How to administer solriamfetol to lactating women

Abstract

Provided herein, according to some embodiments, is a method for reducing the likelihood of adverse events from solriamfetol in an infant fed breast milk obtained from a subject treated with solriamfetol, the method comprising: administering solriamfetol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant breast milk from the subject at least about 5 hours after administration of solriamfetol to the subject, thereby reducing the likelihood of adverse events from solriamfetol in the infant.

Description

[Technical Field]

[0001] Priority statement This application is a continuation of U.S. Patent Application No. 18 / 148,682, filed December 30, 2022 (now U.S. Patent No. 11,771,666); U.S. Patent Application No. 18 / 176,816, filed March 1, 2023 (now U.S. Patent No. 11,771,667); U.S. Patent Application No. 18 / 176,855, filed March 1, 2023 (now U.S. Patent No. 11,793,776); U.S. Patent Application No. 18 / 176,860, filed March 1, 2023 (now U.S. Patent No. 11,779,554); and U.S. Patent Application No. 18 / 323,229, filed May 24, 2023. No. 18 / 323,232, filed May 24, 2023; U.S. Patent Application No. 18 / 323,236, filed May 24, 2023; U.S. Patent Application No. 18 / 491,291, filed October 20, 2023; U.S. Patent Application No. 18 / 491,301, filed October 20, 2023; U.S. Patent Application No. 18 / 491,311, filed October 20, 2023; and U.S. Patent Application No. 18 / 491,319, filed October 20, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention relates to a method of administering solriamfetol to a lactating subject while reducing the likelihood of adverse events from solriamfetol in an infant breastfed by said subject. [Background technology]

[0003] Solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor approved in the United States to improve wakefulness in adult subjects with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). Solriamfetol has been shown to be useful in treating a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, and fibromyalgia.

[0004] Pharmacokinetic studies have shown rapid absorption and high oral bioavailability with dose-proportional exposure (peak serum concentration and area under the concentration-time curve [AUC]) in test animals.

[0005] The present invention overcomes deficiencies in the art by providing a method of administering solriamfetol to a lactating subject while reducing the likelihood of adverse events from solriamfetol in an infant breastfed by said subject. Summary of the Invention

[0006] The present invention relates to the development of methods for reducing the likelihood of adverse events from solriamfetol in infants breastfed from a subject. The present invention further relates to methods for reducing exposure to solriamfetol in infants breastfed from subjects treated with solriamfetol.

[0007] Accordingly, one aspect of the present invention relates to a method for reducing exposure to solriamfetol in an infant fed breast milk obtained from a subject treated with solriamfetol, comprising: orally administering solriamfetol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant breast milk from the subject at least 2 hours (e.g., at least 3, 4, or 5 hours) after administration of solriamfetol to the subject, thereby reducing the exposure of the infant to solriamfetol.

[0008] Another aspect of the present invention relates to a method for reducing the likelihood of adverse events from solriamfetol in an infant who is fed breast milk from a subject treated with solriamfetol, comprising: orally administering to the subject solriamfetol at a daily dose of 37.5 mg to 300 mg; and feeding the infant breast milk from the subject at least 2 hours (e.g., at least 3, 4, or 5 hours) after administering solriamfetol to the subject, thereby reducing the likelihood of adverse events from solriamfetol in the infant. In some embodiments, the daily dose of solriamfetol is 150 mg.

[0009] One aspect of the present invention relates to a method of treating a disorder treatable with solriamfetol in a subject producing breast milk for feeding to an infant, the method comprising: orally administering solriamfetol to the subject at a daily dose of 37.5 mg to 300 mg; and feeding the breast milk from the subject to the infant at least two hours (e.g., at least three, four, or five hours) after administration of solriamfetol to the subject, thereby reducing exposure to solriamfetol and / or reducing the likelihood of adverse events in the infant breastfed by the subject. The disorder treatable with solriamfetol may be, but is not limited to, narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit / hyperactivity disorder, cognitive impairment, or binge-eating disorder.

[0010] Another aspect of the invention is a method of preventing exposure of an infant of a nursing mother being treated with solriamfetol to peak concentrations of solriamfetol excreted in breast milk, comprising withholding breast milk from the infant from the mother within a minimum of 3.5 hours (e.g., a minimum of 4 or 5 hours) of receiving a single oral daily dose of solriamfetol, and preventing exposure of the infant to peak concentrations of solriamfetol excreted in breast milk. max is about 1.1 hours.

[0011] A further aspect of the invention relates to a method for reducing exposure to solriamfetol from breast milk in an infant receiving breast milk from a nursing mother who is being treated with a once-daily dose of about 37.5 mg to about 300 mg of solriamfetol for a disorder amenable to treatment with solriamfetol, comprising feeding the infant breast milk obtained from the mother a minimum of about 5 hours after administration of solriamfetol to the mother, wherein the exposure to solriamfetol in the infant is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of solriamfetol.

[0012] A further aspect of the present invention relates to a method for treating excessive daytime sleepiness in lactating mothers who desire to breastfeed their infant and whose infant is at risk for adverse events from excessive maternal daytime sleepiness, the method comprising: (a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant; (b) administering a starting dose of 37.5 mg of solriamfetol once daily to a mother who has an ESS total score of 15 or greater and experiences sleep attacks while caring for her infant if the excessive daytime sleepiness is associated with obstructive sleep apnea, or ... If excessive sleepiness is associated with narcolepsy, provide a starting dose of 75 mg of solriamfetol once daily, doubling said dose to a maximum of 150 mg once daily at intervals of at least 3 days, wherein the elimination half-life of solriamfetol in the plasma of a postpartum or lactating mother is about 5 hours; and (c) avoid exposing said infant to the maximum concentration of solriamfetol in breast milk by feeding said infant breast milk obtained from said mother at least about 3.5 hours (e.g., 4 or 5 hours) after administration of solriamfetol to said mother, wherein the median T max is approximately 1.1 hours.

[0013] In some embodiments, the method provides a daily infant dose of about 0.3 mg or less of solriamfetol. In some embodiments, the method achieves a relative infant dose of less than about 9% of the subject's weight-adjusted dose. In some embodiments, the method achieves a relative infant dose of less than about 5% of the subject's weight-adjusted dose.

[0014] In some embodiments, the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to exposure to solriamfetol.

[0015] In some embodiments, the subject is 1 day to 24 months postpartum or 10 days to 12 months (52 weeks) postpartum.

[0016] In some embodiments, the subject is being treated with solriamfetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, or binge eating disorder.

[0017] In some embodiments, the subject is a female between the ages of 18 and 45.

[0018] In some embodiments, the adverse event is one or more of restlessness, insomnia, loss of appetite, or decreased weight gain.

[0019] A method for treating a disorder suitable for treatment with solriamfetol in a subject who is breastfeeding an infant, comprising orally administering to the subject a daily dose of between about 37.5 mg and 300 mg of solriamfetol.

[0020] These and other aspects of the invention are described in more detail below in the description of the invention. [Brief explanation of the drawings]

[0021] Figure 1 Time course of mean solriamfetol breast milk and plasma concentration-time profiles (linear and semi-logarithmic scale).

[0022] Figure 2. Mean cumulative solriamfetol amount in breast milk-time profile (linear scale) after administration of a single dose of solriamfetol 150 mg tablets.

[0023] Detailed Description The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Additionally, all references cited herein are incorporated by reference in their entirety.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.The terms used in the description of the present invention herein are only intended to describe specific embodiments and are not intended to limit the present invention.All publications, patent applications, patents, patent publications and other references cited herein are incorporated by reference in their entirety for the teachings related to the sentence and / or paragraph in which the reference is presented.

[0025] It is specifically contemplated that the various features of the invention described herein can be used in any combination, unless the context dictates otherwise.

[0026] Furthermore, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0027] To illustrate, if the specification states that a composite comprises components A, B, and C, it is specifically contemplated that any of A, B, or C, or combinations thereof, singly or in any combination, may be omitted and waived.

[0028] As used in describing the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context dictates otherwise.

[0029] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted as alternatives ("or").

[0030] As used herein, the term "about," when referring to a measurable value such as amount of a polypeptide, dosage, time, temperature, enzyme activity or other biological activity, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0031] As used herein, the transitional phrase "consisting essentially of" (and grammatical variations) should be construed to include the recited materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. Thus, as used herein, the term "consisting essentially of" should not be construed as equivalent to "comprising."

[0032] The terms "therapeutically effective amount" or "effective amount," as used herein, refer to the amount of a composition, compound, or agent of the invention that imparts a modulating effect (which can be, e.g., a beneficial effect) to a subject afflicted with a disorder, disease, or condition, including improving the subject's condition (e.g., in one or more symptoms), slowing or reducing the progression of the condition, preventing or delaying the onset of the disorder, and / or altering clinical parameters, the disease, or condition, as is well known in the art. For example, a therapeutically effective amount or effective amount can refer to the amount of a composition, compound, or agent that improves the condition in a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0033] A "pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") refers to a carrier or excipient useful in preparing pharmaceutical or therapeutic compositions, including carriers that are generally safe and non-toxic and acceptable for veterinary and / or human pharmaceutical or therapeutic use. The term "carrier" or "pharmaceutically acceptable carrier" can include, but is not limited to, phosphate buffered saline, water, emulsions (e.g., oil-in-water or water-in-oil emulsions), and / or various types of wetting agents. As used herein, the term "carrier" includes, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer or other material known in the art for use in pharmaceutical formulations, and as further described herein.

[0034] The terms "modulate," "modulates," or "modulation" refer to an enhancement (eg, an increase) or inhibition (eg, a decrease) in a particular level or activity.

[0035] The term "enhance" or "increase" refers to an increase in a particular parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, 12-fold, or 15-fold, and / or can be expressed as an enhancement and / or increase in a particular level and / or activity of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more.

[0036] As used herein, "inhibition" or "reduction" or grammatical variations thereof refer to a decrease or reduction in a particular level or activity of at least about 1, 5, 10, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In certain embodiments, inhibition or reduction results in little or essentially no detectable activity (at most, an insignificant amount, for example, less than about 10% or less than 5%).

[0037] As used herein in the context of treating a subject, the terms "treat," "treatment," and similar terms refer to providing medical and / or surgical management of a subject. Treatment may include, but is not limited to, administering an agent or composition (e.g., a pharmaceutical composition) to a subject. Treatment is typically performed with the goal of altering the course of a disease (this term is used to refer to any disease, disorder, syndrome, or undesirable condition that warrants or potentially warrants therapy) in a manner beneficial to the subject. The effects of treatment may include regression, alleviation, reduction in severity, delay in onset, cure, inhibition of progression, and / or reduction in the likelihood of the occurrence or recurrence of a disease or one or more symptoms of a disease, or the manifestation of a disease. A therapeutic agent may be administered to a subject who has a disease or who is at high risk of developing a disease compared to members of the general population. In some embodiments, a therapeutic agent may be administered to a subject who had a disease but no longer shows signs of the disease. The agent may be administered, for example, to reduce the likelihood of overt disease recurrence. A therapeutic agent may be administered prophylactically, i.e., before the onset of any symptoms or the manifestation of a disease. "Prophylactic treatment" refers to providing medical and / or surgical management to a subject who does not have or show symptoms of a disease, e.g., to reduce the likelihood of the disease occurring, delay the onset of the disease, or reduce the severity of the disease if it does occur. The subject may be identified as being at risk for developing the disease (e.g., at increased risk compared to the general population or having risk factors that increase the likelihood of developing the disease).

[0038] Grammatical variations of "administer," "administration," and "administering" to a subject include any route of introducing or delivering an agent to a subject. Administration can be by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arterial, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, intravaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques), and the like. As used herein, "concurrent administration," "administration in combination," "simultaneous administration," or "administered simultaneously" means that compounds are administered at the same time, at overlapping times, or one after the other. In the latter case, the two compounds are administered sufficiently close in time that the observed results are indistinguishable from those achieved if the compounds were administered at the same time. "Systemic administration" refers to the introduction or delivery of an agent to a subject via a route that introduces or delivers the agent to a wide area of ​​the subject's body (e.g., more than 50% of the body), for example, through an entry point into the circulatory or lymphatic system. In contrast, "local administration" refers to the introduction or delivery of an agent to a subject via a route that introduces or delivers the agent to the area or an area immediately adjacent to the point of administration, but does not introduce the agent systemically in therapeutically significant amounts. For example, a locally administered agent is readily detectable in the local vicinity of the point of administration, but is undetectable or detectable in negligible amounts in distant parts of the subject's body. Administration includes self-administration and administration by another.

[0039] "Pharmaceutically acceptable," as used herein, means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual in conjunction with a composition of the present invention without causing substantial adverse biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. As is well known to those skilled in the art, the material would naturally be selected to minimize degradation of the active ingredient and to minimize adverse side effects in the subject (see, e.g., Remington's Pharmaceutical Science; 21st ed. 2005).

[0040] "Combined administration" means that the administration is sufficiently close in time to produce a combined effect (i.e., the combination can be simultaneous, or can be two or more events that occur within a short time before or after each other). In some embodiments, the "combined administration" of two or more compounds means that the two compounds are administered close enough in time that the presence of one compound alters the biological effect of the other compound. The two compounds can be administered in the same or different formulations, or sequentially. The combined administration can be carried out by mixing the compounds before administration, or by administering the compounds in two different formulations, for example, at the same time but at different anatomical sites, or by using different administration routes.

