A method of administering Soluliamfetol to women who are lactating.

Abstract

Herein, according to several embodiments, is provided a method for reducing the likelihood of adverse events originating from souliamfetol in infants breastfed from subjects treated with souliamfetol, comprising: orally administering souliamfetol to the subject at a daily dose of approximately 37.5 mg to approximately 300 mg; and breastfeeding the infant from the subject at least approximately 5 hours after administration of souliamfetol to the subject, thereby reducing the likelihood of adverse events originating from souliamfetol in the infant.

Description

[Technical Field]

[0001] The present invention relates to a method for administering Soluliamfetol to a subject who is lactating, while reducing the possibility of adverse events caused by Soluliamfetol in infants who are breastfed by the subject. [Background technology]

[0002] Solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). Solriamfetol has been shown to be helpful in treating a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, and fibromyalgia.

[0003] Pharmacokinetic studies have demonstrated rapid absorption and high oral bioavailability at dose-proportional exposure (peak serum concentration and area under the concentration-time curve [AUC]) in test animals.

[0004] The present invention overcomes the shortcomings in the art by providing a method for administering Soluriamfetol to a subject who is lactating, while reducing the possibility of adverse events derived from Soluriamfetol in infants who are breastfed by the subject. [Overview of the Initiative]

[0005] This invention relates to the development of a method for reducing the likelihood of adverse events derived from Soluriamfetol in infants breastfed from subjects treated with Soluriamfetol. Furthermore, this invention relates to a method for reducing exposure to Soluriamfetol in infants breastfed from subjects treated with Soluriamfetol.

[0006] Accordingly, one aspect of the present invention relates to a method for reducing exposure to soruliamfetol in infants who are breastfed from a subject treated with soruliamfetol, comprising: orally administering soruliamfetol to the subject at a daily dose of approximately 37.5 mg to approximately 300 mg; and reducing the infant's exposure to soruliamfetol by providing breast milk from the subject to the infant at least approximately 5 hours after the administration of soruliamfetol to the subject.

[0007] Another aspect of the present invention relates to a method for reducing the likelihood of adverse events attributable to soruliamfetol in infants breastfed from subjects treated with soruliamfetol, comprising: orally administering soruliamfetol to the subject at a daily dose of 37.5 mg to 300 mg; and reducing the likelihood of adverse events attributable to soruliamfetol in the infant by breastfeeding from the subject to the infant at least about 5 hours after administration of soruliamfetol to the subject. In some embodiments, the daily dose of soruliamfetol is 150 mg.

[0008] One aspect of the present invention relates to a method for treating a souriamfetol-treatable disorder in a subject producing breast milk for infants, comprising: orally administering souriamfetol to the subject at a daily dose of 37.5 mg to 300 mg; and reducing exposure to souriamfetol and / or the likelihood of adverse events in an infant being breastfed by the subject, including, at least about 5 hours after administration of souriamfetol to the subject, breastfeeding the infant from the subject. Disorders treatable with souriamfetol may include, but are not limited to, narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, or bulimia nervosa.

[0009] In some embodiments, the method provides a daily infant dose of approximately 0.3 mg or less of souliamfetol. In some embodiments, the method achieves a relative infant dose of less than approximately 9 percent of the target weight-adjusted dose. In some embodiments, the method achieves a relative infant dose of less than approximately 5 percent of the target weight-adjusted dose.

[0010] In some embodiments, infants do not experience restlessness, insomnia, or decreased weight gain as a result of exposure to Solliam fetol.

[0011] In some embodiments, the target period is from 1 day to 24 months postpartum or from 10 days to 12 months postpartum.

[0012] In some embodiments, the subjects are treated with Soluliamfetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, or bulimia.

[0013] In some embodiments, the subject is a woman aged 18 to 45 years.

[0014] In some embodiments, the adverse events are one or more of the following: restlessness, insomnia, or decreased weight gain.

[0015] A method is provided for treating a disorder suitable for treatment with souliamfetol in a subject who is breastfeeding an infant, the method comprising orally administering souliamfetol to the subject in a daily dose between approximately 37.5 mg and 300 mg.

