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

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 seizure-related mortality risk is due to sudden unexpected death in epilepsy (SUDEP) (see Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376). Patients who participate in investigational antiepileptic drug (AED) clinical trials have generally 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 excessively synchronized and sustained firing of a group of neurons. A sustained increase in neuronal excitability is common to all epilepsy syndromes. Therapeutic strategies in treating epilepsy involve decreasing neuronal excitability through various mechanistic pathways. To broaden the therapeutic spectrum by targeting different mechanisms of action and to improve the risk / benefit profile, several new AEDs have been developed and marketed over the past two decades. Currently available AEDs are believed to act by inhibiting synaptic vesicle glycoproteins, enhancing inhibitory GABAergic neurotransmission, decreasing glutamate-mediated excitatory neurotransmission, or inhibiting voltage-gated sodium or calcium channels. Despite this, up to 30% of patients remain ineffective on 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, patients cannot drive, and patients have difficulty working or living independently. In addition, many patients suffer from behavioral disorders, neurological disorders, and / or intellectual disabilities as sequelae of their seizure disorder. Current drugs have little effect on potassium-dependent channels in neurons, despite the fact that potassium-dependent channels have a major role in controlling neuronal excitability. Therefore, drugs with novel mechanisms of action or that improve on already marketed 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 controlling neuronal excitability. Kv7.2 / Kv7.3 underlie the neuronal "M-current", named following early characterization, because the neuronal current 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. As a result, 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 that manifest as epileptic seizures. In contrast, an increase in Kv7.2-mediated M-current can hyperpolarize 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, especially hyperexcitable, neurons, and thus may be useful in treating certain seizure disorders. This enhancement has been clinically proven to be effective for 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 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", presented at the 68th Annual Meeting of the American Epilepsy Society (AES), Seattle, WA, USA, December 5-9, 2014, Poster 2.324). [Prior art documents] [Patent documents]

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

[0010] [Non-Patent Document 1] Hirtz, D. et al., Neurology (2007), 68:326-337 [Non-Patent Document 2] Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376 [Non-Patent Document 3] Brown, D. A. et al., Nature (1980), 283:673-676 [Non-Patent Document 4] Elger, CE et al., Epilepsy Behav. (2008), 12:501-539 [Non-Patent Document 5] Kupferberg, H., Epilepsia (1989), 30(Suppl.1):S51-S56 [Non-Patent Document 6] Prescott, JS and Evans, CA, "Pigmentary abnormalities (discoloration) associated with ezogabine / retigabine treatment: nonclinical aspects," presented at the 68th Annual Meeting of the American Epilepsy Society (AES), December 5-9, 2014, Seattle, WA, USA, poster 2.324. 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 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 a therapeutically effective amount of Compound A in the postprandial state or between 30 minutes before and 2 hours after a meal. 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, the compound being Compound A, and a therapeutically effective amount of the compound being orally administered to the human in a 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 prevention and / or treatment of C18-related inflammatory bowel disease in humans receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λz or (b), comprising 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 ... max , AUC inf , T max , or t1 / 2 λz The present invention provides a method for increasing one or more of the above.

[0018] In one embodiment, the disclosure provides a compound for use in a method for treating a chronic inflammatory condition, comprising administering to a subject a therapeutically effective amount of the compound to a subject in need thereof. max , AUC inf , T max , or t1 / 2 λz or (b), wherein the compound is Compound A, and the compound is orally administered to the human in a postprandial state or between 30 minutes before and 2 hours after a meal, which oral administration is greater than or equal to C100 or C200 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 compound for use in increasing one or more of the following:

[0019] In one embodiment, the present disclosure provides a method for determining 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 patient is receiving a steroid injection to increase one or more of the following: (b) relying on step (a), orally administering compound A in a postprandial state or between 30 minutes before and 2 hours after a meal; The present invention provides a method comprising:

[0020] In certain such embodiments, the probability that (b) occurs (i.e., that the administration occurs in a postprandial state, or between 30 minutes before and 2 hours after a meal) is increased relative to the method in the absence of 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 said human in a fed state or between 30 minutes before and 2 hours after a meal, said method providing a C-value of Compound A 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 present invention provides a method for increasing one or more of the above.

[0022] In one embodiment, the disclosure provides a method of reducing a 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 said human in a postprandial 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 method in which the therapeutic effect of the present invention is achieved by administering a therapeutically effective amount of the active ingredient, which is a lower dose than is required to achieve one or more of the following:

[0023] In one embodiment, the disclosure is 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 postprandial 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 an amount that is lower than the amount 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 one embodiment, the 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 3.25h 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, said compound being Compound A, and said compound being orally administered to said human. In an embodiment, said oral administration is, for Compound A, C of at least 40 ng / mL max , AUC of at least 2500 h ng / mL inf , T of at least 3.25h 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 in need thereof, comprising orally administering to said 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 RMT or AMT in said human, 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 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, wherein the amount of Compound A is sufficient to increase RMT or AMT in the human, or 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 in need thereof, comprising orally administering to said 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 said human, 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 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, wherein the amount of Compound A is sufficient to increase corticospinal or cortical excitability in the human, 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 a 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 an oral administration of a therapeutically effective amount of Compound A for the treatment of a seizure disorder, comprising orally administering a therapeutically effective amount of Compound A to the human under fed conditions.

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

[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 provided herein which describe in more detail certain background information and procedures, each of which is incorporated by reference in its entirety. [Brief description 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. [Diagram 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). [Diagram 3]FIG. 3 includes a graphical representation (A) depicting Compound A-induced modulation of resting motor threshold showing post-pre RMT (y-axis) across three doses (10 mg, 15 mg, and 20 mg) (x-axis) at 2 and 4 hours after drug intake, and a graphical representation (B) depicting Compound A-induced modulation of active motor threshold showing post-pre AMT (y-axis) across three doses (10 mg, 15 mg, and 20 mg) (x-axis) at 2 and 4 hours after drug intake. [Figure 4] FIG. 4 includes graphical illustrations depicting 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 the TEP recorded on a single EEG channel. Topographic scalp distributions of the amplitudes (μV) of the main TEP components (N15-P25, N45, N100, and P180) before and after drug ingestion are shown in Panels B and C, respectively. Panel D represents t-statistic maps of TEP amplitudes showing post-dose vs. pre-dose differences. "ns" denotes non-significant results, and open "x"s on the topographic scalp distributions indicate areas of positive amplitude and t-statistics, whereas dark areas without "x"s indicate negative amplitude and t-statistics. [Diagram 5] FIG. 5 includes a graphical representation depicting the modulation of TEP amplitude of Compound A at the highest concentration. TEPs were grand averaged across channels that showed significant drug-induced effects. Compared to pre-administration, Compound A induced suppression of 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 TEP following treatment with Compound A and placebo showing TEP amplitude (μV) (y-axis) at N15-P25, N45, and P180 time points (x-axis) following 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 TEPs recorded before dosing (Pre) and 2, 4, and 6 hours post-dose (2hr, 4hr, and 6hr, respectively) are shown. Compound A fingerprints including reduced N15-P25, N45, and P180 components reflect 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 drug-induced modulation of spontaneous brain oscillations over time following 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 Compound A time effect on resting motor threshold showing change from baseline RMT (% maximum 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. Means ± standard error of the mean (SEM) are 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 (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 (Pre) versus 2 and 4 hours after administration of Compound A, showing GMFP (uv2) (y-axis) over time (seconds) (x-axis). Compound A average high concentration = 45 ng / mL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The effect of food on a drug can have a significant impact on patient outcomes by affecting the pharmacokinetics and pharmacodynamics of that drug. This interaction can potentially lead to decreased drug absorption and reduced efficacy or increased drug absorption and increased efficacy. Food can also have either a positive or negative effect on the incidence and severity of adverse events associated with drug use. Whether a drug's bioavailability and / or exposure to a patient is affected by food intake is unpredictable without extensive testing. See, for example, Heimbach, T et al., "Case Studies for Practical Food Effect Assessments across BCS / BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data," The AAPS Journal (2012), Vol. 15, No. 1, pp. 143-158.