[0041] "Bioavailability," as used herein, refers to the estimated area under the curve or AUC of an active drug in the systemic circulation after oral administration in a dosage form disclosed herein compared to the AUC of the active drug in the systemic circulation after intravenous administration of the active drug. The AUC is affected by the extent to which the drug is absorbed in the gastrointestinal tract.

[0042] The product is the relative average C of the test product to the reference product. max , AUC (0-t) and AUC (0-∞) If the difference is within the range of 80-125%, it is considered "bioequivalent."

[0043] The term “AUC (0-t) " means the area under the plasma concentration curve from time 0 to time t.

[0044] The term “AUC (0-∞) " or "AUC 0-inf " means the area under the plasma concentration time curve from time 0 to infinity.

[0045] "C max " refers to the maximum milk or plasma concentration of solriamfetol.

[0046] "T max " refers to the time to peak milk or plasma concentration of a given drug.

[0047] "t 1 / 2 " refers to the period during the terminal elimination phase of a drug during which milk and plasma concentrations decrease by 50%.

[0048] Milk:plasma ratio means the AUC in breast milk divided by the AUC in plasma.

[0049] "A milk " means the amount excreted in breast milk over a 72-hour period.

[0050] "Vd / F" means the apparent volume of distribution in plasma.

[0051] "CL / F" is the apparent oral clearance in plasma.

[0052] AUC0-t is the area under the concentration-time curve from time 0 to time t of the last quantifiable concentration (in milk and plasma).

[0053] "Excessive daytime sleepiness" or "EDS" refers to persistent sleepiness during the daytime, even after a night's sleep that is apparently adequate or even prolonged, during times when an individual is expected to be awake and awake. EDS can be the result of a sleep disorder or a symptom of another underlying disorder, such as narcolepsy, sleep apnea, circadian rhythm sleep disorder, or idiopathic hypersomnia. Although the term includes "daytime," it is understood that sleepiness can occur at other times when the subject should be awake, such as at night or at other times (e.g., when the subject works a night shift). It is also understood that EDS is medically distinct from fatigue and fatigue-related disorders.

[0054] The present invention is based, in part, on the use of Sunosi® (also referred to herein as solriamfetol (also known as (R)-2-amino-3-phenylpropylcarbamate (APC) hydrochloride, formerly known as JZP-110, ADX-N05, R228060, and YKP10A)) in lactating subjects with disorders suitable for treatment with solriamfetol, while reducing the likelihood of adverse events in the subject's breastfed infant. Solriamfetol is approved by the FDA for administration at doses equivalent to 37.5 mg, 75 mg, and 150 mg of APC (corresponding to 44.7 mg, 89.3 mg, and 178.5 mg of APC hydrochloride, respectively). Administration of solriamfetol to breastfeeding subjects presents challenges. In non-clinical studies in rats, solriamfetol was detected in breast milk, and the milk concentration of solriamfetol was higher than the plasma concentration of solriamfetol. It would be desirable to reduce or minimize any adverse effects resulting from the daily dose received by infants breastfed from subjects treated with solriamfetol. Furthermore, it would be desirable to identify methods for considering the safety and tolerability of solriamfetol in nursing mothers.

[0055] Accordingly, one aspect of the present invention relates to a method for reducing exposure to solriamfetol in an infant fed breast milk obtained from a subject treated with solriamfetol, comprising orally administering solriamfetol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant breast milk from the subject at least 2 hours (e.g., at least 3, 4, or 5 hours) after administration of solriamfetol to the subject, thereby reducing the exposure of the infant to solriamfetol.

[0056] One aspect of the present invention includes a method for reducing the likelihood of adverse events from solriamfetol in an infant who is breastfed from a subject treated with solriamfetol, comprising orally administering solriamfetol to the subject at a daily dose of 37.5 mg to 300 mg; and feeding the infant breast milk from the subject at least 2 hours (e.g., at least 3, 4, or 5 hours) after administering solriamfetol to the subject, thereby reducing the likelihood of adverse events from solriamfetol in the infant. In one embodiment, the adverse events are one or more of restlessness, insomnia, loss of appetite, or reduced weight gain.

[0057] Another aspect of the invention is a method of preventing exposure of an infant of a nursing mother being treated with solriamfetol to peak concentrations of solriamfetol excreted in breast milk, comprising withholding breast milk from the infant obtained within at least about 3.5 hours (e.g., at least about 4 or 5 hours) of the mother receiving an oral once-daily dose of solriamfetol, and preventing exposure of the infant to peak concentrations of solriamfetol excreted in breast milk. max In clinical trials, T max The range of T was 1 to 3 hours. Therefore, waiting at least 3.5 hours after administration of solriamfetol is recommended even for subjects with outlying values. max Ensure avoidance of

[0058] A further aspect of the invention relates to a method of reducing exposure to solriamfetol from breast milk in an infant receiving breast milk from a nursing mother being treated for a disorder amenable to treatment with solriamfetol with a once-daily dose of about 37.5 mg to about 300 mg of solriamfetol, comprising feeding the infant breast milk obtained from the mother at least about 5 hours (e.g., at least 6, 7, 8, 9, or 10 hours) after administering solriamfetol to the mother, wherein the infant's exposure to solriamfetol is reduced by at least about 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%) compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administering solriamfetol. In some embodiments, the resulting relative infant dose is no more than about 2% of the maternal weight-adjusted dose. In some embodiments, the daily dose of solriamfetol is 150 mg, and the daily dose of solriamfetol that infants receive through breast milk is about 0.3 mg or less.In some embodiments, the daily dose of solriamfetol is 75 mg, and the daily dose of solriamfetol that infants receive through breast milk is about 0.15 mg or less.In some embodiments, breast milk is obtained from the mother at least about 10 hours (for example, about 2 half-lives) after the administration of solriamfetol to the mother, and the exposure of infants to solriamfetol is reduced by at least about 75% compared to the exposure that occurs when infants are fed breast milk obtained from the mother less than 5 hours after the administration of solriamfetol.In some embodiments, the relative infant dose obtained is about 1% or less of the mother's weight-adjusted dose.

[0059] One aspect of the present invention relates to a method for treating a disorder treatable with solriamfetol in a subject producing breast milk for feeding to an infant, the method comprising: orally administering solriamfetol to the subject at a daily dose of 37.5 mg to 300 mg; and feeding the infant breast milk obtained from the subject at least 2 hours (e.g., at least 3, 4, or 5 hours) after administering solriamfetol to the subject, thereby reducing exposure to solriamfetol and / or reducing the likelihood of adverse events in an infant breastfed by the subject. In one embodiment, the method reduces solriamfetol in the infant, and the infant does not experience restlessness, insomnia, loss of appetite, or decreased weight gain due to solriamfetol exposure. In one embodiment, the adverse event is one or more of restlessness, insomnia, loss of appetite, or decreased weight gain.

[0060] "Suitable disorder for treatment with solriamfetol" or "disorder treatable with solriamfetol" refers to the disorder for which administering solriamfetol to a subject results in the treatment of one or more symptoms of the disorder in the subject.Exemplary disorders suitable for treatment with solriamfetol include narcolepsy, cataplexy, excessive daytime sleepiness, obstructive sleep apnea, shift work disorder, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit hyperactivity disorder (ADHD), cognitive impairment and / or cognitive dysfunction, Parkinson's disease, restless legs syndrome, depression, bipolar disorder, obesity, or binge eating disorder.In some embodiments, the cognitive disorder is related to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.In some embodiments, the disorder suitable for treatment with solriamfetol includes narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, or binge eating disorder. In some embodiments, solriamfetol is administered to improve wakefulness.See, for example, United States Patent Nos. 8,232,315;8,440,715;8,552,060;8,623,913;8,729,120;8,741,950;8,895,609;8,927,602;9,226,910 and 9,359,290; and United States Patent Application Publication No. 2012 / 0004300 and 2015 / 0018414.All of the above-mentioned patents and applications are incorporated herein by reference in their entirety for all purposes.

[0061] "Excessive daytime sleepiness" or "EDS" refers to persistent sleepiness during the daytime, even after a night's sleep that is apparently adequate or even prolonged, during times when an individual is expected to be awake and awake. EDS can be the result of a sleep disorder or a symptom of another underlying disorder, such as narcolepsy, sleep apnea, circadian rhythm sleep disorder, or idiopathic hypersomnia. Although the term includes "daytime," it is understood that sleepiness can occur at other times when the subject should be awake, such as at night or at other times (e.g., when the subject works a night shift). It is also understood that EDS is medically distinct from fatigue and fatigue-related disorders.

[0062] In some embodiments, the cause of EDS may be, but is not limited to, a central nervous system (CNS) pathological abnormality, stroke, narcolepsy, idiopathic CNS hypersomnia; sleep deficiency, sleep apnea, obstructive sleep apnea, insufficient nighttime sleep, chronic pain, acute pain, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, major depression, bipolar disorder, cardiac ischemia; a mismatch between the body's circadian pacemaker and the environment, jet lag, shift work disorder, or sedative medications.

[0063] In certain embodiments, the structure of solriamfetol is shown below as Formula I: [ka] Methods for making solriamfetol and related compounds can be found in U.S. Patent Nos. 10,829,443, 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All of the above patents and applications are incorporated herein by reference in their entirety for all purposes.

[0064] In one embodiment, the method described herein provides that an infant breastfed by a subject receiving solriamfetol does not experience adverse events, such as restlessness, insomnia, loss of appetite, or decreased weight gain due to exposure to solriamfetol.Infants can be monitored for restlessness, insomnia, loss of appetite, or decreased weight gain.For example, monitoring and / or detecting weight loss, decreased weight gain, decreased number of feedings or decreased intake, or decreased volume of milk intake can be performed.In addition, to confirm changes in infants, monitoring can be performed for increased restlessness and / or insomnia (including decreased sleep time and / or time spent falling asleep and staying asleep).In some embodiments, monitoring changes in infants is performed 3 hours or more after the administration of a solriamfetol dose and 3 hours or more after the subject begins to feed the infant breast milk, for example, 3, 4, 5, 6, 7, 8, 9, 10 hours or more after the administration of a solriamfetol dose. Monitoring of changes experienced by the infant (e.g., restlessness, insomnia, loss of appetite, or reduced weight gain) can be carried out over the period that solriamfetol is administered to the subject, which can extend over several days, weeks, or months, and can be monitored at any time within that time frame (including hourly, daily, weekly, monthly, or any range of times therein).

[0065] In one embodiment, the method comprises administering a dose of about 0.4 mg or less, e.g., about 0.39 mg, about 0.38 mg, about 0.37 mg, about 0.36 mg, about 0.35 mg, about 0.34 mg, about 0.335 mg, about 0.33 mg, about 0.32 mg, about 0.21 mg, about 0.30 mg, about 0.29 mg, about 0.28 mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about 0.23 mg, about 0.22 mg, about 0.21 mg The daily infant dose of solriamfetol is provided at about 0.20mg, about 0.19mg, about 0.18mg, about 0.17mg, about 0.16mg, about 0.15mg, about 0.14mg, about 0.13mg, about 0.12mg, about 0.11mg, about 0.10mg, about 0.09mg, about 0.08mg, about 0.07mg, about 0.06mg, about 0.05mg, about 0.04mg, about 0.03mg, about 0.02mg, about 0.01mg or less. Daily infant dose refers to the daily dose that an infant receives through breastfeeding. In some embodiments, subject is orally administered a single dose of about 150mg solriamfetol per day, and the daily infant dose of solriamfetol is reduced to about 0.3mg or less by a waiting period after administration. In some embodiments, the subject is orally administered a once-daily dose of about 75 mg of solriamfetol, with the daily infant dose of solriamfetol being reduced to about 0.15 mg or less by a waiting period after administration. In some embodiments, the subject is orally administered a once-daily dose of about 37.5 mg of solriamfetol, with the daily infant dose of solriamfetol being reduced to about 0.08 mg or less by a waiting period after administration.

[0066] In one embodiment, the method provides a daily infant dose of solriamfetor of about 0.2 mg / kg (based on a nominal infant weight of 6 kg) or less, e.g., about 0.19 mg / kg, about 0.18 mg / kg, about 0.17 mg / kg, about 0.16 mg / kg, about 0.15 mg / kg, about 0.14 mg / kg, about 0.13 mg / kg, about 0.12 mg / kg, about 0.11 mg / kg, about 0.10 mg / kg, about 0.09 mg / kg, about 0.08 mg / kg, about 0.07 mg / kg, about 0.06 mg / kg, about 0.05 mg / kg, about 0.04 mg / kg, about 0.03 mg / kg, about 0.02 mg / kg, about 0.01 mg / kg or less.