[0016] These and other aspects of the present invention will be described in more detail in the following description of the invention. Detailed explanation

[0017] The present invention will now be described in more detail with reference to the accompanying drawings illustrating preferred embodiments. However, the invention may be embodied in different forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments are provided so that the present disclosure may be complete and fully convey to those skilled in the art the scope of the invention. Furthermore, the references cited herein are incorporated in their entirety by reference.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to the extent of the present invention. The terms used in the description of the present invention herein are for the sole purpose of describing specific embodiments and are not intended to limit the invention. All publications, patent applications, patents, patent publications and other references cited herein are incorporated in their entirety for teachings relating to the sentences and / or paragraphs in which the references are presented.

[0019] Unless the context indicates otherwise, the various features of the invention described herein are specifically intended to be used in any combination.

[0020] Furthermore, in some embodiments of the present invention, any feature or combination of features described herein may be excluded or omitted.

[0021] For example, where this specification states that a complex comprises components A, B, and C, it is specifically intended that any one of A, B, or C, or any combination thereof, may be omitted or discarded individually or in any combination.

[0022] When used in the description of this invention and in the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context indicates otherwise.

[0023] Also, as used herein, "and / or" refers to any and all possible combinations of one or more of the associated listed items, as well as the absence of combinations when interpreted as alternatives ("or"), and includes them.

[0024] As used herein, the term "about" when referring to a measurable value such as the amount of a polypeptide, dosage, time, temperature, enzyme activity or other biological activity, means including a variation of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0025] As used herein, the transitional phrase "consisting essentially of" (and grammatical variations) should be construed to include those materials or steps recited, 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".

[0026] The terms "therapeutically effective amount" or "effective amount", as used herein, when referring to a subject afflicted with a disorder, disease or illness, refer to an amount of a composition, compound or agent of the present invention that confers a modulating effect (which can be, for example, a beneficial effect) on the subject, such as an improvement (e.g., in one or more symptoms), a delay or reduction in the progression of the condition, a prevention or delay in the onset of the disorder, and / or a change in clinical parameters, disease or disease state, as is well known in the art. For example, a therapeutically effective amount or effective amount can refer to an amount of a composition, compound or agent / drug that improves the condition in the subject by at least 5%, for example, 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 7%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%.

[0027] A "pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") refers to a carrier or excipient useful in manufacturing a pharmaceutical (medicinal) or therapeutic composition, generally being safe and non-toxic and acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline, water, emulsions (such as oil / water or water / oil emulsions) and / or various types of wetting agents. As used herein, the term "carrier" includes, without limitation, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer or other material well known in the art for use in pharmaceutical formulations and as further described herein.

[0028] The terms "modulate", "modulates" or "modulation" refer to enhancement (e.g., increase) or inhibition (e.g., decrease) at a particular level or activity.

[0029] The terms "enhance" or "increase" refer 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 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.

[0030] As used herein, "inhibit" or "decrease" 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, the inhibition or decrease results in little or essentially no detectable activity (at most, a small amount, e.g., less than about 10% or less than 5%).

[0031] Where used herein in the context of treating a subject, “treat,” “therapy,” and similar terms mean providing medical and / or surgical management of the 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 aimed at altering the course of a disease (this term is used to indicate any disease, disorder, syndrome, or undesirable condition that justifies or potentially justifies therapy) in a manner beneficial to the subject. The effects of treatment may include regression, mitigation, reduction in severity, delay in onset, cure, inhibition of progression, and / or reduction of the likelihood of any of these occurring or recurring of the disease or one or more symptoms, or the onset of the disease. A therapeutic agent may be administered to a subject who has the disease or is at high risk of developing the disease compared to members of the general population. In some embodiments, a therapeutic agent may be administered to a subject who has had the disease but no longer shows signs of the disease. The agent may be administered, for example, to reduce the likelihood of an apparent recurrence of the disease. A therapeutic agent may be administered prophylactically, i.e., before the onset of any symptoms or the onset of the disease. "Preventive treatment" refers to providing medical and / or surgical management to individuals who are not yet diagnosed with the disease or who show no signs of the disease, for example, to reduce the likelihood of developing the disease, to delay its onset, or to reduce its severity if the disease does develop. Such individuals may be identified as being at risk of developing the disease (for example, having a higher risk than the general population or possessing risk factors that increase the likelihood of developing the disease).

