS-EEG and resting EEG power, exhibiting a unique fingerprint at peak drug plasma concentrations. Additionally, this drug-induced modulation was followed by drug plasma exposure with the strongest effect 4 hours after drug administration (Table 21).

[0381] [Table 21]

[0382] Additional measures of cortical excitability, including global mean field power, were similarly affected. Global mean field power (GMFP) represents the overall amount of electrical activity induced by TMS. Figure 12 shows that Compound A induces a decrease in cortical excitability over time with prolonged absorption. Compound A also shifted the power spectrum of the resting EEG toward lower frequencies.

[0383] TMS-EEG allows for the measurement of the pharmacological effects of drugs acting within the brain. This modality is particularly attractive for epilepsy research, where, despite a wide range of AEDs, seizures remain refractory to treatment in 30% of cases, making long-term treatment outcomes unpredictable (Kwan and Brodie, N. Engl. J. Med. 2000, 342:314-319). Lamotrigine and levetiracetam, two of the most commonly prescribed AEDs, have previously been 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 system level, both drugs increased the amplitude of the 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 statistically significant modulation of TEPs in a manner consistent with a reduction in cortical excitability. At the time of peak plasma levels during the TMS assessment, Compound A reduced the amplitude of the initial N15-P25 complex compared with time-matched placebo, and the N45 and P180 potentials provided a unique fingerprint. While the N15 component is generated in the ipsilateral premotor cortex, the origin of the P25 is less clear, but it may reflect activity around the ipsilateral sensorimotor / premotor boundary, the ipsilateral superior cingulate cortex or supplementary motor area, or the contralateral cortex (Maki and Ilmoniemi, Neurosci. Lett. 2010, 478:24-28). The N15-P25 complex inversely correlates with MEP amplitude and thus provides information about the excitability of the stimulated area. Following this interpretation, the reduction in the peak-to-peak amplitude of these early components may reflect a drug-induced decrease in cortical excitability. Over time, Compound A suppressed the N45 amplitude, which has been linked to GABA-A receptor-mediated neurotransmission in studies using benzodiazepines as GABAergic positive modulators to manipulate TEP (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 reduced N45 could reflect less GABA-A receptor-mediated inhibition due to activation of presynaptic GABA-A receptors, which reduces GABA release into the synaptic cleft. Alternatively, the TMS response may not have propagated to the contralateral hemisphere, given the overall increase in cortical inhibition, implying a reduction in N45 amplitude across distant sites. Finally, the reduction in the P180 component is consistent with observations from other AEDs (Premoli et al., 2016).

[0385] In addition to TEPs, brain responses to TMS can be examined by applying time-frequency analysis at the single-trial level, which removes the evoked (i.e., TEP) component from the signal. TMS-induced oscillations are the result of this analysis approach, and they provide neural information on phase desynchronization (Premoli et al., Neuroimage 2017, 163:1-12). The effects of compounds acting on GABAergic neurotransmission on TMS-induced oscillations showed that early alpha synchronization was increased by GABA-A agonists and decreased by GABA-B agonists, late alpha desynchronization was increased by GABA-B agonists, and late beta desynchronization was increased by GABA-A agonists and GABA-B agonists.

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

[0387] The TMS-EMG and TMS-EEG results indicate that 20 mg of Compound A affects cortical excitability upon crossing the blood-brain barrier, as evidenced by modulation of a series of PD markers. The intrinsic properties of neuronal membranes and the levels of cortical excitation and inhibition are relevant points in epileptic seizures. Therefore, these research endpoints may play a crucial role in determining the therapeutic efficacy of Compound A in epileptic patients. For example, RMT is lower and intracortical inhibition is impaired in drug-naive patients compared with healthy controls. For this particular compound, changes in RMT and other PD markers before and after treatment can be used to evaluate the therapeutic response 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 are hereby incorporated by reference in their entirety, including U.S. Provisional Application No. 62 / 670,354, filed May 11, 2018.

[0389] Although the above compositions, methods, and uses have been described in some detail for ease of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments should be considered as illustrative and not restrictive, and the claimed invention 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. 1. Use of an agent in the manufacture of a medicament for the treatment of a human in need thereof, comprising: the agent is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The use, wherein the drug is orally administered to the human between 2 hours before and 2.5 hours after a meal.

2. 2. The use according to claim 1, wherein the medicament is for the treatment of a seizure disorder.

3. The seizure disorder is selected from the group consisting of partial onset (focal) seizures, photosensitive epilepsy (photosensitive seizures), self-induced syncope, intractable 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), myoclonic absence epilepsy, and Otawara syndrome.

3. The use according to claim 2, wherein the disease is selected from the group consisting of: rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis syndrome ...

4. 4. The use according to claim 3, wherein the seizure disorder is focal-onset epilepsy.

5. The use described in any one of claims 2 to 4, wherein the treatment treats the seizure disorder.

6. The use described in any one of claims 2 to 4, wherein the treatment slows or stops the progression of the seizure disorder.

7. The use described in any one of claims 2 to 4, wherein the treatment improves the seizure disorder.

8. The use of claim 5, wherein the treatment of the seizure disorder includes reducing seizure frequency, seizure severity, or both.