[0067] In one embodiment, the method comprises administering a dose of about 0.7 mg or less, e.g., about 0.69 mg, about 0.68 mg, about 0.67 mg, about 0.66 mg, about 0.65 mg, about 0.64 mg, about 0.63 mg, about 0.62 mg, about 0.61 mg, about 0.60 mg, about 0.59 mg, about 0.58 mg, about 0.57 mg, about 0.56 mg, about 0.55 mg, about 0.54 mg, about 0.53 mg, about 0.52 mg, about 0.51 mg, about 0.50 mg, about 0.49 mg, about 0.48 mg, about 0.47 mg, about 0.46 mg, about 0.45 mg, about 0.44 mg, about 0.43 mg, about 0.42 mg, about 0.41 mg, about 0.40 mg, about 0.39 mg, about 0.38 mg g, about 0.37 mg, about 0.36 mg, about 0.35 mg, about 0.34 mg, about 0.355 mg, about 0.33 mg, about 0.32 mg, about 0.31 mg, about 0.30 mg, about 0.29 mg, about 0.28 mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about 0.23 mg, about 0.22 mg, about 0.21 mg, about 0.20 mg, about 0.19 mg, about 0.18 mg, about 0.17 mg, about 0.16 mg, about 0.15 mg, about 0.14 mg, about 0.13 mg, about 0.12 mg, about 0.11 mg, about 0.10 mg

[0068] In some embodiments, the method provides a cumulative median infant dose of solriamfetol after a single dose ( / single administration) that is about 75% to 80%, e.g., about 75%, 76%, 77%, 78%, 79%, or 80%, of the total excreted in 72 hours after 8 hours. In some embodiments, the method provides a cumulative median infant dose of solriamfetol after a single dose ( / single administration) that is about 95% to 100%, e.g., about 95%, 96%, 97%, 98%, 99%, or 100%, of the total excreted in 72 hours after 24 hours.

[0069] In some embodiments, breast milk for feeding to an infant is expressed or produced by the subject 2 hours or more, 2.5 hours or more, 3 hours or more, 3.5 hours or more, 4 hours or more, 4.5 hours or more, or 5 hours or more after the administration of solriamfetol dose to the subject, for example, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours or more. In some embodiments, breast milk produced by the subject for feeding to an infant in the methods detailed herein occurs at or after about the mean elimination half-life of solriamfetol, i.e., about 5 hours after the administration of solriamfetol. In some embodiments, breast milk produced by the subject for feeding to an infant in the methods detailed herein occurs at or after about the mean elimination half-life of solriamfetol. max The administration of solriamfetol occurs at about 2 to 4 times or later, i.e., about 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours after administration of solriamfetol. In some embodiments, breastfeeding of an infant occurs at 3 hours or more, 4 hours or more, or 5 hours or more after administration of a dose of solriamfetol to a subject. In some embodiments, breast milk for feeding an infant is obtained from a subject at 3 hours or more, 4 hours or more, or 5 hours or more after administration of a dose of solriamfetol to a subject.

[0070] In some embodiments, the subject refrains from feeding the infant during the waiting period (e.g., 2 hours or more). In other embodiments, breast milk produced during the waiting period is expressed and not fed to the infant, e.g., the expressed milk is discarded.

[0071] In some embodiments, the method provides for the administration of less than about 10%, less than about 9.5%, less than about 9%, less than about 8.5%, less than about 8%, less than about 7.5%, less than about 7%, less than about 6.5%, less than about 6%, less than about 5.5%, less than about 5%, less than about 4.9%, less than about 4.8%, less than about 4.7%, less than about 4.6%, less than about 4.5%, less than about 4.4%, less than about 4.3%, less than about 4.2%, less than about 4.1%, less than about 4.0%, less than about 3.9%, less than about 3.8%, less than about 3.7%, less than about 3.6%, less than about 3.5%, less than about 3.4%, less than about 3.3%, less than about 3.4%, less than about 3.5%, less than about 3.6%, less than about 3.7%, less than about 3.8%, less than about 3.9%, less than about 3.8%, less than about 3.7%, less than about 3.6%, less than about 3.5%, less than about 3.4%, less than about 3.3%, less than about 3.5%, less than about 3.6%, less than about 3.7%, less than about 3.8%, less than about 3.5%, less than about 3.6%, less than about 3.7%, less than about 3.8%, less than about 3.8%, less than about 3.6%, less than about 3.5%, less than about 3.4%, less than about 3.3%, less than about 3.5%, less than about 3.5%, less than about 3.5%, less than about 3.5%, less than about 3.6%, less than about 3.5%, less than about 3.5%, less than about 3.5%, less than about 3.6%, less than about 3.6%, less than about 3.6 %, less than about 3.2%, less than about 3.1%, less than about 3.0%, less than about 2.9%, less than about 2.8%, less than about 2.7%, less than about 2.6%, less than about 2.5%, less than about 2.4%, less than about 2.3%, less than about 2.2%, less than about 2.1%, less than about 2.0%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, less than about 1.5%, less than about 1.4%, less than about 1.3%, less than about 1.2%, less than about 1.1%, less than about 1.0%.

[0072] In some embodiments, the cumulative median amount of solriamfetor received by an infant fed breast milk produced by a subject treated with solriamfetor according to the methods disclosed herein is less than about 0.70 mg, less than about 0.69 mg, less than about 0.68 mg, less than about 0.67 mg, less than about 0.66 mg, less than about 0.65 mg, less than about 0.64 mg, less than about 0.63 mg, less than about 0.62 mg, less than about 0.61 mg, less than about 0.60 mg over a 72-hour period. g, less than about 0.59 mg, less than about 0.58 mg, less than about 0.57 mg, less than about 0.56 mg, less than about 0.55 mg, less than about 0.54 mg, less than about 0.53 mg, less than about 0.52 mg, less than about 0.51 mg, less than about 0.50 mg, less than about 0.49 mg, less than about 0.48 mg, less than about 0.47 mg, less than about 0.46 mg, less than about 0.45 mg, less than about 0.44 mg, less than about 0.43 mg, less than about 0.42 mg, less than about 0.41 mg, less than about 0.40 mg , less than about 0.39 mg, less than about 0.38 mg, less than about 0.37 mg, less than about 0.36 mg, less than about 0.35 mg, less than about 0.34 mg, less than about 0.335 mg, less than about 0.33 mg, less than about 0.32 mg, less than about 0.31 mg, less than about 0.30 mg, less than about 0.29 mg, less than about 0.28 mg, less than about 0.27 mg, less than about 0.26 mg, less than about 0.25 mg, less than about 0.24 mg, less than about 0.23 mg, less than about 0.22 mg, less than about 0.21 mg, less than about 0.20 mg, less than about 0.19 mg, less than about 0.18 mg, less than about 0.17 mg, less than about 0.16 mg, less than about 0.15 mg, less than about 0.14 mg, less than about 0.13 mg, less than about 0.12 mg, less than about 0.11 mg, less than about 0.10 mg, less than about 0.09 mg, less than about 0.08 mg, less than about 0.07 mg, less than about 0.06 mg, less than about 0.05 mg, less than about 0.04 mg, less than about 0.03 mg, less than about 0.02 mg or less than about 0.01 mg.

[0073] In some embodiments, the cumulative median amount of solriamfetor received by an infant fed breast milk produced by a subject treated with solriamfetor according to the methods disclosed herein is less than about 0.70 mg, less than about 0.69 mg, less than about 0.68 mg, less than about 0.67 mg, less than about 0.66 mg, less than about 0.65 mg, less than about 0.64 mg, less than about 0.63 mg, less than about 0.62 mg, less than about 0.61 mg, less than about 0. Less than 60 mg, less than about 0.59 mg, less than about 0.58 mg, less than about 0.57 mg, less than about 0.56 mg, less than about 0.55 mg, less than about 0.54 mg, less than about 0.53 mg, less than about 0.52 mg, less than about 0.51 mg, less than about 0.50 mg, less than about 0.49 mg, less than about 0.48 mg, less than about 0.47 mg, less than about 0.46 mg, less than about 0.45 mg, less than about 0.44 mg, less than about 0.43 mg, less than about 0.42 mg, less than about 0.41 mg, Less than about 0.39 mg, less than about 0.38 mg, less than about 0.37 mg, less than about 0.36 mg, less than about 0.35 mg, less than about 0.34 mg, less than about 0.33 mg, less than about 0.32 mg, less than about 0.31 mg, less than about 0.30 mg, less than about 0.29 mg, less than about 0.28 mg, less than about 0.27 mg, less than about 0.26 mg, less than about 0.25 mg, less than about 0.24 mg, less than about 0.23 mg, less than about 0.22 mg, less than about 0.21 mg, less than about 0.19 mg, less than about 0.18 mg, less than about 0.17 mg, less than about 0.16 mg, less than about 0.15 mg, less than about 0.14 mg, less than about 0.13 mg, less than about 0.12 mg, less than about 0.11 mg, less than about 0.10 mg, less than about 0.09 mg, less than about 0.08 mg, less than about 0.07 mg, less than about 0.06 mg, less than about 0.05 mg, less than about 0.04 mg, less than about 0.03 mg, less than about 0.02 mg or less than about 0.01 mg.

[0074] In some embodiments, the cumulative median amount of solriamfetor received by an infant fed breast milk produced by a subject treated with solriamfetor according to the methods disclosed herein is less than about 0.70 mg, less than about 0.69 mg, less than about 0.68 mg, less than about 0.67 mg, less than about 0.66 mg, less than about 0.65 mg, less than about 0.64 mg, less than about 0.63 mg, less than about 0.62 mg, less than about 0.61 mg, less than about 0.62 mg, less than about 0.63 mg, less than about 0.64 mg, less than about 0.65 mg, less than about 0.66 mg, less than about 0.67 mg, less than about 0.68 mg, less than about 0.69 mg, less than about 0.68 mg, less than about 0.69 mg, less than about 0.69 mg, less than about 0.68 mg, less than about 0.67 mg, less than about 0.66 mg, less than about 0.65 mg, less than about 0.64 mg, less than about 0.63 mg, less than about 0.62 mg, less than about 0.61 mg, less than about 0.66 mg, less than about 0.67 mg, less than about 0.68 mg, less than about 0.69 mg, less than about 0.69 mg, less than about 0.68 mg, less than about 0.67 mg, less than about 0.68 mg, less than about 0.69 ...9 mg Less than 0 mg, less than about 0.59 mg, less than about 0.58 mg, less than about 0.57 mg, less than about 0.56 mg, less than about 0.55 mg, less than about 0.54 mg, less than about 0.53 mg, less than about 0.52 mg, less than about 0.51 mg, less than about 0.50 mg, less than about 0.49 mg, less than about 0.48 mg, less than about 0.47 mg, less than about 0.46 mg, less than about 0.45 mg, less than about 0.44 mg, less than about 0.43 mg, less than about 0.42 mg, less than about 0.41 mg, Less than about 0.39 mg, less than about 0.38 mg, less than about 0.37 mg, less than about 0.36 mg, less than about 0.35 mg, less than about 0.34 mg, less than about 0.33 mg, less than about 0.32 mg, less than about 0.31 mg, less than about 0.30 mg, less than about 0.29 mg, less than about 0.28 mg, less than about 0.27 mg, less than about 0.26 mg, less than about 0.25 mg, less than about 0.24 mg, less than about 0.23 mg, less than about 0.22 mg, less than about 0.21 mg, less than about 0.19 mg, less than about 0.18 mg, less than about 0.17 mg, less than about 0.16 mg, less than about 0.15 mg, less than about 0.14 mg, less than about 0.13 mg, less than about 0.12 mg, less than about 0.11 mg, less than about 0.10 mg, less than about 0.09 mg, less than about 0.08 mg, less than about 0.07 mg, less than about 0.06 mg, less than about 0.05 mg, less than about 0.04 mg, less than about 0.03 mg, less than about 0.02 mg or less than about 0.01 mg.

[0075] A daily dose of about 1 to about 2,000 mg of solriamfetol or a pharmaceutically acceptable salt thereof can be administered to achieve the therapeutic results disclosed herein. For example, a daily dose of about 1 to 1,000 mg, e.g., about 20 to 500 mg, can be administered in a single dose ( / single administration) or divided doses ( / divided administration). In some embodiments, the daily dose can be about 0.01 to about 150 mg / kg body weight, e.g., about 0.2 to about 18 mg / kg body weight. In some embodiments, the dose contains about 1 mg to about 1,000 mg of the drug, or any range or value therein, e.g., about 10 mg to about 500 mg, e.g., about 37.5 mg, about 75 mg, about 150 mg, or about 300 mg of the drug. For example, in certain such embodiments, the total amount of drug may be selected from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, or any range therein.

[0076] In one embodiment of the present invention, solriamfetol is administered to a subject as needed to treat a disorder.The compound can be administered continuously or intermittently.In one embodiment, the compound is administered to a subject more than once a day, for example, 2, 3 or 4 times a day, or once every 1, 2, 3, 4, 5, 6 or 7 days.In another embodiment, the compound is administered to a subject less than once a week, for example, less than once every 2 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, or once more than once every 6 months.In another embodiment, the compound is administered to a subject using two or more different schedules, for example, more frequently at the beginning (for example, once a day or more to increase to a certain level), and then less frequently (for example, once a week or less).In other embodiments, the compound can be administered by any discontinuous administration regimen. In one example, the compound can be administered no more than once every 3 days, no more than once every 4 days, no more than once every 5 days, no more than once every 6 days, no more than once every 7 days, no more than once every 8 days, no more than once every 9 days, or no more than once every 10 days or more. Administration can continue for 1, 2, 3, or 4 weeks, or for 1, 2, or 3 months, or longer. Optionally, after a drug-free period, the compound can be administered on the same or a different schedule. The drug-free period can be 1, 2, 3, or 4 weeks, or longer, depending on the pharmacodynamic effect of the compound on the subject. In another embodiment, the compound can be administered until it increases to a certain level, and then maintained at a certain level, followed by a tailing dose.