[0037] In certain embodiments, the present disclosure provides improved methods of treatment and administration based on the application of 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 a non-human primate study in which Compound A was orally administered in the fed state, compared to the fasted state, did not increase the bioavailability and exposure of Compound A.

[0038] This finding is unexpected in light of the lack of food effect on bioavailability and exposure following oral administration of another potassium channel opener, retigabine, as discussed above (see, e.g., p. 2 of the United States Food and Drug Administration (FDA) Approved Labeling Text for retigabine, Potiga, 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, and therefore the blue-gray discoloration of the skin, lips or nails and changes in retinal pigmentation in human patients that appear after chronic use of retigabine would not be expected to occur after chronic use of Compound A.

[0040] In the following disclosure, certain specific details are given 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. Unless otherwise stated, throughout this specification and the appended claims, the word "comprise" and its derivatives, such as "comprises" and "comprising," should be construed in an open-ended, inclusive sense, i.e., "including, but not limited to." Moreover, 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. Moreover, 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" is generally used in its sense to include "and / or" unless the context clearly dictates otherwise. Moreover, the term "about" as used herein 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 US Patent No. 8,293,911 and US Patent No. 8,993,593. The mechanism of action of Compound A is different from most known AEDs in that Compound A involves the enhanced or increased opening of the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), which are important in controlling the excitability of neuronal cells. 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 sites of action.

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

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

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

[0053] "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, carbohydrate, and fat, respectively.

[0054] "SD" refers to standard deviation.

[0055] "Seizure disorders" include partial onset (focal) seizures, photosensitive epilepsy (light-sensitive seizures), self-induced syncope, refractory epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, glucose transporter 1 (Glut1) deficiency, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), myoclonic absence It 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 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 maximum (peak) plasma concentration following 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 obtain the desired described effect, including improving or preventing the disease, disorder, or condition, or one or more mechanisms underlying the disease, disorder, or condition. In an embodiment, when Compound A is administered for the treatment of a seizure disorder, a therapeutically effective amount refers to the range of amounts of Compound A that, upon administration to a human, treats, improves, or prevents the seizure disorder in the human, or produces a detectable therapeutic or preventive effect in the human with a seizure disorder. The effect is detected, for example, by a reduction in seizures (frequency) or the severity (quality) of seizures. The exact therapeutically effective amount for a given human will depend on the size and health of the human, the nature and extent of the seizure disorder, the presence of any concomitant drug therapy, 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 capabilities of the clinician.

[0059] As used herein, "treatment" refers to a therapeutic application involving administration of compound A to improve or prevent the indicated disease, disorder or condition or one or more underlying mechanisms thereof, including slowing or stopping the progression of one or more of the indicated diseases, disorders or conditions or underlying mechanisms thereof. In one embodiment, when compound A is administered for the treatment of a seizure disorder, treatment refers to a therapeutic application to slow or stop 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 to slow or stop the seizure disorder in that the reversal method not only completely stops the progression of the seizure disorder, but also moves 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 the food 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, and 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 absence of food from at least 4 hours prior to oral administration of a therapeutically effective amount of Compound A through 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 said human, under postprandial conditions, 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 said human between 30 minutes before and 2 hours after a meal 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.

[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 certain examples, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as focal onset epilepsy.

[0065] In an embodiment, the present disclosure relates to a compound for use in treating a disease, disorder or condition associated with Kv7 potassium channel dysfunction in a 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 a particular example, 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 other embodiments, the method or use is optionally selective for Kv7.5 over Kv7.1. In an embodiment, the method or use is optionally selective for Kv7.2 and Kv7.3 over Kv7.1.

[0067] 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 under postprandial conditions, 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, said compound being Compound A, said compound being orally administered to said human in a postprandial state, in an embodiment, 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, said compound being Compound A, said compound being orally administered to said human between 30 minutes before and 2 hours after a meal, in an embodiment, said amount being sufficient to reduce seizure severity, seizure frequency, or both.

[0071] 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, 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, 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 prevention and / or treatment of C18-related inflammatory bowel disease in humans receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λz The present invention provides a method for increasing one or more of C, C+, C-terminal binding, and C-terminal binding, comprising orally administering to said human an amount of Compound A in a fed state. In one embodiment, the method ... max , AUC inf , T max , or t1 / 2 λz Increase one or more of the following:

[0074] In one embodiment, the disclosure provides a compound for use in a method for treating a chronic inflammatory condition, comprising administering to a subject a therapeutically effective amount of the compound to a subject in need thereof. max , AUC inf , T max , or t1 / 2 λz and 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 reduction in C 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 Increase one or more of the following:

[0075] In one embodiment, the present disclosure provides a method for the prevention and / or treatment of C18-related inflammatory bowel disease in humans receiving oral administration of Compound A. max , AUC inf , T max , or t1 / 2 λzThe present invention provides a method for increasing one or more of C, C+, C-terminal binding, and C-terminal binding, comprising orally administering to said human an amount of Compound A between 30 minutes before and 2 hours after a meal. In one embodiment, the method ... 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 Increase one or more of the following:

[0076] In one embodiment, the disclosure provides a compound for use in a method for treating a chronic inflammatory condition, comprising administering to a subject a therapeutically effective amount of the compound to a subject in need thereof. max , AUC inf , T max , or t1 / 2 λz and / or a combination 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 one embodiment, the oral administration results in a reduction in C 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 Increase one or more of the following:

[0077] In one embodiment, the present disclosure provides a method for determining 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 patient is receiving a steroid injection to increase one or more of the following: (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 in the absence of 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 said human in a fed state. In an embodiment, the method provides a C-value of Compound A compared to when the same amount of Compound A is orally administered to said 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 and 2 hours after a meal. In an embodiment, the method provides a C-value of Compound A of 100 mg / kg / day 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 Increase one or more of the following:

[0080] In one embodiment, the 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 said human in a fed state. In an embodiment, said reduced dose is equal to or greater than the same C of Compound A when orally administered to said 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 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. In an embodiment, said reduced dose is 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 dose is lower than that required to achieve one or more of the following:

[0082] In one embodiment, the disclosure provides a method of lowering 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 said human between 30 minutes before and 2 hours after a meal. In an embodiment, said reduced dose is the same C of Compound A when orally administered to said 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 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 between 30 minutes before a meal and 2 hours after a meal. In an embodiment, said reduced dose is the same C of Compound A when orally administered to said 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:

[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 one embodiment, the method comprises, for Compound A: 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 h, for example at least 150 h, at least 170 h, at least 190 h, or at least 210 h. 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, said compound being Compound A, and said compound being orally administered to said human. In an embodiment, said oral administration is, for Compound A, 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 h, for example at least 150 h, at least 170 h, at least 190 h, or at least 210 h. 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, 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 said human an amount of Compound A, optionally in a postprandial state or between 30 minutes before and 2 hours after a meal. In an embodiment, the amount of Compound A is sufficient to increase the RMT or AMT in said 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 an embodiment, the amount of Compound A is sufficient to increase RMT or AMT in the human. In an embodiment, 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 said human, optionally in a postprandial state or between 30 minutes before and 2 hours after a meal, an amount of Compound A. 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 said 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 said human.