[0032] The grammatical variations “administer,” “give,” and “are administering” to a subject include any route through which the drug is introduced or delivered to the subject. Administration can be performed by inhalation, via an implanted reservoir, or parenterally (e.g., subcutaneous, intramuscular, intra-articular, transdermal, intramuscular, intra-joint, parenteral, intra-arterial, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, or vaginal), by any suitable route including oral, topical, intra-intra-articular, intra-articular, intra-spheric, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques). As used herein, “concurrent administration,” “administration in combination,” “simultaneous administration,” or “administered simultaneously” means that the compounds are administered at the same time, at overlapping times, or one following the other. In the latter case, the two compounds are administered at sufficiently close intervals that the observed results are indistinguishable from the results achieved if the compounds were administered at the same time. “Systemic administration” refers to the introduction or delivery of the agent to a subject via a route that introduces or delivers the agent to a large 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 the agent to a subject via a route that introduces or delivers the agent to the area of ​​the administration site or an area directly adjacent to it, and does not introduce the agent systemically in a therapeutically significant amount. For example, a locally administered agent is readily detectable locally near the administration site, but is undetectable or detectable in negligible amounts in distal parts of the subject's body. Administration includes self-administration and administration by another person.

[0033] As used herein, "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable; that is, the material can be administered to an individual with the composition of the present invention without causing substantially harmful biological effects or interacting in a harmful 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 will naturally be selected to minimize the degradation of the active ingredient and minimize harmful side effects in the subject (see, for example, Remington's Pharmaceutical Science; 21st ed. 2005).

[0034] "Combined administration" means that the two compounds are sufficiently close in time to produce a combined effect (i.e., combined administration can be simultaneous or two or more events occurring within a short time interval before and after each other). In some embodiments, "combined" administration of two or more compounds means that the two compounds are administered in sufficiently close time intervals that the presence of one alters the biological effect of the other. The two compounds may be administered in the same or different formulations, or sequentially. Combined administration can be achieved 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 using different routes of administration.

[0035] "Bioavailability," as used herein, refers to the estimated area under the curve or AUC of the active drug in the systemic circulation after oral administration in the dosage forms 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.

[0036] The product's relative average C of the test product compared to the reference product. max AUC (0-t) and AUC (0-∞) If the percentage falls within the range of 80-125%, the animals are considered "biologically equivalent."

[0037] The term "AUC (0-t) " means the area under the plasma concentration curve from time 0 to time t.

[0038] The term "AUC (0-∞) " or "AUC 0-inf " means the area under the plasma concentration-time curve from time 0 to infinity.

[0039] "C max " refers to the maximum milk or plasma concentration of soluliam fetol.

[0040] "T max " refers to the period to the maximum milk or plasma concentration of a given drug.

[0041] "t 1 / 2 " refers to the period during which the milk and plasma concentrations are reduced by 50% during the terminal elimination phase of the drug.

[0042] The milk:plasma ratio means the AUC in breast milk divided by the AUC in plasma.

[0043] "A milk " means the amount excreted into breast milk over 72 hours.

[0044] "Vd / F" means the apparent volume of distribution in plasma.

[0045] "CL / F" is the apparent oral clearance in plasma. <00所求の期間である。

[0046] AUC0-t is the area under the concentration-time curve from time 0 to the time t of the last quantifiable concentration (in milk and plasma).

[0047] The present invention is based in part on a method for using Sunosi® (hereinafter also called Solliamfetol ((R)-2-amino-3-phenylpropylcarbamate (APC), conventionally known as JZP-110, ADX-N05, R228060, and YKP10A)) in lactating subjects with disorders for which treatment with Solliamfetol is suitable, while reducing the likelihood of adverse events in infants breastfed by the subjects. The administration of Solliamfetol to breastfeeding subjects presents challenges. In non-clinical studies in rats, Solliamfetol was detected in breast milk, and the concentration of Solliamfetol in milk was higher than that in plasma. It is desirable to reduce or minimize any adverse effects resulting from the daily dose received by infants breastfed by subjects treated with Solliamfetol. Furthermore, it is desirable to identify a method for considering the safety and tolerability of Solliamfetol in lactating subjects.