[0077] In one embodiment of the present invention, solriamfetol is delivered to a subject in combination with an additional therapeutic agent. The additional therapeutic agent can be delivered in the same composition as the compound or in a separate composition. The additional therapeutic agent may be delivered to a subject on a different schedule or by a different route compared to the compound. The additional therapeutic agent can be any agent that benefits the subject. Additional agents include, but are not limited to, stimulants, antipsychotics, antidepressants, agents for neurological disorders, and chemotherapeutic agents. One therapeutic agent that can be administered during the same period is Xyrem®, marketed by Jazz Pharmaceuticals, which is used to treat narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0078] The present invention finds use in research, as well as veterinary and medical applications. Suitable subjects are generally mammalian subjects. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), and the like. Human subjects include neonates, infants, juveniles, adults, and geriatric subjects. In some embodiments, the subject is postpartum. In some embodiments, the subject is a female between the ages of 18 and 45.

[0079] Suitable subjects are generally lactating mammalian subjects. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), and the like. A human subject can be a lactating individual who frequently or regularly breastfeeds an infant. In some embodiments, the human subject is a female. The female can be between about 18 and 45 years of age. The term "breastfeeding," which may also be referred to as chestfeeding (or grammatical variations thereof), refers to delivering an individual's breast milk directly to an infant, extracting breast milk from an individual using a device and subsequently delivering it to an infant, extracting breast milk from an individual using a device and storing the breast milk for a period of time, and subsequently delivering the stored breast milk to an infant, or a combination thereof.

[0080] A subject of the present disclosure can be lactating, e.g., an individual who is lactating (e.g., breastfeeding), nursing, or breastfeeding. The subject can be lactating after pregnancy, i.e., after parturition, or due to induced lactation (e.g., with metoclopramide, oral contraceptives, herbal medicines, pump stimulation, or any combination thereof).

[0081] In some embodiments, the subject is 1 day to 24 months postpartum, about 1 day to 12 months postpartum, about 10 days to 12 months (52 weeks) postpartum, or about 15 weeks to about 37 weeks postpartum. In some embodiments, the subject expresses mature milk, which typically occurs about 10 to about 30 days postpartum (e.g., about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days) or about 10 to about 20 days after the start of milk expression during induced lactation. Infancy begins at birth and ends around age 2; therefore, the breastfed infancy stage includes the period of breastfeeding.

[0082] The subject can be, for example, a subject "in need" of the methods of the invention, e.g., a subject in need of the therapeutic effect of the methods of the invention. For example, the subject can be a subject experiencing a disorder suitable for treatment with solriamfetol, suspected of having a disorder suitable for treatment with solriamfetol, and / or predicted to experience a disorder suitable for treatment with solriamfetol, and for whom the methods and compositions of the invention are used for therapeutic and / or prophylactic treatment.

[0083] In some embodiments, the subject is a mother whose disease or disorder puts her baby at risk of adverse events due to her condition (for example, she falls asleep while caring for her baby), and who wishes to breastfeed.Research has shown that at least 60% of women with narcolepsy report that their symptoms make it difficult to care for their baby, and they fear that their disease will worsen (because it is related to caring for their baby).

[0084] Accordingly, one aspect of the present invention relates to a method for treating excessive daytime sleepiness in lactating mothers who desire to breastfeed their infant and whose infant is at risk for adverse events resulting from excessive maternal daytime sleepiness, the method comprising: (a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant; (b) administering a starting dose of 37.5 mg of solriamfetol once daily to mothers who have an ESS total score of 15 or greater and who experience sleep attacks while caring for their infant if the excessive daytime sleepiness is associated with obstructive sleep apnea, or administering a starting dose of 37.5 mg of solriamfetol once daily to mothers who experience sleep attacks while caring for their infant if the excessive daytime sleepiness is associated with obstructive sleep apnea, or administering a starting dose of 37.5 mg of solriamfetol once daily to mothers who have an ESS total score of 15 or greater and ... If excessive sleepiness is associated with narcolepsy, provide a starting dose of 75 mg of solriamfetol once daily, doubling the dose (to a maximum of 150 mg once daily) at intervals of at least 3 days, where the elimination half-life of solriamfetol in the plasma of a postpartum or lactating mother is about 5 hours; and (c) avoid exposing the infant to the maximum concentration of solriamfetol in breast milk by feeding the infant breast milk obtained from the mother at least about 3.5 hours (e.g., 4 or 5 hours) after administration of solriamfetol to the mother, where the median T max is approximately 1.1 hours.

[0085] The method selects appropriate subjects for treatment based on the severity of the disease, interference with infant care, and the mother's desire to provide her infant with the developmental and health benefits of breastfeeding.

[0086] The ESS is a subjective sleepiness test that is well known in the art and commonly used to measure a subject's sleepiness level. The scale is designed to measure daytime sleepiness by using a short questionnaire that asks the subject to rate the likelihood of falling asleep in eight different situations that most people encounter in their daily lives on a scale of increasing likelihood from 0 to 3. The scores of the eight questions are summed to obtain a single number that estimates the subject's average sleep propensity (ASP). A number within the range of 0 to 10 is considered normal, while a number of 11 to 12 indicates mild excessive sleepiness, 13 to 15 indicates moderate excessive sleepiness, and a number of 16 or higher indicates severe excessive sleepiness. The average score for narcolepsy patients is approximately 17. The average score for obstructive sleep apnea (OSA) patients with excessive sleepiness is approximately 15.

[0087] As used herein, "sleep attack" refers to a strong urge to sleep, often followed by periods of sleep where you cannot control when you fall asleep. These periods can last from a few seconds to 30 minutes.

[0088] In some embodiments, the lactating mother experiences a decrease in ESS total score of 5 or more, eg, 6, 7, 8, 9, or 10 or more.

[0089] In some embodiments, the lactating mother experiences a reduction in the frequency of sleep attacks while holding, nursing, feeding, or otherwise caring for her infant, which reduction in frequency can be at least about 10%, 20%, 30%, 40%, or 50% compared to an untreated mother.

[0090] In some embodiments, lactating mothers experience a decrease in automatic movements (movements of body parts, such as their hands, while sleeping) while caring for their infant. The decrease in automatic movements can be at least about 10%, 20%, 30%, 40%, or 50% compared to untreated mothers.

[0091] Having described the invention, the same will be more particularly described in the following examples (which are included herein for illustrative purposes only and are not intended to limit the invention). [Example]

[0092] example Example 1. Phase 4 clinical trial in lactating subjects A phase 4, open-label, single-dose study to evaluate the pharmacokinetics (pharmacodynamics) of solriamfetol in breast milk and plasma of healthy postpartum women after oral administration of 150 mg solriamfetol tablets.

[0093] This study was conducted in six healthy, lactating adult women between 15 and 37 weeks postpartum. Sunosin was administered a single oral dose of 150 mg. Sunosin was excreted in breast milk, with a milk-to-plasma AUC ratio of approximately 2:1. The median T of Sunosin in breast milk was 1.2 mg / kg. maxThe mean elimination half-life in breast milk was approximately 1.1 hours, and the mean elimination half-life in breast milk was approximately 5.0 hours. The mean amount received by infants was estimated to be 0.59 mg over 24 hours, which is approximately 4.0% of the maternal dose on a weight-adjusted basis. Data from lactation studies indicate that SUNOSI is excreted in breast milk from nursing mothers, with a relative infant dose (RID) of approximately 4% of the maternal weight-adjusted dose. No data are provided to evaluate the effects of SUNOSI on breastfed infants or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SUNOSI and potential adverse effects on the breastfed child from SUNOSI or from underlying maternal conditions. Breastfed infants should be monitored for adverse events, such as restlessness, insomnia, poor appetite, or reduced weight gain.

[0094] Solriamfetol has a short systemic elimination half-life of 5.0 to 7.6 hours, and the estimated accumulation ratio of 1.06 with a once-daily dose ( / once-daily administration) was slightly higher than 1, indicating essentially no accumulation with repeated doses ( / repeated administration). Therefore, a single therapeutic dose of solriamfetol was administered in this study. Because the purpose of this study was to evaluate the PK of solriamfetol in breast milk and plasma and to estimate the daily drug dose that infants receive from breast milk, the highest approved therapeutic dose of 150 mg solriamfetol was administered.

[0095] The subjects were between 10 days and 52 weeks postpartum. The lower limit of 10 days postpartum represented the time after which mature milk is produced (US FDA 2019). The upper limit of 52 weeks postpartum was selected based on a prospective study showing that fat, total solids, and "energy" (kcal / dL) were all statistically increased in breast milk collected 12-18 months postpartum (N=25) compared with breast milk collected 1-12 months postpartum (N=35) (Czosnykowska Lukacka 2018). Additionally, there was a lack of data regarding breast milk nutrient composition beyond 12 months postpartum (Wu 2018). This study included frequent collection of breast milk samples from mothers for 72 hours after administration to allow for detection of the potential presence of solriamfetol in breast milk. Plasma concentrations of solriamfetol were also determined during the same time period to assess the potential accumulation of solriamfetol in breast milk compared with plasma.

[0096] Subjects were instructed to refrain from breastfeeding their infants for 72 hours after administration. Based on the short half-life of the drug, this period (10 x half-lives) was expected to be sufficient for complete elimination of solriamfetol from both the systemic circulation and breast milk.

[0097] Pharmacokinetic results All subjects in the PK population were included in the PK analysis. The pharmacokinetic population was defined as all subjects who received the study drug and provided post-dose breast milk or plasma PK data for at least one collection period or time point. Subjects 1003, 1004, and 1007 had numerous protocol deviations regarding the timing of food consumption; however, these deviations were unlikely to affect solriamfetol PK, and these subjects were included in descriptive statistics or PK parameter analyses. Furthermore, the PK of solriamfetol in fed and fasted subjects met bioequivalence criteria, indicating that solriamfetol can be administered regardless of food intake.

[0098] Figure 1 shows the mean plasma and breast milk solriamfetol concentration time profiles. Figure 1 shows the time course of mean plasma and breast milk solriamfetol concentrations on day 1 after administration of a single dose of solriamfetol 150 mg tablets in the morning, 2 hours after the end of a light breakfast. After reaching peak solriamfetol concentrations approximately 1.00 to 3.00 hours after oral administration, plasma and breast milk exposures followed parallel single-exponential declines. Soriamfetol concentrations in breast milk were approximately two-fold higher than plasma concentrations.

[0099] The mean breast milk cumulative solriamfetol dose-time profile is shown in Figure 2. Figure 2 shows the mean breast milk cumulative solriamfetol dose-time profile following administration of a single dose of a 150 mg tablet of solriamfetol in the morning, 2 hours after the end of a light breakfast. The arithmetic mean ± SD amount excreted in breast milk over 72 hours was 0.6880 ± 0.4672 mg. However, nearly all excretion was observed within 24 hours after administration.

[0100] As no subjects had an adjusted Rsq value <0.700 or a %AUCex >20%, all lambda_z and AUC0-inf related parameters were considered reliable and included in the descriptive statistics.

[0101] Table 1 summarizes the plasma and breast milk PK parameters for solriamfetol after single-dose administration.

[0102] Solriamfetol exposure was approximately two-fold higher in breast milk than in plasma, with a geometric mean C max 1861 vs. 892.5 ng / mL, AUC 0-t 12770 vs. 6236 h*ng / mL, AUC 0-inf The geometric mean milk:plasma ratio was 2.047.

[0103] Plasma solriamfetol max The mean HR in breast milk (0.98-3.02 hours, median 1.25 hours) was similar to that in breast milk (1.00-3.00 hours, median 1.12 hours).

[0104] Geometric Mean Solriamfettle 1 / 2 The V was clearly similar between plasma (4.751 h) and breast milk (4.869 h). Furthermore, the geometric mean plasma solriamfetol CL / F was 23.66 L / h, and V z The geometric mean A / F was 162.2 L. milk was 0.5651 mg, and the daily infant dose and relative infant dose were 0.5856 mg and 4.030%, respectively. [Table 1]

[0105] Pharmacokinetic Conclusions Solriamfetol for both plasma and breast milk max The time course of solriamfetol exposure (C) was similar and ranged between 1 and 3 hours. After reaching the maximum solriamfetol concentration, plasma and breast milk exposure followed parallel single exponential declines. max and AUC) were two-fold higher than in plasma. Furthermore, the geometric mean milk:plasma ratio was 2.047. 1 / 2 appeared similar in plasma and breast milk at approximately 5 hours. The study was conducted exclusively in postpartum women, a very different population from the study population (healthy male and non-postpartum female patients) reported in the pharmacokinetics section of the current Sunosi® drug label. The Sunosi® drug label indicates that the oral bioavailability of solriamfetol is approximately 95%, with peak plasma concentrations of solriamfetol reaching a median T of 2 hours (range 1.25-3.0 hours) after administration in healthy male and non-postpartum female patients under fasting conditions. max In fact, the median T reported on drug labels for healthy male and non-postpartum female patients max The T in this lactation study was reported to be 2 hours. maxSimilarly, the apparent mean elimination plasma half-life is 7.1 hours for healthy male and non-postpartum female patients with Sunosi® drug labeling, compared to 4.8 hours in plasma and 4.95 hours in breast milk in this lactation study.

[0106] CL / F and V z The arithmetic mean CL / F was 24.40 L / h, V z / F was 168.9L. milk The daily infant dose and relative infant dose were determined for breast milk solriamfetol only. milk The arithmetic mean was 0.6880 mg, the daily infant dose was 0.6927 mg, and the relative infant dose was 4.602%.