[0091] In one embodiment, the disclosure provides a compound for use in decreasing corticospinal or cortical excitability 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, wherein the amount of Compound A is sufficient to increase corticospinal or cortical excitability in the human. 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 said 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 postprandial 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, "postprandial state" includes the ingestion of food at or in close proximity to the 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 total caloric content of the meal 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 from protein, carbohydrate, 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, the 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 be performed from about 60 minutes, 45 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes before a meal to about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 135 minutes, 150 minutes, 165 minutes, 180 minutes, 195 minutes, 210 minutes, 225 minutes, or 240 minutes after a meal. In some aspects, Compound A can be administered simultaneously with or within 15 minutes of eating food.

[0096] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods described herein reduces the C-terminal end of Compound A compared to when the same amount of Compound A is orally administered 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 max In some embodiments, the oral administration increases AUC inf In some embodiments, the oral administration increases T max In some embodiments, the oral administration increases the t1 / 2 λz In some embodiments, the oral administration increases C max and AUC inf In some embodiments, the oral administration increases C max and T max In some embodiments, the oral administration increases C 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, the oral administration increases T max and t1 / 2 λz In some embodiments, the oral administration increases C max , AUC inf , and T max In some embodiments, the oral administration increases C max , AUC inf , and t1 / 2 λz In some embodiments, the oral administration increases C 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, the oral administration increases C max , AUC inf , T max , and t1 / 2 λz Increase the

[0097] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods described herein may result in a C-value of Compound A compared to when the same amount of Compound A is orally administered 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%, for example 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, the C 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 20ng / mL to about 200ng / mL, for example, about 25 to about 200ng / mL, about 30 to about 200ng / mL, about 35 to about 200ng / mL, about 40 to about 175ng / mL, about 40 to about 150ng / mL, about 40 to about 125ng / mL, about 40 to about 100ng / mL, about 40 to about 90ng / mL, about 40 to about 80ng / mL, about 40 to about 70ng / mL, about 40 to about 60ng / 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, 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 reduces the AUC of Compound A compared to when the same amount of Compound A is orally administered to said human in a fasted state. inf In some embodiments, the AUC inf 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 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 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 2000h·ng / mL to about 5000h·ng / mL, for example, about 2500 to about 5000h·ng / mL, about 2500 to about 4500h·ng / mL, about 2500 to about 4250h·ng / mL, about 2500 to about 4000h·ng / mL, about 2500 to about 3750h·ng / mL, about 2500 to about 3500h·ng / mL, about 2500 to about 3250h·ng / mL, about 2500 to about 3000h·ng / mL, or about 2500 to about 2750h·ng / mL, for example, about 2500h·ng / mL, 2600h·ng / mL, 2700h·ng / mL, 2800h·ng / mL, 2900h·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 results in a T of Compound A that is greater than or equal to 100 mg / kg / day 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 hr. 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 range from 3.25 hr to about 6.5 hr, from about 3.25 hr to about 6 hr, from about 3.25 hr to about 5.5 hr, from about 3.25 hr to about 5 hr, or from about 3.25 hr to about 4.5 hr, for example, to about 3.25 hr, 3.5 hr, 3.75 hr, 4 hr, 4.25 hr, 4.5 hr, 4.75 hr, 5 hr, 5.25 hr, 5.5 hr, 5.75 hr, 6 hr, 6.25 hr, 6.5 hr, 6.75 hr, 7 hr, 7.25 hr, 7.5 hr, 7.75 hr, 8 hr, 8.25 hr, 8.5 hr, 8.75 hr, 9 hr, 9.25 hr, 9.5 hr, 9.75 hr, or 10 hr.

[0107] In some embodiments, oral administration of Compound A to a human in need thereof according to the methods disclosed herein reduces the t1 / 2 decrease 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%, such as 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 hr. 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 0.2-0.5 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 orally administering 2 to 200 mg of Compound A. For example, the methods can be administered orally at about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39mg, 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 143mg, about 144mg, about 145mg, about 146mg, about 147mg, about 148mg, about 149mg, about 150mg, about 151mg, about 152mg, about 153mg, about 154mg, about 155mg, about 156mg, about 157mg, about 158mg, about 159mg, about 160mg, about 161mg, about 162mg, about 163mg, about 164mg, about 165mg, about 166mg, about 167mg, about 168mg, about 169mg, about 170mg, about 171mg, about 172mg, about 17 The method may comprise 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 contains 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 orally administering 5-1000 mg of Compound A per day, e.g., 5-500 mg or 5-250 mg per day of Compound A. For example, the methods may be administered orally 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 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 400 mg, about 400 mg, about 450 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 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 about 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 from 10 to 200 mg of Compound A per day, e.g., from 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg per day to 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of Compound A per day, e.g., from 20 to 150 mg per day. In some embodiments, the oral administration comprises from 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 orally administered as multiple doses per day, for example, 2, 3, 4 or 5 doses per day. For example, a daily dose of 100 mg 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, 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, for example, 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 one 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, comprising orally administering Compound A to said 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 said human in a postprandial state or between 30 minutes before and 2 hours after a meal.

[0117] In one embodiment of the present disclosure, the administration of compound A is for treating seizure disorders that would benefit from the opening of 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 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 an embodiment, the disclosure provides a method of orally administering Compound A to a human exhibiting a reduced RMT or AMT relative to the average human, 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 more), 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 more). In some aspects, at 2 hours, 4 hours, and 6 hours after administration, 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 more).

[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 more), Compound A reduces (e.g., 40% or more) early theta (4-7 Hz) TMS-induced oscillations (30-390 ms) or alpha (8-12 Hz) TMS-induced oscillations (220-400 ms) compared to placebo and / or increases (e.g., 40% or more) beta (13-30 Hz) TMS-induced power (220-310 ms) after a TMS pulse compared to placebo. In some aspects, at 2 hours after administration, Compound A reduces (e.g., 30% or more) early theta TMS-induced oscillations after a TMS pulse compared to placebo. In some aspects, at 4 hours after administration, Compound A reduces (e.g., 30% or more) alpha TMS-induced oscillations after a TMS pulse compared to placebo. In some embodiments, 6 hours after administration, Compound A reduces theta TMS-induced oscillations following a TMS pulse compared to placebo (eg, by 30% or more).

[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 more), 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 more). 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 more) 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 pharma- ceutically acceptable oral composition comprising Compound A and one or more pharma- ceutically 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 pharma- ceutically acceptable oral compositions containing Compound A include solid formulations (tablets, capsules, lozenges, dragees, granules, powders, multiparticulates, and films, etc.) and liquid formulations (aqueous solutions, elixirs, tinctures, suspensions, and dispersions). In one embodiment, pharma-ceutically acceptable oral compositions of Compound A include suspensions or granules for pediatric use. 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 a fed state to enhance bioavailability and exposure of Compound A upon oral administration. Such a kit includes a plurality of oral dosage unit forms of Compound A in combination with instructions for oral administration of Compound A in a 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 following oral administration of a therapeutically effective amount of Compound A in a fed state to AUC following oral administration of a therapeutically effective amount of Compound A in a 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 a human administered oral Compound A in the fasted state, a similar comparison can be made involving a human who has not ingested food during the period from about 4 hours prior to 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 prior to 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, if 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, refractory epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, glucose transporter 1 deficiency, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome. The seizure disorder is selected from: myoclonic absence epilepsy (LGS), 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 in need thereof, comprising orally administering to said human a therapeutic amount of Compound A in a postprandial state, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

[0135] Embodiment 2. 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 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 enhances the opening of Kv7 potassium channels.

[0137] Embodiment 4. The method of embodiment 3, wherein said 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 in need thereof, comprising orally administering to said human under postprandial conditions 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 said seizure disorder in said human.