[0048] Accordingly, one aspect of the present invention relates to a method for reducing exposure to soruliamfetol in infants who are breastfed from a subject treated with soruliamfetol, comprising: orally administering soruliamfetol to the subject at a daily dose of approximately 37.5 mg to approximately 300 mg; and reducing the infant's exposure to soruliamfetol by providing breast milk from the subject to the infant at least approximately 5 hours after the administration of soruliamfetol to the subject.

[0049] One aspect of the present invention is a method for reducing the likelihood of adverse events attributable to soruliamfetol in an infant breastfed from a subject treated with soruliamfetol, comprising: orally administering soruliamfetol to the subject at a daily dose of 37.5 mg to 300 mg; and reducing the likelihood of adverse events attributable to soruliamfetol in the infant by breastfeeding the infant from the subject at least about 5 hours after administration of soruliamfetol to the subject. In one embodiment, the adverse event is one or more of the following: restlessness, insomnia, or decreased weight gain.

[0050] One aspect of the present invention relates to a method for treating a souriamufetol-treatable disorder in a subject producing breast milk for infants, comprising: orally administering souriamufetol to the subject at a daily dose of 37.5 mg to 300 mg; and reducing exposure to souriamufetol and / or reducing the likelihood of adverse events in an infant being breastfed by the subject, wherein breast milk produced from the subject is given to the infant at least about 5 hours after administration of souriamufetol to the subject. In one embodiment, the method reduces souriamufetol exposure in the infant, and the infant does not experience restlessness, insomnia, or reduced weight gain due to souriamufetol exposure. In one embodiment, the adverse event is one or more of restlessness, insomnia, or reduced weight gain.

[0051] "Disorders for which treatment with sorriamfetol is appropriate" or "disorders treatable with sorriamfetol" refers to disorders in which administration of sorriamfetol to a subject results in the treatment of one or more symptoms of the disorder in the subject. Examples of disorders for which treatment with sorriamfetol is appropriate include narcolepsy, cataplexy, excessive daytime sleepiness, obstructive sleep apnea, drug dependence, sexual dysfunction, fatigue, fibromyalgia, attention deficit hyperactivity disorder (ADHD), cognitive impairment and / or cognitive dysfunction, restless limb syndrome, depression, bipolar disorder, obesity, or bulimia nervosa. In some embodiments, disorders for which treatment with sorriamfetol is appropriate include narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, or bulimia nervosa. See, for example, U.S. Patents No. 8,232,315; No. 8,440,715; No. 8,552,060; No. 8,623,913; No. 8,729,120; No. 8,741,950; No. 8,895,609; No. 8,927,602; No. 9,226,910 and No. 9,359,290; and U.S. Patent Publication Nos. 2012 / 0004300 and 2015 / 0018414. All of the above patents and applications are incorporated herein by reference in their entirety for all purposes.

[0052] "Daytime excessive sleepiness," or "EDS," refers to persistent daytime sleepiness during times when an individual is expected to be awake and alert, even during the daytime after clearly adequate or even prolonged nighttime sleep. EDS may be a result of a sleep disorder or 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 (for example, if the subject works a night shift). It is also understood that EDS is medically distinct from fatigue and fatigue-related disorders.

[0053] In some embodiments, the causes of EDS may include, but are not limited to, central nervous system (CNS) pathological abnormalities, stroke, narcolepsy, idiopathic CNS hypersomnia; sleep deficiency, sleep apnea, obstructive sleep apnea, insufficient nocturnal 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, myocardial ischemia; mismatch between the body's circadian pacemaker and the environment, jet lag, shift work, or sedatives.

[0054] In a particular embodiment, the structure of Solliamufetol is shown below as formula I: [ka] Methods for producing solliamfetol and related compounds can be found in U.S. Patents 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.