9. The use according to any one of claims 1 to 8, wherein the medicament is orally administered to the human between 30 minutes before and 2 hours after a meal.

10. The use described in any one of claims 1 to 9, wherein the diet is a standard diet.

11. The use described in any one of claims 1 to 9, wherein the feeding is a high-fat diet and / or a high-calorie diet.

12. The use according to any one of claims 1 to 11, wherein the medicament is for oral administration during or within 15 minutes after eating.

13. the oral administration results in a C of the agent compared to the same amount of the agent administered orally to the human in a fasted state from at least 2 hours before oral administration through 2.5 hours after oral administration. ｍａｘ , AUC ｉｎｆ , T ｍａｘ or t １／２λｚ The use according to any one of claims 1 to 12, wherein the use increases one or more of the following:

14. The use according to any one of claims 1 to 13, wherein said oral administration enhances the opening of Kv7 potassium channels.

15. The use of claim 14, wherein the oral administration enhances the opening of Kv7.2 / Kv7.3 potassium channels.

16. The treatment has the same C of the agent when orally administered to the human in a fasted state from at least 2 hours before oral administration through 2.5 hours after oral administration. ｍａｘ , AUC ｉｎｆ , T ｍａｘ or t １／２λｚ The use according to any one of claims 1 to 15, comprising administering to said human a dose of said agent that is lower than the dose required to achieve one or more of the following:

17. Oral administration of the drug to the human reduces the C of the drug compared to oral administration of the same amount of the drug to the human in a food-fast state from at least 2 hours before oral administration through 2.5 hours after oral administration. ｍａｘ The use according to any one of claims 1 to 16, wherein the

18. C after oral administration of the drug in the absence of food for at least 2 hours before oral administration until 2.5 hours after oral administration ｍａｘ C after oral administration of the drug to ｍａｘ 18. The use according to claim 17, wherein the ratio is greater than 1.2 or greater than 2.

19. Oral administration of the drug to the human reduces the C of the drug compared to oral administration of the same amount of the drug to the human in a food-fast state from at least 2 hours before oral administration through 2.5 hours after oral administration. ｍａｘ 18. The use according to claim 17, which increases the

20. the oral administration of the drug to the human decreases the AUC of the drug compared to the same amount of the drug administered orally to the human in a food-fast state from at least 2 hours prior to oral administration through 2.5 hours after oral administration. ｉｎｆ The use according to any one of claims 1 to 19, wherein the

21. AUC after oral administration of the drug in the absence of food from at least 2 hours before oral administration until 2.5 hours after oral administration ｉｎｆ AUC after oral administration of the drug ｉｎｆ 21. The use according to claim 20, wherein the ratio is greater than 1.

3.

22. the oral administration of the drug to the human decreases the AUC of the drug compared to the same amount of the drug administered orally to the human in a food-fast state from at least 2 hours prior to oral administration through 2.5 hours after oral administration. ｉｎｆ 21. The use according to claim 20, wherein the amount of erythrocyte mass is increased by at least 50%.

23. Oral administration of the drug to the human increases the T of the agent compared to oral administration of the same amount of the drug to the human in a food-fast state from at least 2 hours before oral administration through 2.5 hours after oral administration. ｍａｘ 23. The use according to any one of claims 1 to 22, wherein the

24. Agent T ｍａｘ 24. The use according to claim 23, wherein the increase is at least 50%.

25. Oral administration of the drug to the human reduces the time taken by the drug to pass the drug compared to oral administration of the same amount of the drug to the human in a food-fast state from at least 2 hours before oral administration through 2.5 hours after oral administration. １／２λｚ 25. The use according to any one of claims 1 to 24, wherein the

26. Agent t １／２λｚ 26. The use according to claim 25, wherein the increase is at least 20%.

27. 27. The use according to any one of claims 1 to 26, wherein the medicament is for use in increasing the resting motor threshold (RMT) or the active motor threshold (AMT) in a human being in need thereof.

28. 28. The use according to any one of claims 1 to 27, wherein the medicament is for use in reducing corticospinal or cortical excitability in a human in need thereof.

29. 29. The use according to any one of claims 1 to 28, wherein 2 to 100 mg of the agent is administered.

30. 30. The use according to any one of claims 1 to 29, wherein 5 to 50 mg of the agent is administered.

31. 31. The use according to any one of claims 1 to 30, wherein 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of the agent is administered.

32. 32. The use according to any one of claims 1 to 31, wherein 10 mg of the agent is administered.

33. 32. The use according to any one of claims 1 to 31, wherein 15 mg of the agent is administered.

34. 32. The use according to any one of claims 1 to 31, wherein 20 mg of the agent is administered.

35. 32. The use according to any one of claims 1 to 31, wherein 25 mg of the agent is administered.

36. The use of any one of claims 1 to 31, wherein 30 mg of the agent is administered.

37. The use according to any one of claims 1 to 36, wherein the medicament is for administration once per day.

38. The use of any one of claims 1 to 37, wherein the drug is an immediate release formulation.

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