[0142] Embodiment 9. A method of treating a seizure disorder in a human 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 wherein the amount of Compound A is sufficient to treat said seizure disorder in said human.

[0143] Embodiment 10. A method of treating a seizure disorder in a human in need thereof, comprising orally administering to said human an amount of Compound A under postprandial conditions, 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 between 2 and 200 mg.

[0144] Embodiment 11. A method of treating a seizure disorder in a human 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 between 2 and 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 under postprandial conditions.

[0146] Embodiment 13. 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 between 30 minutes before and 2 hours after a meal.

[0147] Embodiment 14. A method of orally administering compound A to a human 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 under fed conditions.

[0148] Embodiment 15. A method of orally administering compound A to a human 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 between 30 minutes before and 2 hours after a meal.

[0149] Embodiment 16. The method comprises administering to said human a C 2 H 3 O 4 of Compound A compared to an equivalent 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 the following is increased:

[0150] Embodiment 17. C-cell proliferation of Compound A in humans 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, said compound A being N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, said method increasing C max , AUC inf , T max , or t1 / 2 λz A method to increase one or more of the above.

[0151] Embodiment 18. C-cell proliferation of Compound A in humans receiving oral administration of Compound A max , AUC inf , T max , or t1 / 2 λz or (b), the method 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 wherein said method increases C 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 in need thereof, comprising orally administering 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 wherein said method results in a C-value of compound A of 100% or more compared to when the same amount of compound A is orally administered to said human 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 in need thereof, comprising orally administering 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 wherein said method reduces C-value of compound A compared to when the same amount of compound A is orally administered to said human 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 administered orally 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 in the range of 0.1 to 1.0 times the C value of Compound A when orally administered to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The dosage is lower than that required to achieve one or more of the following:

[0155] Embodiment 22. A method of reducing a 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 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 in the range of 0.1 to 1.0 times the C value of Compound A when orally administered to said human in a fasted state. max, AUC inf , T max , or t1 / 2 λz The dosage is lower than that required to achieve one or more of the following:

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

[0157] Embodiment 24. C after oral administration of Compound A in the fasted state max C after oral administration of compound A to max 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 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 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 is at least 50%.

[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 reduces the AUC of Compound A compared to the same amount of Compound A administered orally to said human in a fasted state. inf The method of any one of embodiments 16 to 28, wherein the method increases

[0163] Embodiment 30. AUC after oral administration of Compound A in the fasted state inf AUC after oral administration of Compound A to inf 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 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 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 is at least 50%.

[0167] Embodiment 34. AUC of Compound A inf 30. The method of embodiment 29, wherein the increase in is at least 75%.

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

[0169] Embodiment 36. T after oral administration of Compound A in the fasted state max T after oral administration of Compound A to max 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 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 The method of embodiment 35, wherein the ratio is greater than 2.

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

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

[0174] Embodiment 41. Oral administration of Compound A to said human reduces the t1 / 2 of Compound A compared to when the same amount of Compound A is orally administered to said human in the fasted state. λz The method of any one of embodiments 16 to 40, wherein the method increases

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

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

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

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

[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 the method comprises administering to Compound A: C of at least 40 ng / mL max , AUC of at least 2500 h ng / mL inf , T of at least 3.25hr max or t1 / 2 of at least 130h λz A method of producing 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 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 increase RMT or AMT in said human.

[0181] Embodiment 48. A method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human 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 between 2 and 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 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.

[0184] Embodiment 51. A method of decreasing corticospinal or cortical excitability in a human 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 between 2 and 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 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 under postprandial conditions.

[0198] Embodiment 65. 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 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 and 2 hours after a meal.

[0199] Embodiment 66. A compound for use according to embodiment 63 or embodiment 64, wherein said method enhances 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. A compound for use according to embodiment 66, 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.

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

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

[0204] Embodiment 71. A compound for use in treating a seizure disorder in a human 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 under postprandial conditions.

[0205] Embodiment 72. A compound for use in treating a seizure disorder in a human 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 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 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 wherein the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the compound is orally administered to the human under fed conditions, and the oral administration of the compound is increased in C compared to the same amount of the compound administered orally to the human under fasted conditions. max , AUC inf , T max , or t1 / 2 λz The compound for use in an embodiment of the present invention increases one or more of the following:

[0208] Embodiment 75. A compound for use, comprising: max , AUC inf , T max , or t1 / 2 λz or (b), 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 and 2 hours after a meal, and wherein the oral administration of the compound reduces C max , AUC inf , T max , or t1 / 2λz The compound for use in an embodiment of the present invention increases one or more of the following:

[0209] Embodiment 76. A compound for use in reducing the dose of said compound administered orally to a human in need thereof as part of a treatment regimen, said compound being N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, wherein the reduced dose of said compound is administered orally to said human in a fed state, and said reduced dose has the same C of said compound as when administered orally to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The compound for use in an amount less 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 administered orally to a human in need thereof as part of a treatment regimen, said compound being N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, said reduced dose of said compound being administered orally to said human between 30 minutes before and 2 hours after a meal, said reduced dose having the same C of said compound when administered orally to said human in a fasted state. max , AUC inf , T max , or t1 / 2 λz The compound for use in an amount less than that required to achieve one or more of the following:

[0211] Embodiment 78. Oral administration of the compound to the human reduces 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, which 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 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 above compound max The compound for use according to embodiment 78, wherein the increase in is at least 100%.

[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 a fasted state. inf The compound for use according to any one of embodiments 73 to 78, which increases

[0218] Embodiment 85. AUC after oral administration of the compound in the fasted state inf AUC after oral administration of the above compound to 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 to 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 to 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 reduces the TLR 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 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. The T max The compound for use according to embodiment 75, wherein the increase in

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

[0229] Embodiment 96. Oral administration of the compound to the human reduces the t1 / 2 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, which increases

[0230] Embodiment 97. The t1 / 2 following 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. The t1 / 2 following 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 above compound λz The compound for use according to embodiment 96, wherein the increase in

[0233] Embodiment 100. The t1 / 2 of the above 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 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, and the oral administration of the compound provides, for the compound: C of at least 40 ng / mL max , AUC of at least 2500 h ng / mL inf , T of at least 3.25hr max or t1 / 2 of at least 130h λz The compound for use in providing one or more of the following:

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

[0236] Embodiment 103. A 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 in need thereof, said compound being N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and said compound being orally administered to said human.

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

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

[0242] Embodiment 109. The compound for use according to embodiment 105, wherein 20 mg of said 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 said 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 a 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 to 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 an oral administration of a therapeutically effective amount of Compound A for the treatment of a seizure disorder, comprising orally administering to said human a therapeutically effective amount of Compound A in a postprandial 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 to 10a, wherein said therapeutically effective amount of Compound A is from about 0.05 mg / kg to about 2.0 mg / kg. EXAMPLES

[0261] The following studies were performed to determine the effect of food, if any, on the bioavailability and exposure of Compound A when Compound A is administered orally. Further studies were performed 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 Three cynomolgus monkeys (n = 3) of Vietnamese origin were used in this study. At the time of the first dose, the 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 and food was returned 4 hours after dosing. For Group 2, the same three monkeys were fasted overnight and food was provided approximately 1 hour prior to dosing and food was returned 4 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 on the morning of dose administration and kept at room temperature until dosing. The remaining capsules were placed in -20°C storage.

[0267] 1.3. Administration of Oral Dosage Units 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 finally successfully dosed.

[0269] Group 2: All animals were weighed on the morning of dose administration. 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 vacutainer tubes containing K2EDTA, and kept on wet ice until processed for plasma. Blood samples were collected at the time of dosing (0.0 h, time zero) and 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after dosing.