[0055] In one embodiment, the method detailed herein provides that infants breastfed from an object administered with Soluriamfetol do not experience adverse events due to Soluriamfetol exposure, such as restlessness, insomnia, or decreased weight gain. Infants can be monitored for restlessness, insomnia, or decreased weight gain. For example, monitoring and / or detection of weight loss, decreased weight gain, decreased feeding frequency or intake, or decreased volume of milk consumed can be performed. Monitoring for increased restlessness and / or insomnia (including decreased sleep duration and / or time spent falling asleep and remaining asleep) can also be performed to confirm changes in the infant. In some embodiments, monitoring of infant changes is performed at least 3 hours after administration of the Soluriamfetol dose and at least 3 hours after the start of breastfeeding from the object to the infant, for example, at 3, 4, 5, 6, 7, 8, 9, and 10 hours or more after administration of the Soluriamfetol dose. Monitoring of changes experienced by the infant (e.g., restlessness, insomnia, or decreased weight gain) can be performed over the period during which Solliamfetol is administered to the subject, which can be over several days, weeks, or months, and can be performed at any time interval within that time frame (including hourly, daily, weekly, monthly, or any time range within those intervals).

[0056] In one embodiment, the method provides a daily infant dose of souriamfetol of about 0.3 mg or less, for example, 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, or about 0.10 mg or less. The daily infant dose refers to the daily dose received by the infant through breastfeeding.

[0057] In one embodiment, the method provides a daily infant dose of soluriamfetol of about 0.2 mg / kg (based on a nominal infant weight of 6 kg) or less, for example, 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, and about 0.01 mg / kg or less.

[0058] In one embodiment, the method is used for amounts of approximately 0.7 mg or less, for example, approximately 0.69 mg, approximately 0.68 mg, approximately 0.67 mg, approximately 0.66 mg, approximately 0.65 mg, approximately 0.64 mg, approximately 0.63 mg, approximately 0.62 mg, approximately 0.61 mg, approximately 0.60 mg, approximately 0.59 mg, approximately 0.58 mg, approximately 0.57 mg, approximately 0.56 mg, approximately 0.55 mg, approximately 0.54 mg, approximately 0.53 mg, approximately 0.52 mg, approximately 0.51 mg, approximately 0.50 mg, approximately 0.49 mg, approximately 0.48 mg, approximately 0.47 mg, approximately 0.46 mg, approximately 0.45 mg, approximately 0.44 mg, approximately 0.43 mg, approximately 0.42 mg, approximately 0.41 mg, approximately 0.40 mg, approximately 0.39 mg The cumulative infant dose of souliamfetol over 72 hours after a single dose is provided, with doses of approximately 0.38 mg, 0.37 mg, 0.36 mg, 0.35 mg, 0.34 mg, 0.33 mg, 0.32 mg, 0.31 mg, 0.30 mg, 0.29 mg, 0.28 mg, 0.27 mg, 0.26 mg, 0.25 mg, 0.24 mg, 0.23 mg, 0.22 mg, 0.21 mg, 0.20 mg, 0.19 mg, 0.18 mg, 0.17 mg, 0.16 mg, 0.15 mg, 0.14 mg, 0.13 mg, 0.12 mg, 0.11 mg, and 0.10 mg or less.

[0059] In some embodiments, the method provides, after 8 hours, the total amount of Soluriamfetor excreted in breast milk after a single dose, which is approximately 75% to 80% of the total amount excreted in 72 hours. In some embodiments, the method provides, after 24 hours, the total amount of Soluriamfetor excreted in breast milk after a single dose, which is approximately 95% to 100% of the total amount excreted in 72 hours.

[0060] In some embodiments, breast milk for infants is expressed or produced from the subject at least 3 hours, 4 hours, or 5 hours after administration of a dose of sorriamfetol to the subject, for example, at least 3, 4, 5, 6, 7, 8, 9, or 10 hours after administration. In some embodiments, breast milk produced from the subject for infants in the method detailed herein occurs at or after the approximately average elimination half-life of sorriamfetol, i.e., about 5 hours after administration of sorriamfetol. In some embodiments, infant feeding takes place at least 3 hours, 4 hours, or 5 hours after administration of a dose of sorriamfetol to the subject. In some embodiments, breast milk for infants is obtained from the subject at least 3 hours, 4 hours, or 5 hours after administration of a dose of sorriamfetol to the subject.