[0107] Safety Results Adverse events: An overall summary of treatment-emergent adverse events (TEAEs) is summarized in Table 2. A total of 3 (50%) subjects experienced at least one AE; of these, 2 (33.3%) subjects experienced a TEAE related to the study drug, and 1 (16.7%) subject experienced a TEAE unrelated to the study drug. Mild TEAEs were reported in 2 (33.3%) subjects, and moderate TEAEs were reported in 1 (16.7%) subject. No SAEs were reported in the study. No subjects discontinued due to a TEAE. [Table 2]

[0108] Of the three subjects who reported TEAEs, one subject experienced dizziness and headache (SOC: Nervous system disorders), one subject experienced restlessness (SOC: Psychiatric disorders), and one subject experienced a headache event (SOC: Nervous system disorders) (Table 3). A total of four TEAEs were reported, with three TEAEs (dizziness, headache, and restlessness) being mild and one TEAE (headache) being moderate. All three mild TEAEs were related to the study drug, and the moderate TEAE was unrelated to the study drug. All TEAEs resolved. [Table 3]

[0109] Vital signs: There were no significant changes in vital sign parameters from baseline to hours 2 and 4 on day 1, days 2, 3, and 4. A summary of clinically notable vital signs at post-baseline visits is summarized in Table 4. [Table 4]

[0110] There were no significant changes in ECG parameters from baseline to pre-dose and 2 hours on Day 1, Day 2, Day 3, and Day 4. No abnormal or clinically significant ECG findings were reported.

[0111] A summary of clinically notable ECG findings at post-baseline visits is summarized in Table 5. [Table 5]

[0112] No subjects reported suicidal ideation or events on the Columbia-Classification Algorithm for Suicide Assessment.

[0113] Safety Conclusions Overall, six subjects were enrolled in the safety analysis and treated with a single oral dose of solriamfetol, which was safe and well tolerated.

[0114] Three of six subjects (50%) experienced at least one adverse event. Of the three subjects who reported TEAEs: one subject experienced dizziness and headache (SOC: Nervous system disorders), both mild and related to the study drug; one subject experienced mild agitation (SOC: Psychiatric disorders), related to the study drug; and one subject experienced moderate headache (SOC: Nervous system disorders), unrelated to the study drug. No SAEs, deaths, or other significant AEs were reported in the study. No subjects discontinued due to TEAEs. No subjects had abnormal, clinically significant laboratory findings. There were no significant changes in vital signs from baseline to hours 2 and 4 on Day 1, or days 2, 3, and 4, or in ECG parameters from baseline to predose and hour 2 on Day 1, or days 2, 3, and 4. No subjects reported suicidal ideation or events per the Columbia Classification Algorithm for Suicide Assessment.

[0115] Consideration This was a phase 4, open-label, single-dose study to evaluate the PK of solriamfetol in breast milk and plasma of healthy postpartum women after oral administration of 150 mg solriamfetol tablets. A total of six subjects were enrolled and included in both PK and safety analyses. All six subjects completed the study. No premature discontinuations were reported in the study.

[0116] The primary objective (PK) of this study was to evaluate the PK of solriamfetol in plasma and breast milk after a single oral dose of solriamfetol 150 mg tablets in the morning, 2 hours after the end of a light breakfast. Solriamfetol exposure was approximately 2-fold higher in breast milk than in plasma, with a geometric mean C max 1861 vs. 892.5 ng / mL, AUC 0-t12770 vs. 6236 h*ng / mL, AUC 0-inf The geometric mean milk:plasma ratio was 2.047. max The mean mean solubility in fetal bovine milk (0.98-3.02 hours, median 1.25 hours) was similar to that in breast milk (1.00-3.00 hours, median 1.12 hours). 1 / 2 The V was clearly similar between plasma (4.751 h) and breast milk (4.869 h). Furthermore, the geometric mean plasma solriamfetol CL / F was 23.66 L / h, and V z The geometric mean A / F was 162.2 L. milk was 0.5651 mg, and the daily infant dose and relative infant dose were 0.5856 mg and 4.030%, respectively.

[0117] A secondary objective of the study was to evaluate the safety and tolerability of solriamfetol in healthy postpartum women. Overall, the study drug was safe and well tolerated. No SAEs, deaths, or other significant AEs were reported in the study. No subjects discontinued due to TEAEs. Of the six subjects, three reported adverse events. All AEs (dizziness, headache, and restlessness) were mild, except for one AE (headache) which was moderate.

[0118] No subjects had abnormal or clinically significant laboratory findings. There were no significant changes in vital signs from baseline to hours 2 and 4 on Day 1, or days 2, 3, and 4, and no significant changes in ECG parameters from baseline to predose and hours 2 on Day 1, or days 2, 3, and 4. No subjects reported suicidal ideation or events per the Columbia Classification Algorithm for Suicide Assessment.

[0119] conclusion Solriamfetol T in both plasma and breast milk maxThe time course of solriamfetol exposure (C) was similar and ranged between 1 and 3 hours. After reaching the maximum solriamfetol concentration, plasma and breast milk exposure followed parallel single exponential declines. max The AUC (Area Underlying Conditions) was two-fold higher than in plasma. Furthermore, the geometric mean milk:plasma ratio was 2.047. 1 / 2 appeared similar in plasma and breast milk at approximately 5 hours. Solriamfetol was safe and well tolerated.

[0120] Further analysis of the data indicates that the daily infant dose is 0.112 mg / kg (based on a nominal infant weight of 6 kg), with a relative infant dose (RID) of approximately 5.5% of the maternal weight-adjusted dose. The data are insufficient to determine the effects of solriamfetol on breastfed infants or its effect on milk production.

[0121] The cumulative median amount excreted in breast milk over 72 hours was 0.67 mg, which is approximately 5.5% of the maternal dose on a weight-adjusted basis. Of the total amount of solriamfetol excreted in breast milk over 72 hours, approximately 78% and 98% were excreted by 8 and 24 hours, respectively, with an apparent mean elimination half-life in breast milk of approximately 5 hours.

[0122] The developmental and health benefits of breastfeeding should be considered together with the mother's clinical need for solriamfetol, and any potential adverse effects on the breastfed infant from solriamfetol or from an underlying maternal condition.

[0123] Infants exposed to solriamfetol should be monitored for signs of restlessness, insomnia, and reduced weight gain.

[0124] methodology On Day -1, eligible subjects underwent baseline procedures. On Day 1, 2 hours after a light breakfast, subjects received a single dose of 150 mg of solriamfetol with 240 mL of water. Subjects were required to fast for approximately 4 hours after the first dose; water was permitted except for 1 hour before and 1 hour after administration of the study drug.

[0125] Pharmacokinetic analysis of breast milk (pumped) from both breasts was assessed before and up to 72 hours after dose administration. Blood samples were also collected for plasma solriamfetol quantification and PK analysis before and up to 72 hours after dose administration. Soriamfetol concentrations in breast milk and plasma were measured using validated bioanalytical methods. Safety was assessed throughout the study by 12-lead ECG, vital sign measurements, Columbia-Suicide Severity Rating Scale (C-SSRS), and incidence of adverse events (AEs).

[0126] The study drug was a yellow film-coated tablet containing the excipients hydroxypropyl cellulose and magnesium stearate and a polymeric film coat (Opadry®).

[0127] The overall total study duration (from initial subject screening to last subject safety follow-up) was approximately 11 months.

[0128] Vital signs (blood pressure, pulse rate, temperature, and respiratory rate) were measured with subjects in a sitting or supine position, resting for a minimum of 5 minutes before measurements were taken. Blood pressure and pulse rate were measured using the dominant arm. On Day 1, vital signs were collected pre-dose and approximately 2 hours (blood pressure and pulse) and 4 hours (blood pressure and pulse) after dosing.

[0129] 12-lead ECGs were taken with subjects in the supine position and resting for a minimum of 10 minutes before measurements were taken. On Day 1, ECGs were collected pre-dose and approximately 2 hours post-dose.

[0130] Subjects must fast for a minimum of 8 hours before chemistry and hematology blood draws. All laboratory tests were performed at screening only (rescreening was allowed).

[0131] Screening / Baseline C-SSRS version at screening and since Last Visit version on days -1 and 2 (or at ET).

[0132] Breast milk samples were collected on days 1 to 4 at -2 to 0 (pre-dose), 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 18, 24 to 32, 32 to 40, 40 to 48, and 48 to 72 hours after dosing.

[0133] Blood samples for plasma PK assessment were collected at the following time points: pre-dose on Day 1, 1, 1.5, 3, 6, 8.5, 10, 13, 15, 21, 24, 28, 36, 44 and 72 hours post-dose. The overall study methodology is outlined in Table 6. [Table 6]

[0134] The standardized meals included an as-needed meal on Day -1, a light breakfast approximately 2.5 hours prior to dosing on Day 1 (completed approximately 2 hours prior to dosing), followed by lunch approximately 4 hours after dosing, dinner approximately 8 hours after dosing, and a snack approximately 11 hours after dosing, followed by a standardized meal.

[0135] Records were from 30 days prior to screening through a safety follow-up phone call 5–7 days after checkout from the study site (day 4 or ET).

[0136] Adverse events were monitored throughout the study by safety assessments, observations, and subject reports, including a safety FU call on Day 4 or 5–7 days after ET checkout from the study site (i.e., Days 9–11).

[0137] Breast milk collection: Soriamfetol concentrations in breast milk and plasma were assessed based on samples collected pre- and post-dose on days 1 to 4. Breast milk was collected from both breasts using an electric breast pump during the following time periods: -2 to 0 (pre-dose), and 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 18, 18 to 24, 24 to 32, 32 to 40, 40 to 48, and 48 to 72 hours after dosing on day 1. The midpoint of each breast milk collection period was used as the time variable.

[0138] Breast milk was collected as needed during the assigned period; however, at the end of each period, breast milk was pumped and collected from both breasts. At the end of each collection period, all milk expressed from both breasts during that period was pooled. To ensure homogeneity of milk composition, the milk was thoroughly mixed by gently inverting the collection container 10 times. The weight and volume of milk collected during each period were also recorded.

[0139] Serial blood samples (4 mL) were collected and dispensed into labeled K2EDTA tubes. The actual time of blood collection for all samples was recorded on the eCRF. Soriamfetol concentrations in breast milk and plasma were determined using a validated bioanalytical method (LC-MS / MS) at Origin Bioanalytical Laboratory. The analytical range (lower limit of quantification [LLOQ] to upper limit of quantification) for plasma solriamfetol was 8.42–4210.00 ng / mL, and for breast milk solriamfetol was 10.0–8000 ng / mL.

[0140] Pharmacokinetic parameters were measured using Phoenix (登録商標) WinNonlin (登録商標) Version 8.3 (Certara, Inc., Princeton, New Jersey, USA) and / or SAS (登録商標) The data were obtained using Version 9.4 (SAS Institute, Inc., Cary, North Carolina, USA).

[0141] Subject Criteria: Each subject who met the following criteria was included in the study: a healthy adult female, aged 18–50 years (inclusive) at the time of consent; weighing at least 50 kg and having a mean blood pressure of 18–35 kg / m 2 (18kg / m 2 and 35 kg / m 2 Body mass index of ≥ 10 days (inclusive); postpartum between 10 days and 52 weeks (inclusive) after delivery of a normal, healthy infant by the time of dosing and actively lactating from both breasts; if breastfeeding, agreed to refrain from breastfeeding their infant from approximately 2 hours before dosing until approximately 72 hours after dosing and resumed breastfeeding after completion of the procedure on study Day 4 or decided to wean their infant before enrollment in the study; agreed to abstain from using nicotine-containing products, including tobacco (cigarettes, cigars, chewing tobacco, snuff), e-cigarettes, and nicotine lozenges / gum / patches, for 3 days prior to check-in on Day -1 and for the duration of the study; used a medically acceptable method of contraception for a minimum of 2 months prior to dosing on Day 1. were fully vaccinated for a minimum of 14 days after the last (or only) dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 [COVID-19]) vaccine; or chose not to be vaccinated before the study began. (Participants who chose not to be fully vaccinated before the start of the study did not receive any dose of a COVID-19 vaccine and remained in the study.)

[0142] Laboratory tests, including hematology, serum chemistry, urinalysis, and thyroid panel, were collected only at screening.

[0143] A complete physical examination included, at a minimum, evaluation of the cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. BMI was calculated at screening and baseline / randomization visits to verify eligibility.

[0144] Vital signs included oral temperature, pulse rate, respiratory rate, and BP. Clinically significant abnormal vital sign results reported during screening / randomization were recorded as medical history, and those reported after study drug administration were recorded as AEs.

[0145] Blood pressure and pulse were assessed with subjects in a sitting or supine position, resting for a minimum of 5 minutes before measurements were taken. Blood pressure and pulse rate were measured on the dominant arm. On Day 1, vital signs were collected pre-dose and approximately 2 and 4 hours post-dose.

[0146] Twelve-lead ECGs were collected at screening and from Day -1 through Day 4. A single 12-lead ECG was obtained using an ECG device that automatically calculated heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals. Any abnormal safety assessment, including ECG measurements considered clinically significant in the investigator's medical and scientific judgment, was reported as an AE. The investigator had to review the ECG and document it in the source document. Clinically significant abnormal ECG results reported during screening were recorded in the medical history, and those reported after study drug administration were recorded as AEs.

[0147] All clinical tests were performed in accordance with the study manual. Tests detailed in Table 7 were performed by a central laboratory. Additional tests may be performed at any time during the study if deemed necessary by the investigator or required by local regulations.