[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 split into two aliquots and each aliquot was transferred directly to individual tubes appropriately labeled with 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-reproductive 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. The 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 in Treatment Period 1 was fed in Treatment Period 2, and the group that was fed in Treatment Period 1 was fasted in 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 an overnight fast of at least 10 hours, a standard high-fat, high-calorie breakfast was provided per FDA guidelines. This breakfast was provided 30 minutes prior to the scheduled dosing time and was completed 10 minutes prior to dosing. A typical breakfast included 2 slices of buttered toast, 2 fried eggs, 2 slices of bacon, 4 ounces of hash browns, and 8 ounces of whole milk. Subjects did not eat or drink anything for at least 4 hours after dosing.

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

[0285] For all subjects, blood samples for measurement 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 dosing.

[0286] 2.1.Results Plasma concentrations (ng / mL) of Compound A in subjects who received an oral dose of Compound A under fed conditions 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 depicted in FIG. 2.

[0289] Pharmacokinetic parameters for subjects who received 20 mg of Compound A orally under fed conditions 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] As the pharmacokinetic results of this study demonstrate, the bioavailability and exposure of Compound A was significantly increased when administered orally in the fed state compared to the bioavailability and exposure of Compound A administered orally in the fasted state. These results were unexpected in light of 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 (5mg, 15mg, 20mg, 25mg or 30mg) or placebo. The study featured an adaptive design. A crossover food effect cohort (N=10) also completed a single dose of 20mg. A subset of 8 male subjects was also evaluated for effects on cortical excitability using transcranial magnetic stimulation (TMS) (see Example 4 and Example 5).

[0298] Repeated doses of Compound A (15 mg once daily) were evaluated under fasted and fed conditions for 7 and 10 days, respectively. Repeated doses of Compound A (25 mg once daily) were also evaluated under fed conditions for 10 days.

[0299] Compound A was formulated as an immediate release capsule. 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 with 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 Cs up to 104 ng / mL and 107 ng / mL, respectively. max Treatment was well tolerated at baseline and at baseline baseline. 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 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 examined (single doses up to 30 mg and multiple doses of 25 mg once daily (QD)).

[0305] The above PK profile, including an effective half-life of greater than 24 hours, supports a once-daily dosing schedule using an immediate release formulation, with steady state achieved within a week without the need for dose titration.

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

[0307] A pilot study used TMS to non-invasively 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) with Compound A.

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

[0309] 4.2.Results Compound A suppressed TEP amplitude at late latencies (e.g., 1.92±0.03 μV at 180 ms peak (P180) after TMS, p<0.01, N=3) at 4 hours after 20 mg (Cplasma=50±10 ng / mL). The 10 mg (N=2) and 15 mg (N=3) doses did not show significant robust TEP modulation, with mean plasma levels of Compound A of 23.1 ng / mL and 36.3 ng / mL at 4 hours. At 4 hours after 20 mg, RMT was elevated from baseline by 4.3±0.6% (Poster 3.282) and theta power was elevated 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 motor threshold (except SICI) assessed using TMS / EMG. Black bars show effect 2 hours after drug intake, grey bars represent 4 hours after drug (change from baseline as % maximum stimulation 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 alternative 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 study 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 study 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 a postprandial state, but the timing of dosing relative to the meal was varied during the study, varying between a high-fat or standard meal eaten 2 hours or 30 minutes before dosing, and a high-fat or standard meal eaten 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 included 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 ), 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, CL / F normalized by body weight, mean residence time from time zero to the last quantifiable concentration (MRT last ), mean residence time (MRT inf ), apparent volume of distribution during the terminal phase (Vz / F), and Vz / F normalized by body weight.

[0318] PD assessment included resting state electroencephalogram (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 Day 7 / 8 and / or Day 14). For subjects who received Compound A in Period 1, additional PK time points beyond 24 hours were obtained from PK samples collected prior to 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 Day 14 PK sample. Thus, subjects who were randomized to receive Compound A in Period 2 and enrolled prior to the administration of the additional Day 14 PK sample did not have PK data beyond 24 hours. The complete PK profile dataset consists of 16 subjects who had PK samples collected beyond 24 hours post-dose. For the following PK parameter discussion, the complete PK profile dataset was generally used, as 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 your 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 No clear differences were observed between the two groups. 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 for the complete PK profile were recorded. 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 concentrations of Compound A 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 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 data set inf The median (range) extrapolated area was 19.9% ​​(range 10.6-40.5%). This relatively high level of extrapolated area in several subjects was consistent with the parameters calculated from λz (half-life, MRT infThis suggests that the drug-dose ratios (e.g., drug release rate, clearance, and volume of distribution) should be analyzed with caution and may have a higher inherent variance in their calculations.

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

[0328] The body 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 dosing. Once absorbed, Compound A was distributed from the plasma to surrounding tissues and slowly removed from the systemic circulation at a rate well below hepatic blood flow, indicating minimal extraction (metabolism) from the liver. Compound A showed 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 periods between periods were not long enough for Compound A concentrations to fall below the limit of quantification in subjects who received placebo in Period 2 (mean 3.1 ng / mL, range 1.3 to 6.8 ng / mL).

[0332] 5.2. Pharmacodynamic analysis All 20 subjects underwent TMS-EMG and TMS-EEG sessions pre-dose and 2 and 4 hours post-dose on days 1 and 7. Due to a 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 of the Compound A treatment period due to side effects (vomiting).TMS procedures for subject 940 could not be completed at hour 2 of the placebo treatment period due to technical issues, so this subject only underwent RMT and resting-state EEG procedures at 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 to 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 effects 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 the 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 brackets 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 the grand-averaged (all-subjects all-responses arithmetic mean) TEPs and were kept identical during analysis of pre- and post-administration measures as well as across conditions. To analyze drug-induced modulation of TEPs, we selected a region of interest (ROI) consisting of 27 channels over and around the stimulation site (left M1) and the corresponding contralateral site ("FC1", "FC3", "FC5", "C1", "C3", "C5", "CP1", "CP3", "CP5", "P1", "P3", "P5", "Cz", "CPz", "Pz", "FC2", "FC4", "FC6", "C2", "C4", "C6", "CP2", "CP4", "CP6", "P2", "P4", "P6").

[0340] To analyze the significance of TEP amplitude modulation induced by Compound A, multiple paired t-test comparisons (post- vs. pre-administration) were applied for each TOI in all electrodes within the indicated ROIs. 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 the TMS-induced EEG potentials is in agreement with previous reports in the literature (Figure 4-A). Early components (N15, P25) are mainly located in the stimulated left M1, followed by a prominent negativity over the contralateral sites 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 4-B). Comparisons between pre-administration 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 produced a significant modulation of early TEPs (N45 and P180).

[0342] Concentration analysis (N=16): Cluster-based permutation analysis was applied between post- and pre-dose conditions to test 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 early TEP components measured at 15-35 ms (peak-to-peak amplitude of 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 (Figure 4-D, Figure 5). Figure 6 shows that Compound A significantly modulates TEPs and reduces cortical excitability.

[0343] Temporal analysis (subjects with drug exposure at time of measurement): Cluster-based permutation analysis was applied between post-dose and pre-dose conditions to test the effect 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): A cluster-based permutation analysis was applied between post- and pre-dosing conditions to test the effect of Compound A at 2 hours (n=19), 4 hours (n=20), and 6 hours (n=8) post-dosing in all available subjects. Compared to pre-dosing, the first N15-P25 complex was reduced at 2 hours (p=0.006) and 4 hours (p=0.01). Furthermore, at 4 hours post-dosing, 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 beta power decrease (desynchronization), and a final late response of increased beta power.