[0061] In some embodiments, the method achieves relative infant doses, i.e., percentages of the target weight-adjusting dose excreted in breast milk over 24 hours, of less than 10%, less than 9.5%, less than 9%, less than 8.5%, less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, less than 5.5%, less than 5%, less than 4.9%, less than 4.8%, less than 4.7%, less than 4.6%, less than 4.5%, less than 4.4%, less than 4.3%, less than 4.2%, less than 4.1%, and less than 4.0% of the target weight-adjusting dose.

[0062] In some embodiments, the method achieves relative infant doses, i.e., percentages of the target weight-adjusting dose excreted in breast milk over 72 hours, of less than 10%, less than 9.5%, less than 9%, less than 8.5%, less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, less than 5.5%, less than 5%, less than 4.9%, less than 4.8%, less than 4.7%, less than 4.6%, less than 4.5%, less than 4.4%, less than 4.3%, less than 4.2%, less than 4.1%, and less than 4.0% of the target weight-adjusting dose.

[0063] In some embodiments, the average amount of sorriamufetol received by an infant through breast milk produced by a subject treated with sorriamufetol according to the methods disclosed herein is less than approximately 0.70 mg, less than approximately 0.69 mg, less than approximately 0.68 mg, less than approximately 0.67 mg, less than approximately 0.66 mg, less than approximately 0.65 mg, less than approximately 0.64 mg, less than approximately 0.63 mg, less than approximately 0.62 mg, less than approximately 0.61 mg, less than approximately 0.60 mg, or less than approximately 0.59 mg over a 24-hour period.

[0064] In some embodiments, the average amount of sorriamufetol received by an infant through breast milk produced by a subject treated with sorriamufetol according to the methods disclosed herein is less than approximately 0.70 mg, less than approximately 0.69 mg, less than approximately 0.68 mg, less than approximately 0.67 mg, less than approximately 0.66 mg, less than approximately 0.65 mg, less than approximately 0.64 mg, less than approximately 0.63 mg, less than approximately 0.62 mg, less than approximately 0.61 mg, less than approximately 0.60 mg, or less than approximately 0.59 mg over a 72-hour period.

[0065] A daily dose of about 1 to about 2000 mg of souliamfetol or a pharmaceutically acceptable salt thereof may be administered to achieve the therapeutic outcomes disclosed herein. For example, a daily dose of about 1 to 1000 mg, e.g., about 20 to 500 mg, may be administered as a single dose or in divided doses. In some embodiments, the daily dose may 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 may contain about 1 mg to about 1000 mg of the drug, or any range or value within that range, 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 a particular embodiment, the total amount of the 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.

[0066] In one embodiment of the present invention, Solliamufetol 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 the subject more than once a day, for example, two, three or four times a day, or once every 1, 2, 3, 4, 5, 6 or 7 days. In another embodiment, the compound is administered to the subject at least once a week, for example, at least once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or once every six months or more. In yet another embodiment, the compound is administered using two or more different schedules, for example, more frequently initially (for example, once a day or more to increase to a certain level), and then at a lower frequency (for example, at least once a week). In yet another embodiment, the compound can be administered by any discontinuous dosing regimen. In one example, the compound may be administered at intervals of 3 days or less, 4 days or less, 5 days or less, 6 days or less, 7 days or less, 8 days or less, 9 days or less, or 10 days or more or less. Administration may be continued for 1, 2, 3 or 4 weeks, or 1, 2 or 3 months, or longer. Optionally, the compound may be administered on the same or a different schedule after a drug-free period. The drug-free period may 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 may be administered until it increases to a specific level, then maintained at a constant level, and then at a tailing dose.