[0148] All laboratory tests with abnormal values ​​considered clinically significant (and considered related to the study drug by the investigator) during the study or within 14 days after the last dose of study drug were repeated until the value returned to normal or baseline, or was no longer considered clinically significant by the investigator or medical monitor. If a clinically significant value did not return to normal / baseline within a time period deemed reasonable by the investigator, the etiology was to be determined. [Table 7]

[0149] Statistics / Analysis Unless otherwise specified, continuous data were summarized using descriptive statistics, including the number of exposed subjects (N) and the number of subjects with data to be summarized (n), mean, standard deviation (SD), median, minimum (min), maximum (max), geometric mean, coefficient of variation (CV%), and geometric coefficient of variation (CV%). Categorical variables were presented using numbers and percentages. SAS (登録商標) Analysis and summary output was generated using Version 9.4 (SAS Institute, Inc., Cary, North Carolina, USA).

[0150] The PK population consisted of all subjects who received the study drug and provided post-dose breast milk or plasma PK data for at least one collection period or time point. This population was used for evaluable PK concentration data and for summarizing and listing PK parameters. The safety population consisted of all subjects who received the study drug. This population was used for summarizing and listing demographic and baseline characteristics, as well as safety data.

[0151] Pharmacokinetic concentrations and parameters were summarized using descriptive statistics, including n, arithmetic mean, SD, coefficient of variation (CV%), median, min, max, geometric mean, and geometric coefficient of variation (CV%). PK parameters tmax Regarding , only n, median, minimum and maximum values ​​are shown.

[0152] Subjects with partial data were evaluated on a case-by-case basis to determine whether sufficient data were available for reliable calculation of PK parameters. In cases of incomplete milk collection (partial / spilled samples resulting in inaccurate information on total milk volume for samples per collection period), the amount recovered per collection period was listed but not included in the summary, and cumulative recovery was reported by the most recent complete milk collection only. Data per collection period in which the subject was unable to lactate (produce milk) was treated as a zero amount (for the affected period) in the sum of cumulative recovery calculations.

[0153] Plasma and milk concentrations were summarized using descriptive statistics. Concentrations that were below the lower limit of quantitation (BLQ) were treated as follows for the calculation of descriptive statistics:

[0154] Summary statistics for times with one or more BLQ values ​​were calculated by assigning 1 / 2LLOQ to all values ​​less than the LLOQ. When the calculated arithmetic (and geometric) mean was the BLQ, the SD and CV% were shown as "ND." and the mean was shown as "BLQ." However, because a high percentage of BLQ values ​​may have affected the SD, if a value greater than 50% was entered, the mean was not calculated for that time point, and again only the BLQ value was shown for the mean. Any minimum or median value calculated to be the BLQ within the summary statistics was shown as the BLQ within the summary presentation.

[0155] Concentrations collected outside the protocol-accepted sampling method were included in the descriptive statistics unless the PK scientist observed that the deviation was substantial enough to affect the descriptive statistics, in which case the excluded concentrations were identified in the CSR.

[0156] To plot the arithmetic mean concentration profile: The arithmetic mean at times with one or more BLQ values ​​was calculated by assigning 1 / 2 the LLOQ to all BLQ values. If the calculated mean value was the BLQ, that time point was plotted as zero in the mean pharmacokinetic profile. However, because a high percentage of BLQ values ​​may have affected the SD, if more than 50% of values ​​were entered, no mean was calculated for that time point, and a value of zero was also plotted. A line labeled LLOQ was overlaid on the concentration axis to indicate the LLOQ level.

[0157] Safety analyses were based on the safety population. Secondary endpoints to assess subject safety and tolerability included the incidence of reported AEs and laboratory findings for all subjects.

[0158] Adverse events: Adverse events recorded in the electronic case report form (eCRF) were coded to SOC and PT using MedDRA (Medical Dictionary for Regulatory Activities). Treatment-emergent adverse events (TEAEs) were defined as events with an onset date at or after the first dose of study drug, ongoing events that worsened in severity after the date of the first dose of study drug, or events that were present at baseline but were subsequently considered by the investigator to be related to the study drug by the end of the study. The occurrence of TEAEs was indicated by severity, relationship to study drug, start and end dates, seriousness, and outcome. The investigator assessed the severity and relationship of each AE to the study drug. Columbia-Suicide Rating Scale (C-SSRS) data were compiled and listed at scheduled visits. Other safety analyses were performed as appropriate.

[0159] 12-Lead ECG: The number and percentage of subjects with the following post-baseline clinically noteworthy ECG interval abnormalities were summarized: ventricular rate ≥ 100 beats / min or ≤ 60 beats / min; PR interval ≥ 200 msec or ≤ 120 msec; QRS duration ≥ 100 msec or ≤ 80 msec; QT interval ≥ 440 msec or ≤ 350 msec; QTc Bazette and QTc Fredericia ≥ 470 msec or ≤ 330 msec; RR interval ≥ 1200 msec or ≤ 600 msec; and an increase in QTc Bazette and QTc Fredericia from study baseline values ​​> 30 msec.

[0160] Vital Signs: The following clinically significant vital sign abnormalities were noted: mean systolic blood pressure ≥150mmHg or ≤80mmHg; mean diastolic blood pressure ≥95mmHg or ≤60mmHg; mean heart rate ≥120bpm or ≤50bpm; respiratory rate <10 breaths / min or >24 breaths / min; body temperature >37.9°C or <35.5°C; systolic and diastolic blood pressure change >20% from study baseline value / recording; pulse change >20% from study baseline value / recording; weight change ≥7% (weight loss / weight gain) from subject's baseline value; and body temperature change >1.8% from subject's baseline temperature recording.

[0161] Physical Examination: Physical examination data for each subject were listed. Clinically significant adverse changes (i.e., worsening) in physical examination findings after screening were recorded as AEs.

[0162] Subject Disposition. A total of six subjects were enrolled and treated in the study. All six subjects completed the study. No premature discontinuations were reported in the study. All six subjects received study drug (safety population) and provided post-dose breast milk or plasma PK data (PK population) for at least one collection period or time point. All six subjects were female and were not of Hispanic or Latino ethnicity. The mean (SD) age, weight, height, and BMI for the entire population were 28.7 (5.54) years, 79.15 (12.162) kg, 168.62 (6.013) cm, and 27.90 (4.513) kg / m, respectively. 2 It was. [Table 8]

[0163] Prior and Concomitant Medications: Two subjects received medication during the study for AEs: one subject received acetaminophen and the other subject received ibuprofen.

[0164] Medical and Surgical History: A total of five of the six subjects had a medical and surgical history. Of these subjects, one subject had a history of appendectomy, cesarean section, and tubal ligation. One subject had asthma and cesarean section. One subject had cholelithiasis, pancreatitis, and cholecystectomy. One subject had umbilical hernia repair, heartburn, and cesarean section, and one subject had vaginal birth and hip pain from vaginal birth. References: Czosnykowska- Lukacka, M., Krolak-Olejnik, B., & Orczyk-Pawilowicz, M. (2018). Breast Milk Macronutrient Components in Prolonged Lactation. Nutrients, 10(12), 1893. Doi:10.3390 / nu10121893. Jones B. E. (2000). Basic mechanisms of sleep-wake states. In: Kryger, M. H.; Roth, T.; and Dement, W. C., eds. Principles and Practice of Sleep Medicine 3d ed. Philadelphia: W. B Saunders. pp. 134-154. Li Y., Panossian, L. A., Zhang, J., Zhu, Y., Zhan, G., Chou, Y. T., Fenik, P., Bhatnagar, S., Piel, D. A., Beck, S. G., & Veasey, S. (2014). Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response. Sleep, 37(1), 51-64. Doi:10.5665 / sleep.3306. Lockwood P. A., Pauer, L., Scavone, J. M., Allard, M., Mendes da Costa, L., Alebic-Kolbah, T., Plotka, A., Alvey, C. W., & Chew, M. L. (2016). The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women. Journal of human lactation: official journal of International Lactation Consultant Association, 32(3), NP1-NP8. Doi:10.1177 / 0890334415626148. Posner K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., Currier, G. W., Melvin, G. A., Greenhill, L., Shen, S., & Mann, J. J. (2011). The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. The American journal of psychiatry, 168(12), 1266-1277. Doi:10.1176 / appi.ajp.2011.10111704. Siegel J. M. Brainstem mechanisms generating REM sleep. In: Principals and Practice of Sleep Medicine, Second Edition. Edited by M. K. Kryger, T. Roth, W. C. Dement. New York: Saunders, 2000. Tsujino N., Tsunematsu, T., Uchigashima, M., Konno, K., Yamanaka, A., Kobayashi, K., Watanabe, M., Koyama, Y., & Sakurai, T. (2013). Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice. PloS one, 8(7), e70012. Doi:10.1371 / journal.pone.0070012. US Food and Drug Administration. Center for Drug Evaluation and Research (2019). Guidance for Industry. Clinical Lactation Studies: Considerations for Study Design. Draft guidance. Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD. US Food and Drug Administration. Center for Drug Evaluation and Research (2019). Guidance for Industry. Clinical Lactation Studies: Considerations for Study Design. Draft guidance. Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD. Wisor J. P., Nishino, S., Sora, I., Uhl, G. H., Mignot, E., & Edgar, D. M. (2001). Dopaminergic role in stimulant-induced wakefulness. The Journal of neuroscience : the official journal of the Society for Neuroscience, 21(5), 1787-1794. Doi:10.1523 / JNEUROSCI.21-05-01787.2001. Wu X., Jackson, RT, Khan, SA, Ahuja, J., & Pehrsson, PR (2018). Human Milk Nutrient Composition in the United States: Current Knowledge, Challenges, and Research Needs. Current developments in nutrition, 2(7), nzy025. Zhu Y., Fenik, P., Zhan, G., Xin, R., & Veasey, SC (2015). Degeneration in Arousal Neurons in Chronic Sleep Disruption Modeling Sleep Apnea. Frontiers in neurology, 6, 109. Doi:10.3389 / fneur.2015.00109.

[0165] The foregoing is illustrative of the present invention and should not be construed as limiting thereof. The present invention is defined by the following claims, including equivalents of the claims. All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entirety for the teachings relevant to the sentence and / or paragraph in which the reference is presented.

Claims

1. 1. A method of reducing exposure to solriamfetol in an infant fed breast milk obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 37.5 mg to about 300 mg; and providing breast milk to the infant from the subject at least about 5 hours after administering solriamfetol to the subject, thereby reducing exposure of the infant to solriamfetol; The method comprising:

2. 10. The method of claim 1, which provides a daily infant dose of about 0.3 mg or less of solriamfetol.

3. 10. The method of claim 1, wherein the method achieves a relative infant dose of less than about 9% of the subject's weight-adjusted dose.

4. 4. The method of claim 3, wherein the method achieves a relative infant dose of less than about 5% of the subject's weight-adjusted dose.

5. 10. The method of claim 1, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to solriamfetol exposure.

6. 10. The method of claim 1, wherein the subject is between 1 day and 24 months postpartum.

7. 7. The method of claim 6, wherein the subject is 10 days to 12 months postpartum.

8. 10. The method of claim 1, wherein the subject is being treated with solriamfetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

9. 10. The method of claim 1, wherein the subject is a female between the ages of 18 and 45.

10. 2. The method of claim 1, wherein the daily dose of solriamfetol is 150 mg.

11. 1. A method of reducing the likelihood of adverse events from solriamfetol in a breast-fed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of between 37.5 mg and 300 mg; and providing breast milk to the infant from the subject at least about 5 hours after administration of solriamfetol to the subject, thereby reducing the likelihood of adverse events from solriamfetol in the infant; The method comprising:

12. 12. The method of claim 11, wherein the adverse event is one or more of restlessness, insomnia, loss of appetite, or reduced weight gain.

13. 12. The method of claim 11, wherein the subject is being treated with solriamfetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

14. 12. The method of claim 11, which provides a daily infant dose of about 0.3 mg or less of solriamfetol.

15. 12. The method of claim 11, wherein the relative infant dose is less than about 9% of the subject's weight-adjusted dose.

16. 16. The method of claim 15, wherein the method achieves a relative infant dose of less than about 5% of the subject's weight-adjusted dose.

17. 12. The method of claim 11, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to solriamfetol exposure.

18. 12. The method of claim 11, wherein the subject is between 1 day and 24 months postpartum.

19. 19. The method of claim 18, wherein the subject is 10 days to 12 months postpartum.

20. 12. The method of claim 11, wherein the daily dose of solriamfetol is 150 mg.

21. The method of claim 11, wherein the subject is a female between the ages of 18 and 45.

22. 1. A method for treating a solriamfetol-treatable disorder in a subject producing breast milk for feeding to an infant, comprising administering: orally administering to said subject solriamfetol at a daily dose of between 37.5 mg and 300 mg; and reducing the exposure of the infant to solriamfetol and / or reducing the likelihood of an adverse event in the infant breastfed from the subject, comprising feeding the infant breast milk obtained from the subject at least about 5 hours after administering solriamfetol to the subject; The method comprising:

23. 23. The method of claim 22, wherein the disorder treatable with solriamfetol is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, depression or binge eating disorder.

24. 23. The method of claim 22, which provides a daily infant dose of about 0.3 mg or less of solriamfetol.

25. 23. The method of claim 22, wherein the method achieves a relative infant dose of less than about 9% of the subject's weight-adjusted dose.