[0348] The effect of active compounds on TMS-induced oscillations was then analyzed by cluster-based permutation analysis, following the same procedure employed in the analysis of TEPs. Theta (4–7 Hz), alpha (8–12 Hz) and beta (13–30 Hz) TMS-induced oscillations were compared from 30 ms (the first time-frequency point considered to be free of artifacts) to 800 ms between drug conditions. This method was preferred instead of a set of predefined time windows, given that there is no consensus on which time windows of interest should be used for TMS-induced oscillation analysis. Moreover, the present cluster-based statistical approach is appropriate for exploratory analyses, as it minimizes false positives involved in testing multiple time points.

[0349] Concentration analysis (N=16): Cluster-based permutation analysis was applied between post- and pre-dose 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 30ms to 390ms), alpha TMS-induced oscillations (p=0.02; significant effect from 220ms to 400ms), and increased beta TMS-induced power (p=0.04; significant effect from 220ms to 310ms).

[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): A cluster-based permutation analysis was applied between post- and pre-dose conditions to test the effect of Compound A at 2 hours (n=15), 4 hours (n=16), and 6 hours (n=7) after dosing. Compared to pre-dose, Compound A did not modulate the oscillations registered at 2 hours after dosing, but at 4 hours, Compound A suppressed early theta TMS-induced oscillations (p=0.03; significant effect from 30ms to 180ms), alpha TMS-induced oscillations (p=0.03; significant effect from 250ms to 390ms), and elevated beta TMS-induced desynchronization (p=0.04; significant effect from 250ms to 330ms). Finally, at 6 hours after dosing, the results showed a significant reduction in theta-induced oscillations (p<0.001; significant effect from 30ms to 280ms).

[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 post- and pre-dosing conditions to test the effect of Compound A at 2 hours (n=19), 4 hours (n=20), and 6 hours (n=8) post-dosing. Compared to pre-dosing, Compound A showed a trend to suppress theta TMS-induced oscillations at 2 hours post-dosing. At 4 hours, Compound A suppressed alpha TMS-induced oscillations (p=0.03; significant effect from 250ms to 400ms). Finally, at 6 hours post-dosing, results showed a significant reduction in theta-induced oscillations (p=0.03; significant effect from 80ms to 300ms) and a trend to suppress the alpha band (trend p=0.07; 270ms to 390ms).

[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 non-parametric, 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), all other comparisons showed non-significant results.

[0357] The difference between post-dose and pre-dose states within each drug condition was calculated, and then the calculated differences (post-dose minus pre-dose) between Compound A and placebo were 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 test the effect of Compound A at 2 hours (n=15), 4 hours (n=16), and 6 hours (n=7) after dosing.

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

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

[0361] Time 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 post-administration vs. pre-administration: delta, p<0.001; theta, p=0.006; 4 hours post-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 post-administration vs. pre-administration: p=0.005; 4 hours post-administration vs. pre-administration: p<0.001; 6 hours post-administration vs. pre-administration: p=0.009).

[0363] Placebo caused increases in power in the delta (2 hours post-dose vs. pre-dose: 2 clusters p=0.02 and p=0.04; 4 hours post-dose vs. pre-dose: 2 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 percentage of maximum stimulation intensity (%MSO). Drug-induced modulation of TMS-EMG parameters was assessed across three time points (2 h, 4 h, and 6 h) and for the time point with highest drug exposure.

[0365] 5.2.4.1. Resting motor threshold The individual and average RMT values ​​at baseline and the change at each time point for all 20 subjects 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 registered 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 after administration. Figure 8 shows that RMT increased in proportion to the plasma concentration of Compound A, with a mean ± SEM increase of 4.9 ± 0.7% at 6 hours. This significant increase in RMT indicates a decrease in corticospinal excitability, and thus 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 registered 2 hours after taking Compound A and placebo, respectively.

[0369] There were no significant differences from baseline values ​​in either group. AMT was elevated after treatment with Compound A. The change from baseline in AMT for Compound A was significantly different from placebo at 6 hours after dosing (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 interstimulus interval (ISI) of 2 ms, where the conditioning stimuli were set at 80% of the AMT and suprathreshold stimuli 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 dose of Compound A (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 evaluations were performed to determine the acute effects of Compound A, a potassium channel opener, on corticospinal and cortical excitability as measured by TMS-EMG and TMS-EEG, respectively.

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

[0377] In addition, 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] Results showed that Compound A significantly affected motor threshold, indicating a decrease in corticospinal excitability. RMT was modulated in a time-dependent and plasma concentration-dependent manner, particularly compared to placebo. At 2, 4, and 6 hours 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 an increase in 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 not known, however, it is consistent with other AEDs (Ziemann et al., Ann. Neuro. 1996, 40:367-378). During voluntary muscle activation, the lowering of motor threshold is thought to occur via increased excitability of corticospinal output or spinal motoneurons or both. Subthreshold activation of the former elements, which are probably also the target of TMS, explains why AMT is less easily elevated than RMT by drugs acting on membrane ion channels. During voluntary muscle activation, many physiological and anatomical elements 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 intracortical inhibition via GABA-A receptors. 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, and this drug-induced modulation was followed by drug plasma exposure with the strongest effect 4 hours after drug intake (Table 21).

[0381] [Table 21]

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

[0383] TMS-EEG allows the measurement of the pharmacological action of drugs acting in the brain. This modality is particularly attractive for epilepsy research, where, despite a wide range of AEDs, seizures are refractory to treatment in 30% of cases and long-term treatment outcomes cannot be predicted (Kwan and Brodie, N. Engl. J. Med. 2000, 342:314-319). Lamotrigine and levetiracetam are two of the most frequently prescribed AEDs and have been previously evaluated using TMS-EEG. Lamotrigine is a voltage-dependent Na+ channel blocker, whereas 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 the 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 first N15-P25 complex compared to time-matched placebo, and the N45 and P180 potentials provided unique fingerprints. While the N15 component is generated in the ipsilateral premotor cortex, the origin of the P25 is less clear, but may reflect activity around the ipsilateral sensorimotor / premotor border, the ipsilateral superior cingulate or supplementary motor area, or the contralateral cortex (Maki and Ilmoniemi, Neurosci. Lett. 2010, 478:24-28). The N15-P25 complex is inversely correlated with MEP amplitude and thus provides information about the excitability of the stimulated area. Following this interpretation, the reduction in peak-to-peak amplitude of these early components may reflect a drug-induced reduction in cortical excitability. Over time, Compound A suppressed the N45 amplitude, which has been linked to GABA-A receptor-mediated neurotransmission by studies manipulating TEPs with benzodiazepines as GABAergic positive modulators (Premoli et al., J.Neurosci.:J.Soc.Neurosci.2014, 34:5603-5612; Darmani et al., J.Neurosci.:J.Soc.Neurosci.2016, 36:12312-12320). The 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. As an alternative explanation, the TMS response is not propagating to the contralateral hemisphere, given the overall increase in cortical inhibition, which would imply 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 of 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 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 delta, theta and beta bands.

[0387] The TMS-EMG and TMS-EEG results show that 20 mg of Compound A, upon crossing the blood-brain barrier, affects cortical excitability, as demonstrated by the 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 study endpoints may play a crucial role in determining the therapeutic efficacy of Compound A in epilepsy patients. For example, RMT is lower and intracortical inhibition is impaired in drug-naive patients compared to healthy controls. For this particular compound, the 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 entireties, 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 made 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 and equivalents of the appended claims.

Claims

1. 1. A method for treating a disease, disorder or condition associated with Kv7 potassium channel dysfunction in a human in need thereof, comprising orally administering to said human under postprandial conditions a therapeutically effective amount of Compound A; The method wherein compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

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

3. 3. The method of claim 1 or claim 2, wherein the method enhances the opening of Kv7 potassium channels.