[0067] In one embodiment of the present invention, solliamfetol is delivered to a subject in combination with an additional therapeutic agent. The additional therapeutic agent may be delivered in the same composition as the compound or in a separate composition. The additional therapeutic agent may be delivered to the subject on a different schedule or by a different route compared to the compound. The additional therapeutic agent may be any agent that benefits the subject. Further agents include, but are not limited to, stimulants, antipsychotics, antidepressants, agents for neurological disorders, and chemotherapeutic agents. One therapeutic agent that may be administered during the same period is Xyrem®, marketed by Jazz Pharmaceuticals, which is used to treat narcolepsy and cataplexy. See U.S. Patents 8,952,062 and 9,050,302.

[0068] This invention finds use in research and 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, and rodents (e.g., rats or mice). Human subjects include neonates, infants, young children, adults, and elderly subjects. In some embodiments, the subjects are postpartum. In some embodiments, the subjects are women aged 18 to 45 years.

[0069] Suitable subjects are generally lactating 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). Human subjects may be lactating individuals who are frequently or regularly breastfeeding infants. In some embodiments, human subjects are female. Females may be between approximately 18 and 45 years of age. The term “breastfeeding” may also be called chestfeeding (or its grammatical variation) and refers to the direct delivery of an individual’s breast milk to an infant, the extraction of breast milk from an individual using a device and subsequent delivery to an infant, the extraction of breast milk from an individual using a device, the storage of the breast milk for a period of time and subsequent delivery of the stored breast milk to an infant, or a combination thereof.

[0070] The subjects of this disclosure may be individuals in a lactating period, for example, individuals that are lactating (e.g., producing breast milk), nursing, or lactating. The subjects may be in a lactating period after pregnancy, i.e., after delivery, or due to induced lactation (e.g., with metoclopramide, oral contraceptives, herbal medicines, pump stimulation, or any combination thereof).

[0071] In some embodiments, the subjects are between 1 day and 24 months postpartum, between approximately 1 day and 12 months postpartum, or between approximately 10 days and 12 months postpartum. In some embodiments, the subjects are milked, which is typically done between approximately 10 and 30 days postpartum (for example, approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30), or between approximately 10 and 20 days postpartum, or between approximately 10 and 20 days after the start of milking during induced lactation. Infancy begins at birth and ends around the age of two; therefore, the breastfeeding period is included in the infant stage.

[0072] The subject may be, for example, a subject that "needs" the method of the present invention, for example, a subject that needs the therapeutic effect of the method of the present invention. For example, the subject may be a subject that is experiencing a disorder for which treatment with sorriamfetor is appropriate, is suspected of having a disorder for which treatment with sorriamfetor is appropriate, and / or is expected to experience a disorder for which treatment with sorriamfetor is appropriate, and the method and composition of the present invention is used for therapeutic and / or prophylactic treatment.

[0073] Having described the present invention, it will be described in more detail in the following examples (these examples are included herein for illustrative purposes only and are not intended to limit the present invention). [Examples]

[0074] example Example 1. Phase 4 clinical trial in breastfeeding subjects

[0075] Data available from a lactation study in six women indicate the presence of sorriamfetol in human breast milk. The daily infant dose was 0.112 mg / kg (based on a nominal infant weight of 6 kg), and the relative infant dose (RID) was approximately 5.5% of the maternal weight-adjusted dose. The data are insufficient to determine the effects of sorriamfetol on breastfed infants or its effects on milk production.

[0076] The developmental and health benefits of breastfeeding should be considered together with the mother's clinical need for Solliamufetol, as well as the potential adverse effects on the breastfed infant from Solliamufetol or from the mother's underlying condition.

[0077] Infants exposed to Solliamfetol should be monitored for signs of restlessness, insomnia, and decreased weight gain.

[0078] A single-dose lactation study was conducted in six healthy women who received a single oral dose of 150 mg of souliamfetol between 10 days and 52 weeks postpartum. The cumulative median excreted in breast milk was 0.67 mg over 72 hours, which is approximately 5.5% of the maternal dose on a weight-adjusted basis. Of the total amount of souliamfetol excreted in breast milk over 72 hours, approximately 78% and 98% were excreted by 8 hours and 24 hours, respectively, and the apparent mean elimination half-life in breast milk was approximately 5 hours.