26. 26. The method of claim 25, achieving a relative infant dose of less than about 5% of the subject's weight-adjusted dose.

27. 23. The method of claim 22, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to solriamfetol exposure.

28. 23. The method of claim 22, wherein the adverse event is one or more of restlessness, insomnia, loss of appetite, or reduced weight gain.

29. 23. The method of claim 22, wherein the subject is between 1 day and 24 months postpartum.

30. 30. The method of claim 29, wherein the subject is 10 days to 12 months postpartum.

31. 23. The method of claim 22, wherein the subject is a female between the ages of 18 and 45.

32. 23. The method of claim 22, wherein the daily dose of solriamfetol is 150 mg.

33. 1. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression or cognitive impairment in a lactating mother who is feeding her infant her breast milk, comprising administering to a lactating mother: orally administering to said mother solriamfetol in a once-daily dose of about 150 mg; and feeding said infant breast milk obtained from said mother at least about 5 hours after administration of solriamfetol to said mother; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less, and reducing the likelihood of adverse events in the infant due to solriamfetol; The method.

34. 34. The method of claim 33, wherein the adverse event is restlessness, insomnia, loss of appetite, or reduced weight gain.

35. 34. The method of claim 33, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

36. 34. The method of claim 33, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

37. 34. The method of claim 33, wherein the lactating mother is between 1 day and 24 months postpartum.

38. 34. The method of claim 33, wherein the lactating mother is between 10 days and 12 months postpartum.

39. 34. The method of claim 33, wherein the lactating mother is between 18 and 45 years of age.

40. 1. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression or cognitive impairment in a lactating mother who is feeding her infant her breast milk, comprising administering to a lactating mother: orally administering to said mother solriamfetol in a once-daily dose of about 75 mg; and feeding said infant breast milk obtained from said mother at least about 5 hours after administration of solriamfetol to said mother; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less, and reducing the likelihood of adverse events in the infant due to solriamfetol; The method.

41. 41. The method of claim 40, wherein the adverse event is restlessness, insomnia, loss of appetite, or reduced weight gain.

42. 41. The method of claim 40, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

43. 41. The method of claim 40, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

44. 41. The method of claim 40, wherein the lactating mother is between 1 day and 24 months postpartum.

45. 41. The method of claim 40, wherein the lactating mother is between 10 days and 12 months postpartum.

46. 41. The method of claim 40, wherein the lactating mother is between 18 and 45 years of age.

47. 1. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression or cognitive impairment in a lactating mother who is feeding her infant her breast milk, comprising administering to a lactating mother: orally administering to said mother solriamfetol in a once-daily dose of about 150 mg; and feeding said infant breast milk obtained from said mother at least about 5 hours after administration of solriamfetol to said mother; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less, and the infant's exposure to solriamfetol from the breast milk is reduced; The method.

48. 48. The method of claim 47, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

49. 48. The method of claim 47, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

50. 48. The method of claim 47, wherein the lactating mother is between 1 day and 24 months postpartum.

51. 48. The method of claim 47, wherein the lactating mother is between 10 days and 12 months postpartum.

52. 48. The method of claim 47, wherein the lactating mother is between 18 and 45 years of age.

53. 1. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression or cognitive impairment in a lactating mother who is feeding her infant her breast milk, comprising administering to a lactating mother: orally administering to said mother solriamfetol in a once-daily dose of about 75 mg; and feeding said infant breast milk obtained from said mother at least about 5 hours after administration of solriamfetol to said mother; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less, and the infant's exposure to solriamfetol from the breast milk is reduced; The method.

54. 54. The method of claim 53, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

55. 54. The method of claim 53, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

56. 54. The method of claim 53, wherein the lactating mother is between 1 day and 24 months postpartum.

57. 54. The method of claim 53, wherein the lactating mother is between 10 days and 12 months postpartum.

58. 54. The method of claim 53, wherein the lactating mother is between 18 and 45 years of age.

59. 1. A method for treating a lactating postpartum human subject for a disorder suitable for treatment with solriamfetol, comprising: orally administering to said subject solriamfetol at a once-daily dose of about 150 mg; and feeding the infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less, and reducing the likelihood of adverse events in the infant due to solriamfetol; The method.

60. 60. The method of claim 59, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

61. 60. The method of claim 59, wherein the subject is between 1 day and 24 months postpartum.

62. 60. The method of claim 59, wherein the subject is 10 days to 12 months postpartum.

63. 60. The method of claim 59, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

64. 64. The method of claim 63, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

65. 64. The method of claim 63, wherein the cognitive impairment results from narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

66. 1. A method for treating a lactating postpartum human subject for a disorder suitable for treatment with solriamfetol, comprising: orally administering to said subject solriamfetol at a once-daily dose of about 75 mg; and feeding the infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less, and reducing the likelihood of adverse events in the infant due to solriamfetol; The method.

67. 67. The method of claim 66, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to solriamfetol from the breast milk.

68. 67. The method of claim 66, wherein the subject is between 1 day and 24 months postpartum.

69. 67. The method of claim 66, wherein the subject is 10 days to 12 months postpartum.

70. 67. The method of claim 66, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

71. 71. The method of claim 70, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

72. 71. The method of claim 70, wherein the cognitive impairment results from narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

73. 1. A method for treating a lactating postpartum human subject for a disorder suitable for treatment with solriamfetol, comprising: orally administering to said subject solriamfetol at a once-daily dose of about 150 mg; and feeding the infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less, and the infant's exposure to solriamfetol from the breast milk is reduced; The method.

74. 74. The method of claim 73, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

75. 74. The method of claim 73, wherein the subject is between 1 day and 24 months postpartum.

76. 74. The method of claim 73, wherein the subject is 10 days to 12 months postpartum.

77. 74. The method of claim 73, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

78. 78. The method of claim 77, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

79. 78. The method of claim 77, wherein the cognitive impairment results from narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

80. 1. A method for treating a lactating postpartum human subject for a disorder suitable for treatment with solriamfetol, comprising: orally administering to said subject solriamfetol at a once-daily dose of about 75 mg; and feeding the infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less, and the infant's exposure to solriamfetol from the breast milk is reduced; The method.

81. 81. The method of claim 80, wherein the infant does not experience restlessness, insomnia, loss of appetite, or reduced weight gain due to the solriamfetol from the breast milk.

82. 81. The method of claim 80, wherein the subject is between 1 day and 24 months postpartum.

83. 81. The method of claim 80, wherein the subject is 10 days to 12 months postpartum.

84. 81. The method of claim 80, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

85. 85. The method of claim 84, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

86. 85. The method of claim 84, wherein the cognitive impairment results from narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

87. 1. A method of reducing the risk of restlessness in a breastfed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 150 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less. The method.

88. 88. The method of claim 87, wherein the infant does not experience restlessness due to solriamfetol exposure.

89. 88. The method of claim 87, wherein the subject is between 1 day and 24 months postpartum.

90. 88. The method of claim 87, wherein the subject is 11 days to 12 months postpartum.

91. 88. The method of claim 87, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

92. 92. The method of claim 91, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

93. 92. The method of claim 91, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

94. 88. The method of claim 87, wherein the subject is being treated with solriamfetol to improve wakefulness.

95. 88. The method of claim 87, wherein the subject is a female between the ages of 18 and 50.

96. 1. A method of reducing the risk of restlessness in a breastfed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 75 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less. The method.

97. 97. The method of claim 96, wherein the infant does not experience restlessness due to solriamfetol exposure.

98. 97. The method of claim 96, wherein the subject is between 1 day and 24 months postpartum.

99. 97. The method of claim 96, wherein the subject is 11 days to 12 months postpartum.

100. 97. The method of claim 96, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

101. 101. The method of claim 100, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

102. 101. The method of claim 100, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

103. 97. The method of claim 96, wherein the subject is being treated with solriamfetol to improve wakefulness.

104. 97. The method of claim 96, wherein the subject is a female between the ages of 18 and 50.

105. 1. A method of reducing the risk of insomnia in a breastfed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 150 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less. The method.

106. 106. The method of claim 105, wherein the infant does not experience insomnia due to solriamfetol exposure.

107. 106. The method of claim 105, wherein the subject is between 1 day and 24 months postpartum.

108. 106. The method of claim 105, wherein the subject is 11 days to 12 months postpartum.

109. The method of claim 105, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

110. 110. The method of claim 109, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

111. 110. The method of claim 109, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

112. 106. The method of claim 105, wherein the subject is being treated with solriamfetol to improve wakefulness.

113. 106. The method of claim 105, wherein the subject is a female between the ages of 18 and 50.

114. 1. A method of reducing the risk of insomnia in a breastfed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 75 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less. The method.

115. 115. The method of claim 114, wherein the infant does not experience insomnia due to solriamfetol exposure.

116. 115. The method of claim 114, wherein the subject is between 1 day and 24 months postpartum.

117. 115. The method of claim 114, wherein the subject is 11 days to 12 months postpartum.

118. 115. The method of claim 114, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

119. 119. The method of claim 118, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

120. 119. The method of claim 118, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

121. 115. The method of claim 114, wherein the subject is being treated with solriamfetol to improve wakefulness.

122. 115. The method of claim 114, wherein the subject is a female between the ages of 18 and 50.

123. 1. A method of reducing the risk of anorexia and / or reduced weight gain in a breast-fed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 150 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less. The method.

124. 124. The method of claim 123, wherein the infant does not experience loss of appetite, or reduced weight gain, or weight loss due to exposure to solriamfetol.

125. 124. The method of claim 123, wherein the subject is between 1 day and 24 months postpartum.

126. 124. The method of claim 123, wherein the subject is 11 days to 12 months postpartum.

127. 124. The method of claim 123, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

128. 128. The method of claim 127, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

129. 128. The method of claim 127, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

130. 124. The method of claim 123, wherein the subject is being treated with solriamfetol to improve wakefulness.

131. 124. The method of claim 123, wherein the subject is a female between the ages of 18 and 50.

132. 1. A method of reducing the risk of anorexia and / or reduced weight gain in a breast-fed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 75 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less. The method.

133. 133. The method of claim 132, wherein the infant does not experience loss of appetite, reduced weight gain, or weight loss due to exposure to solriamfetol.

134. 133. The method of claim 132, wherein the subject is between 1 day and 24 months postpartum.

135. 133. The method of claim 132, wherein the subject is 11 days to 12 months postpartum.

136. 133. The method of claim 132, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

137. 137. The method of claim 136, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

138. 137. The method of claim 136, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

139. 133. The method of claim 132, wherein the subject is being treated with solriamfetol to improve wakefulness.

140. 133. The method of claim 132, wherein the subject is a female between the ages of 18 and 50.

141. 1. A method of preventing a decrease in the number of feeds and / or the volume of milk ingested in a breastfed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 150 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less. The method.

142. 142. The method of claim 141, wherein the infant does not experience a decrease in the number of feedings and / or a decrease in the volume of milk ingested due to exposure to solriamfetol.

143. 142. The method of claim 141, wherein the subject is between 1 day and 24 months postpartum.

144. 142. The method of claim 141, wherein the subject is 11 days to 12 months postpartum.

145. 142. The method of claim 141, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

146. 146. The method of claim 145, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

147. 146. The method of claim 145, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

148. 142. The method of claim 141, wherein the subject is being treated with solriamfetol to improve wakefulness.

149. 142. The method of claim 141, wherein the subject is a female between the ages of 18 and 50.

150. 1. A method of preventing a decrease in the number of feeds and / or the volume of milk ingested in a breastfed infant obtained from a subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a daily dose of about 75 mg; and feeding said infant breast milk obtained from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less. The method.

151. 151. The method of claim 150, wherein the infant does not experience a decrease in the number of feedings and / or a decrease in the volume of milk ingested due to exposure to solriamfetol.

152. 151. The method of claim 150, wherein the subject is between 1 day and 24 months postpartum.

153. 151. The method of claim 150, wherein the subject is 11 days to 12 months postpartum.

154. The method of claim 150, wherein the subject is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

155. 155. The method of claim 154, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

156. 155. The method of claim 154, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

157. 151. The method of claim 150, wherein the subject is being treated with solriamfetol to improve wakefulness.

158. 151. The method of claim 150, wherein the subject is a female between the ages of 18 and 50.

159. 1. A method of preventing exposure of an infant of a nursing human mother being treated with solriamfetol to peak concentrations of solriamfetol excreted in breast milk, the method comprising withholding breast milk from the infant within a minimum of about 3.5 hours of the mother receiving a single oral daily dose of about 150 mg of solriamfetol, and ｍａｘ is about 1.1 hours, The daily infant dose of solriamfetol is reduced to about 0.3 mg or less. The method.

160. 160. The method of claim 159, wherein the infant is not given breast milk that is obtained within a minimum of about 5 hours of the mother receiving an oral once-daily dose of solriamfetol.

161. 160. The method of claim 159, wherein the infant does not experience restlessness due to exposure to solriamfetol.

162. 160. The method of claim 159, wherein the infant does not experience insomnia due to exposure to solriamfetol.

163. 160. The method of claim 159, wherein the infant does not experience loss of appetite and / or reduced weight gain due to exposure to solriamfetol.

164. 160. The method of claim 159, wherein solriamfetol is excreted in breast milk in a milk to plasma AUC ratio of about 2:

1.

165. The method of claim 159, wherein the elimination half-life of solriamfetol excreted in breast milk is about 5 hours.