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

5.

5. 5. The method of claim 4, wherein the 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.

6. 6. The method of any one of claims 1 to 5, wherein the disease, disorder or condition is a seizure disorder.

7. 7. The method of claim 6, wherein the seizure disorder is focal onset epilepsy.

8. 1. A method of treating a seizure disorder in a human in need thereof, comprising orally administering to said human an amount of Compound A under fed conditions; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, wherein the amount of Compound A is sufficient to treat said seizure disorder in said human.

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

10. 1. A method of treating a seizure disorder in a human in need thereof, comprising orally administering to said human an amount of Compound A under fed conditions; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method wherein the amount of Compound A is 2 to 200 mg.

11. 1. A method for treating a seizure disorder in a human in need thereof, comprising orally administering to said human an amount of Compound A between 30 minutes before and 2 hours after a meal; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method wherein the amount of Compound A is 2 to 200 mg.

12. 1. A method of treating a seizure disorder in a human in need thereof, comprising orally administering to said human a 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 comprises orally administering said Compound A to said human under fed conditions.

13. 1. A method of treating a seizure disorder in a human in need thereof, comprising orally administering to said human a 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 comprises orally administering said Compound A to said human between 30 minutes before and 2 hours after a meal.

14. 1. A method of orally administering compound A to a human 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 comprises orally administering said Compound A to said human under fed conditions.

15. 1. A method of orally administering compound A to a human 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 comprises orally administering said Compound A to said human between 30 minutes before and 2 hours after a meal.

16. The method comprises administering to said human a C 2 H 2 O , C , D , E , F , H , I ... ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ 16. The method of claim 8, wherein one or more of the following is increased:

17. C of Compound A in humans receiving oral administration of Compound A ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ orally administering to said human an amount of Compound A under postprandial conditions; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method provides a method for determining whether a given amount of Compound A is greater than or equal to C when compared to when the same amount of Compound A is orally administered to the human in a fasted state. ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ A method for increasing one or more of the above.

18. C of Compound A in humans receiving oral administration of Compound A ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ orally administering to said human an amount of Compound A between 30 minutes before and 2 hours after a meal; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method provides a method for determining whether a given amount of Compound A is greater than or equal to C when compared to when the same amount of Compound A is orally administered to the human in a fasted state. ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ A method for increasing one or more of the above.

19. 1. A method of orally administering Compound A to a human in need thereof, comprising orally administering Compound A to said human in a fed state; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method comprises administering to said human a C 2 H 2 O , C , D , E , F , H , I ... ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ A method for increasing one or more of the above.

20. 1. A method for orally administering Compound A to a human in need thereof, comprising the steps of orally administering Compound A to said human between 30 minutes before and 2 hours after a meal; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method comprises administering to said human a C 2 H 2 O , C , D , E , F , H , I ... ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ A method for increasing one or more of the above.

21. 1. A method of reducing a 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 said human under fed conditions; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The reduced dose has the same C value as Compound A when orally administered to the human in the fasted state. ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ The dosage is lower than that required to achieve one or more of the following:

22. 1. A method of reducing a 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 said human between 30 minutes before and 2 hours after a meal; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The reduced dose has the same C value as Compound A when orally administered to the human in the fasted state. ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ The dosage is lower than that required to achieve one or more of the following:

23. Oral administration of Compound A to said human reduces C of Compound A compared to when the same amount of Compound A is orally administered to said human in a fasted state. ｍａｘ 23. The method according to any one of claims 16 to 22, wherein the

24. C after oral administration of Compound A in the fasted state ｍａｘ C after oral administration of Compound A to ｍａｘ The method of claim 23, wherein the ratio is greater than 1.

3.

25. C after oral administration of Compound A in the fasted state ｍａｘ C after oral administration of Compound A to ｍａｘ The method of claim 23, wherein the ratio is greater than 2.

26. C after oral administration of Compound A in the fasted state ｍａｘ C after oral administration of Compound A to ｍａｘ The method of claim 23, wherein the ratio is greater than 3.

27. Compound A C ｍａｘ 24. The method of claim 23, wherein the increase is at least 50%.

28. Compound A C ｍａｘ 24. The method of claim 23, wherein the increase is at least 100%.

29. Oral administration of Compound A to said human reduces the AUC of Compound A compared to when the same amount of Compound A is orally administered to said human in a fasted state. ｉｎｆ 29. The method according to any one of claims 16 to 28, wherein the

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 claim 29, wherein the ratio is greater than 1.

3.

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 claim 29, wherein the ratio is greater than 1.

5.

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 claim 29, wherein the ratio is greater than 1.

8.

33. AUC of Compound A ｉｎｆ 30. The method of claim 29, wherein the increase is at least 50%.

34. AUC of Compound A ｉｎｆ 30. The method of claim 29, wherein the increase is at least 75%.

35. Oral administration of Compound A to said human reduces the T of Compound A compared to when the same amount of Compound A is orally administered to said human in a fasted state. ｍａｘ 35. The method of any one of claims 16 to 34, wherein the

36. T after oral administration of Compound A in the fasted state ｍａｘ T after oral administration of Compound A to ｍａｘ The method of claim 35, wherein the ratio is greater than 1.

3.

37. T after oral administration of Compound A in the fasted state ｍａｘ T after oral administration of Compound A to ｍａｘ The method of claim 35, wherein the ratio is greater than 1.

8.

38. T after oral administration of Compound A in the fasted state ｍａｘ T after oral administration of Compound A to ｍａｘ The method of claim 35, wherein the ratio is greater than 2.

39. Compound A T ｍａｘ The method of claim 35, wherein the increase is at least 50%.

40. Compound A T ｍａｘ The method of claim 35, wherein the increase is at least 75%.

41. Oral administration of Compound A to said human reduces the t1 / 2 of Compound A compared to when the same amount of Compound A is orally administered to said human in a fasted state. λｚ 41. The method of any one of claims 16 to 40, wherein the

42. t1 / 2 after oral administration of Compound A in the fasted state λｚ t1 / 2 after oral administration of Compound A to λｚ The method of claim 41, wherein the ratio is greater than 1.

2.

43. t1 / 2 after oral administration of Compound A in the fasted state λｚ t1 / 2 after oral administration of Compound A to λｚ The method of claim 41, wherein the ratio is greater than 1.

4.

44. t1 / 2 of Compound A λｚ 42. The method of claim 41, wherein the increase is at least 20%.

45. t1 / 2 of Compound A λｚ 42. The method of claim 41, wherein the increase is at least 35%.

46. 1. A method for treating a seizure disorder in a human in need thereof, comprising orally administering to said human Compound A; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method further 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 hr ｍａｘ or t1 / 2 of at least 130 h λｚ A method for producing one or more of the following:

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

48. A method of increasing resting motor threshold (RMT) or active motor threshold (AMT) in a human in need thereof, comprising orally administering to said human an amount of Compound A; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method wherein the amount of Compound A is 2 to 200 mg.

49. 49. The method of claim 47 or claim 48, wherein the increase in RMT or AMT is proportional to the plasma concentration of compound A.

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

51. 1. A method of decreasing corticospinal or cortical excitability in a human in need thereof, comprising orally administering to said human an amount of Compound A; Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method wherein the amount of Compound A is 2 to 200 mg.

52. The method of any one of claims 1 to 7, comprising orally administering 2 to 200 mg of Compound A.

53. 53. The method of any one of claims 8 to 52, comprising orally administering 2 to 100 mg of Compound A.

54. 54. The method of claim 53, comprising orally administering 5 to 50 mg of Compound A.

55. 54. The method of claim 53, comprising orally administering 10 mg, 20 mg, or 25 mg of Compound A.

56. 54. The method of claim 53, comprising orally administering 20 mg of Compound A.

57. 55. The method of any one of claims 8 to 54, comprising orally administering at least 20 mg of Compound A.

58. 58. The method of any one of claims 8 to 57, comprising orally administering 5 to 500 mg of Compound A per day.

59. 59. The method of claim 58, comprising orally administering 20 to 150 mg of Compound A per day.

60. 59. The method of claim 58, comprising orally administering 100 mg of Compound A per day.

61. 61. The method of any one of claims 1 to 60, comprising orally administering 0.05 to 2.0 mg / kg of Compound A.

62. 62. The method of claim 61, comprising orally administering 0.1 to 1.0 mg / kg of Compound A.

63. 62. The method of claim 61, comprising orally administering 0.2-0.5 mg / kg of Compound A.

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

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

66. 66. A compound for use according to claim 64 or claim 65, wherein the method enhances the opening of Kv7 potassium channels.

67. 67. The compound for use according to claim 66, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.

5.

68. 68. The compound for use according to claim 67, wherein the 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.

69. 69. A compound for use according to any one of claims 64 to 68, wherein the disease, disorder or condition is a seizure disorder.

70. 70. The compound for use according to claim 69, wherein the seizure disorder is focal onset epilepsy.

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

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

73. Oral administration of the compound reduces the C of the compound compared to when the same amount of the compound is orally administered to the human in a fasted state. ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ 73. A compound for use according to any one of claims 64 to 72, which increases one or more of:

74. 20. A compound for use in a human receiving oral administration of said compound, ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ and wherein the compound is for use in increasing one or more of the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The compound is orally administered to the human in a fed state, and the oral administration of the compound reduces C ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ The compound for use in an embodiment of the present invention increases one or more of the following:

75. 20. A compound for use in a human receiving oral administration of said compound, ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ and wherein the compound is for use in increasing one or more of the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the compound is orally administered to the human between 30 minutes before and 2 hours after a meal; Oral administration of the compound reduces the C ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ The compound for use in an embodiment of the present invention increases one or more of the following:

76. 1. 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, the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, a reduced dose of the compound is orally administered to the human under fed conditions; The reduced dose has the same C ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ The compound for use in an amount less than that required to achieve one or more of the following:

77. 1. 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, the compound is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, the reduced dose of the compound is orally administered to the human between 30 minutes before and 2 hours after a meal; The reduced dose has the same C ｍａｘ , A.U.C. ｉｎｆ , T ｍａｘ , or t λｚ The compound for use in an amount less than that required to achieve one or more of the following:

78. Oral administration of the compound to the human reduces the C of the compound compared to when the same amount of the compound is orally administered to the human in a fasted state. ｍａｘ 78. A compound for use according to any one of claims 73 to 77, which increases

79. C after oral administration of the compound in the fasted state ｍａｘ C after oral administration of the compound to ｍａｘ 79. The compound for use according to claim 78, wherein the ratio is greater than 1.

3.

80. C after oral administration of the compound in the fasted state ｍａｘ C after oral administration of the compound to ｍａｘ 79. The compound for use according to claim 78, wherein the ratio is greater than 2.

81. C after oral administration of the compound in the fasted state ｍａｘ C after oral administration of the compound to ｍａｘ 79. The compound for use according to claim 78, wherein the ratio is greater than 3.

82. C of the compound ｍａｘ 79. The compound for use according to claim 78, wherein the increase in is at least 50%.

83. C of the compound ｍａｘ 79. The compound for use according to claim 78, wherein the increase in is at least 100%.

84. Oral administration of the compound to the human reduces the AUC of the compound compared to when the same amount of the compound is orally administered to the human in a fasted state. ｉｎｆ 79. A compound for use according to any one of claims 73 to 78, which increases

85. AUC after oral administration of the compound in the fasted state ｉｎｆ AUC after oral administration of the compound to ｉｎｆ 85. The compound for use according to claim 84, wherein the ratio is greater than 1.

3.

86. AUC after oral administration of the compound in the fasted state ｉｎｆ AUC after oral administration of the compound to ｉｎｆ 85. The compound for use according to claim 84, wherein the ratio is greater than 1.

5.

87. AUC after oral administration of the compound in the fasted state ｉｎｆ AUC after oral administration of the compound to ｉｎｆ 85. The compound for use according to claim 84, wherein the ratio is greater than 1.

8.

88. The AUC of the compound ｉｎｆ 85. The compound for use according to claim 84, wherein the increase in is at least 50%.

89. The AUC of the compound ｉｎｆ 85. The compound for use according to claim 84, wherein the increase in is at least 75%.

90. Oral administration of the compound to the human reduces the T value of the compound compared to when the same amount of the compound is orally administered to the human in a fasted state. ｍａｘ 90. A compound for use according to any one of claims 73 to 89, which increases

91. T after oral administration of the compound in the fasted state ｍａｘ T after oral administration of the compound to ｍａｘ 91. The compound for use according to claim 90, wherein the ratio is greater than 1.

3.

92. T after oral administration of the compound in the fasted state ｍａｘ T after oral administration of the compound to ｍａｘ 91. The compound for use according to claim 90, wherein the ratio is greater than 1.

8.

93. T after oral administration of the compound in the fasted state ｍａｘ T after oral administration of the compound to ｍａｘ 91. The compound for use according to claim 90, wherein the ratio is greater than 2.

94. T of the compound ｍａｘ 76. The compound for use according to claim 75, wherein the increase in is at least 50%.

95. T of the compound ｍａｘ 91. The compound for use according to claim 90, wherein the increase in is at least 75%.

96. Oral administration of the compound to the human reduces the t1 / 2 value of the compound compared to the same amount of the compound being orally administered to the human in a fasted state. λｚ 96. A compound for use according to any one of claims 73 to 95, which increases

97. t1 / 2 following oral administration of the compound in the fasted state λｚ t1 / 2 after oral administration of the compound to λｚ 97. The compound for use according to claim 96, wherein the ratio is greater than 1.

2.

98. t1 / 2 following oral administration of the compound in the fasted state λｚ t1 / 2 after oral administration of the compound to λｚ 97. The compound for use according to claim 96, wherein the ratio is greater than 1.

4.

99. The t1 / 2 of the compound λｚ 97. The compound for use according to claim 96, wherein the increase in is at least 20%.

100. The t1 / 2 of the compound λｚ 97. The compound for use according to claim 96, wherein the increase in is at least 35%.

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

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

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

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

105. 90. The compound for use according to any one of claims 64 to 89, wherein 2 to 200 mg of the compound is administered.

106. The compound for use according to claim 105, wherein 2-100 mg of said compound is administered.

107. The compound for use according to claim 105, wherein 5 to 50 mg of said compound is administered.

108. 106. The compound for use according to claim 105, wherein 10 mg, 20 mg, or 25 mg of the compound is administered.

109. 106. The compound for use according to claim 105, wherein 20 mg of the compound is administered.

110. 108. The compound for use according to any one of claims 64 to 107, wherein at least 20 mg of the compound is administered.

111. The compound for use according to any one of claims 64 to 110, wherein 5 to 500 mg of said compound is administered per day.

112. The compound for use according to claim 111, wherein 20-150 mg of said compound is administered per day.

113. 112. The compound for use according to claim 111, wherein 100 mg of the compound is administered per day.

114. The compound for use according to any one of claims 64 to 113, wherein 0.05 to 2.0 mg / kg of the compound is administered.

115. The compound for use according to claim 114, wherein 0.1 to 1.0 mg / kg of said compound is administered.

116. The compound for use according to claim 114, wherein 0.2-0.5 mg / kg of said compound is administered.

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