166. 160. The method of claim 159, wherein breast milk produced by the nursing mother during a minimum of about 3.5 hours of the mother receiving an oral once-daily dose of solriamfetol is expressed and discarded.

167. 160. The method of claim 159, wherein the mother is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression or cognitive impairment.

168. 168. The method of claim 167, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

169. 168. The method of claim 167, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

170. 160. The method of claim 159, wherein the mother is being treated with solriamfetol to improve wakefulness.

171. 160. The method of claim 159, wherein the lactating mother is from about 1 day to about 24 months postpartum.

172. 160. The method of claim 159, wherein the lactating mother is from about 10 days to about 52 weeks postpartum.

173. 160. The method of claim 159, wherein the lactating mother is between 18 and 45 years of age.

174. 1. A method of preventing exposure of an infant of a nursing human mother being treated with solriamfetol to peak concentrations of solriamfetol excreted in breast milk, the method comprising withholding breast milk from the infant from the mother within a minimum of about 3.5 hours of receiving a single oral daily dose of about 75 mg of solriamfetol, and ｍａｘ is about 1.1 hours, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less. The method.

175. 175. The method of claim 174, wherein the infant is not given breast milk that is obtained within a minimum of about 5 hours of the mother receiving an oral once-daily dose of solriamfetol.

176. 175. The method of claim 174, wherein the infant does not experience restlessness due to exposure to solriamfetol.

177. 175. The method of claim 174, wherein the infant does not experience insomnia due to exposure to solriamfetol.

178. 175. The method of claim 174, wherein the infant does not experience loss of appetite and / or reduced weight gain due to exposure to solriamfetol.

179. 175. The method of claim 174, wherein solriamfetol is excreted in breast milk in a milk to plasma AUC ratio of about 2:

1.

180. The method of claim 174, wherein the elimination half-life of solriamfetol excreted in breast milk is about 5 hours.

181. 175. The method of claim 174, wherein breast milk produced by the nursing mother during a minimum of about 3.5 hours after the mother receives an oral once-daily dose of solriamfetol is expressed and discarded.

182. 175. The method of claim 174, wherein the mother is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression or cognitive impairment.

183. 183. The method of claim 182, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

184. 183. The method of claim 182, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

185. 175. The method of claim 174, wherein the mother is being treated with solriamfetol to improve wakefulness.

186. 175. The method of claim 174, wherein the lactating mother is from about 1 day to about 24 months postpartum.

187. 175. The method of claim 174, wherein the lactating mother is from about 10 days to about 52 weeks postpartum.

188. 175. The method of claim 174, wherein the lactating mother is between 18 and 45 years of age.

189. 1. A method of reducing exposure to solriamfetol from breast milk in an infant receiving breast milk from a nursing human mother who is being treated for a disorder amenable to treatment with solriamfetol with a once-daily dose of about 150 mg of solriamfetol, comprising feeding the infant breast milk obtained from the mother a minimum of about 5 hours after administration of solriamfetol to the mother, wherein the exposure to solriamfetol in the infant is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of solriamfetol; The daily infant dose of solriamfetol is reduced to about 0.3 mg or less. The method.

190. 190. The method of claim 189, wherein the resulting relative infant dose is no more than about 2% of the maternal weight-adjusted dose.

191. 190. The method of claim 189, wherein the breast milk is obtained from the mother at least about 7 hours after administration of solriamfetol to the mother.

192. 190. The method of claim 189, wherein the breast milk is obtained from the mother at least about 10 hours after administration of solriamfetol to the mother.

193. 190. The method of claim 189, wherein breast milk produced by the nursing mother for a minimum of about 5 hours following administration of solriamfetol to the mother is expressed and discarded.

194. 190. The method of claim 189, wherein the infant does not experience restlessness due to exposure to solriamfetol.

195. 190. The method of claim 189, wherein the infant does not experience insomnia due to exposure to solriamfetol.

196. 190. The method of claim 189, wherein the infant does not experience loss of appetite and / or reduced weight gain due to exposure to solriamfetol.

197. 190. The method of claim 189, wherein the mother is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression or cognitive impairment.

198. 198. The method of claim 197, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

199. 198. The method of claim 197, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

200. 190. The method of claim 189, wherein the mother is being treated with solriamfetol to improve wakefulness.

201. 190. The method of claim 189, wherein the lactating mother is from about 1 day to about 24 months postpartum.

202. 190. The method of claim 189, wherein the lactating mother is from about 10 days to about 52 weeks postpartum.

203. 190. The method of claim 189, wherein the lactating mother is between 18 and 45 years of age.

204. 1. A method of reducing exposure to solriamfetol from breast milk in an infant receiving breast milk from a nursing human mother who is being treated for a disorder amenable to treatment with solriamfetol with a once-daily dose of about 75 mg of solriamfetol, comprising feeding the infant breast milk obtained from the mother a minimum of about 5 hours after administration of solriamfetol to the mother, wherein the exposure to solriamfetol in the infant is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of solriamfetol, The daily infant dose of solriamfetol is reduced to about 0.15 mg or less. The method.

205. 205. The method of claim 204, wherein the resulting relative infant dose is about 2% or less of the maternal weight-adjusted dose.

206. 205. The method of claim 204, wherein the breast milk is obtained from the mother at least about 7 hours after administration of solriamfetol to the mother.

207. The method of claim 204, wherein the breast milk is obtained from the mother at least about 10 hours after administration of solriamfetol to the mother.

208. 205. The method of claim 204, wherein breast milk produced by the nursing mother for a minimum of about 5 hours following administration of solriamfetol to the mother is expressed and discarded.

209. 205. The method of claim 204, wherein the infant does not experience restlessness due to exposure to solriamfetol.

210. 205. The method of claim 204, wherein the infant does not experience insomnia due to exposure to solriamfetol.

211. 205. The method of claim 204, wherein the infant does not experience loss of appetite and / or reduced weight gain due to exposure to solriamfetol.

212. The method of claim 204, wherein the mother is being treated with solriamfetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression or cognitive impairment.

213. 213. The method of claim 212, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

214. 213. The method of claim 212, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

215. 205. The method of claim 204, wherein the mother is being treated with solriamfetol to improve wakefulness.

216. 205. The method of claim 204, wherein the lactating mother is from about 1 day to about 24 months postpartum.

217. 205. The method of claim 204, wherein the lactating mother is from about 10 days to about 52 weeks postpartum.

218. 205. The method of claim 204, wherein the lactating mother is between 18 and 45 years of age.

219. 1. A method of treating excessive daytime sleepiness in a lactating human mother who wishes to breastfeed her infant, wherein said infant is at risk for an adverse event from said mother's excessive daytime sleepiness, comprising administering to said infant: a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant; b) providing mothers with an ESS total score of 15 or greater who experience narcolepsy while caring for the infant with a starting dose of 37.5 mg solriamfetol once daily if the excessive daytime sleepiness is associated with obstructive sleep apnea, or 75 mg solriamfetol once daily if the excessive daytime sleepiness is associated with narcolepsy, doubling the dose at intervals of at least 3 days, to a maximum of 150 mg once daily; and c) feeding said infant breast milk obtained from said mother at least about 3.5 hours after administration of solriamfetol to said mother, thereby avoiding exposing said infant to the highest concentration of solriamfetol in breast milk; Including, The median T of solriamfetol excreted in breast milk ｍａｘ is about 1.1 hours, and The daily infant dose of solriamfetol is reduced to about 0.3 mg or less after a 150 mg dose, to about 0.15 mg or less after a 75 mg dose, and to about 0.08 mg or less after a 37.5 mg dose. The method.

220. 220. The method of claim 219, wherein the lactating mother experiences a decline in ESS total score of 5 or more.

221. 220. The method of claim 219, wherein the lactating mother experiences a decrease in the frequency of sleep attacks while holding her infant.

222. 220. The method of claim 219, wherein the lactating mother experiences a decrease in the frequency of sleep attacks while nursing her infant.

223. 220. The method of claim 219, wherein the lactating mother experiences a decrease in the frequency of sleep attacks while feeding her infant.

224. 220. The method of claim 219, wherein the lactating mother experiences a decrease in the frequency of motor movements while caring for her infant.

225. 220. The method of claim 219, wherein the infant is not given breast milk that is obtained within a minimum of about 5 hours of the mother receiving an oral once-daily dose of solriamfetol.

226. 220. The method of claim 219, wherein the infant does not experience restlessness due to exposure to solriamfetol in breast milk.

227. 220. The method of claim 219, wherein the infant does not experience insomnia due to exposure to solriamfetol in breast milk.

228. 220. The method of claim 219, wherein the infant does not experience loss of appetite and / or reduced weight gain due to exposure to solriamfetol in breast milk.

229. 220. The method of claim 219, wherein solriamfetol is excreted in breast milk at a milk to plasma AUC ratio of about 2:

1.

230. The method of claim 219, wherein the elimination half-life of solriamfetol excreted in breast milk is about 5 hours.

231. 220. The method of claim 219, wherein breast milk produced by the mother for a minimum of about 3.5 hours after administration of solriamfetol to the mother is expressed and discarded.

232. 220. The method of claim 219, wherein the lactating mother is from about 1 day to about 24 months postpartum.

233. 220. The method of claim 219, wherein the lactating mother is from about 10 days to about 52 weeks postpartum.

234. 220. The method of claim 219, wherein the lactating mother is between 18 and 45 years of age.

235. 1. A method for reducing the likelihood of adverse events from solriamfetol in breast-fed infants obtained from a human subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a once-daily dose of about 150 mg; and feeding said infant breast milk from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The cumulative amount of solriamfetol excreted in breast milk over 8 hours is reduced to about 0.26 mg or less. The method.

236. 236. The method of claim 235, wherein the adverse event is one or more of restlessness, insomnia, or reduced weight gain.

237. The method of claim 235, wherein the subject is being treated with solriamfetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, depression or binge eating disorder.

238. The method of claim 235, wherein the infant does not experience restlessness, insomnia, or reduced weight gain due to exposure to solriamfetol.

239. 236. The method of claim 235, wherein the lactating mother is between 1 day and 24 months postpartum.

240. 240. The method of claim 239, wherein the subject is between 10 days and 52 weeks postpartum.

241. 1. A method for reducing the likelihood of adverse events from solriamfetol in breast-fed infants obtained from a human subject treated with solriamfetol, comprising: orally administering to said subject solriamfetol at a once-daily dose of about 150 mg; and feeding said infant breast milk from said subject at least about 5 hours after administering solriamfetol to said subject; Including, The cumulative amount of solriamfetol excreted in breast milk over 24 hours is reduced to about 0.35 mg or less. The method.

242. 242. The method of claim 241, wherein the adverse event is one or more of restlessness, insomnia, or reduced weight gain.

243. The method of claim 241, wherein the subject is being treated with solriamfetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, depression or binge eating disorder.

244. The method of claim 241, wherein the infant does not experience restlessness, insomnia, or reduced weight gain due to exposure to solriamfetol.

245. 242. The method of claim 241, wherein the lactating mother is between 1 day and 24 months postpartum.

246. The method of claim 245, wherein the subject is between 10 days and 52 weeks postpartum.

247. 1. A method for treating a solriamfetol-treatable disorder in a human subject producing breast milk for feeding to an infant, comprising administering to said subject: orally administering to said subject solriamfetol at a once-daily dose of about 150 mg; and reducing the exposure of the infant to solriamfetol and / or reducing the likelihood of an adverse event in the infant breastfed from the subject, comprising feeding the infant breast milk obtained from the subject at least about 5 hours after administering solriamfetol to the subject; Including, The cumulative median amount of solriamfetol excreted in breast milk over 8 hours is reduced to about 0.26 mg or less. The method.

248. The method of claim 247, wherein the disorder treatable with solriamfetol is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, depression or binge eating disorder.

249. The method of claim 247, wherein the infant does not experience restlessness, insomnia, or reduced weight gain due to exposure to solriamfetol.

250. The method of claim 247, wherein the adverse event is one or more of restlessness, insomnia, or reduced weight gain.

251. The method of claim 247, wherein the subject is between 1 day and 24 months postpartum.

252. 252. The method of claim 251, wherein the subject is 10 days to 52 weeks postpartum.

253. The method of claim 247, wherein the subject is a female between the ages of 18 and 45.

254. 1. A method for treating a solriamfetol-treatable disorder in a human subject producing breast milk for feeding to an infant, comprising administering to said subject: orally administering to said subject solriamfetol at a once-daily dose of about 150 mg; and reducing the exposure of the infant to solriamfetol and / or reducing the likelihood of an adverse event in the infant breastfed from the subject, comprising feeding the infant breast milk obtained from the subject at least about 5 hours after administering solriamfetol to the subject; Including, The cumulative median amount of solriamfetol excreted in breast milk over 24 hours is reduced to about 0.35 mg or less. The method.

255. The method of claim 254, wherein the disorder treatable with solriamfetol is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, depression or binge eating disorder.

256. The method of claim 254, wherein the infant does not experience restlessness, insomnia, or reduced weight gain due to exposure to solriamfetol.

257. 255. The method of claim 254, wherein the adverse event is one or more of restlessness, insomnia, or reduced weight gain.

258. The method of claim 254, wherein the subject is between 1 day and 24 months postpartum.

259. The method of claim 258, wherein the subject is between 10 days and 52 weeks postpartum.

260. The method of claim 254, wherein the subject is a woman between the ages of 18 and 45.

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