[0079] The foregoing is illustrative of the present invention and should not be construed as limiting it. The present invention is defined by the appended claims, which include equivalents thereof. All publications, patent applications, patents, patent publications and other references cited herein are incorporated in their entirety for teaching relating to the sentences and / or paragraphs in which the references are presented.

Claims

1. A method for reducing the likelihood of adverse events derived from Soluliamfetol in infants breastfed with breast milk obtained from human subjects treated with Soluliamfetol, the following: Oral administration of approximately 150 mg of souliamfetol once daily to the subject; and At least approximately 5 hours after administering Soluliamfetol to the subject, the subject shall breastfeed the infant. Includes, The daily infant dose of Solliamufetol decreases to approximately 0.1 mg / kg or less. The aforementioned method.

2. The method according to claim 1, wherein the adverse event is one or more of restlessness, insomnia, or decreased weight gain.

3. The method according to claim 2, wherein the subject is being treated with sourium fetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, or bulimia nervosa.

4. The method according to claim 2, wherein the infant does not experience restlessness, insomnia, or decreased weight gain as a result of exposure to Solliam fetol.

5. The method according to claim 4, wherein the subject is 1 day to 24 months postpartum.

6. The method according to claim 4, wherein the subject is 10 days to 12 months postpartum.

7. A method for reducing the likelihood of adverse events derived from Soluliamfetol in infants breastfed with breast milk obtained from human subjects treated with Soluliamfetol, the following: Oral administration of approximately 75 mg of souliamfetol once daily to the subject; and At least approximately 5 hours after administering Soluliamfetol to the subject, the subject shall breastfeed the infant. Includes, The daily infant dose of Solliamufetol decreases to approximately 0.05 mg / kg or less. The aforementioned method.

8. The method according to claim 7, wherein the adverse event is one or more of restlessness, insomnia, or decreased weight gain.

9. The method according to claim 8, wherein the subject is being treated with sourium fetol for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, or bulimia nervosa.

10. The method according to claim 8, wherein the infant does not experience restlessness, insomnia, or decreased weight gain as a result of exposure to Solliam fetol.

11. The method according to claim 10, wherein the subject is 1 day to 24 months postpartum.

12. The method according to claim 10, wherein the subject is 10 days to 12 months postpartum.

13. A method for treating a soluriamfetor-treatable disorder in human subjects producing breast milk for infants, the following: Oral administration of approximately 150 mg of souliamfetol once daily to the subject; and Reducing the infant's exposure to soluria fetol and / or reducing the likelihood of adverse events in the infant being breastfed from the subject, including providing the infant with breast milk obtained from the subject at least approximately 5 hours after administering soluria fetol to the subject. Includes, The daily infant dose of Solliamufetol decreases to approximately 0.1 mg / kg or less. The aforementioned method.

14. The method according to claim 13, wherein the disorder treatable with Soluriamfetol is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, or bulimia nervosa.

15. The method according to claim 13, wherein the infant does not experience restlessness, insomnia, or decreased weight gain as a result of exposure to Solliam fetol.

16. The method according to claim 13, wherein the adverse event is one or more of restlessness, insomnia, or decreased weight gain.

17. The method according to claim 13, wherein the subject is 1 day to 24 months postpartum.

18. The method according to claim 13, wherein the subject is 10 days to 12 months postpartum.

19. The method according to claim 13, wherein the subject is a woman between the ages of 18 and 45.

20. A method for treating a soluriamfetor-treatable disorder in human subjects producing breast milk for infants, the following: Oral administration of approximately 75 mg of souliamfetol once daily to the subject; and Reducing the infant's exposure to soluria fetol and / or reducing the likelihood of adverse events in the infant being breastfed from the subject, including providing the infant with breast milk obtained from the subject at least approximately 5 hours after administering soluria fetol to the subject. Includes, The daily infant dose of Solliamufetol decreases to approximately 0.05 mg / kg or less. The aforementioned method.

21. The method according to claim 20, wherein the disorder treatable with Soluriamfetol is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, or bulimia nervosa.

22. The method according to claim 20, wherein the infant does not experience restlessness, insomnia, or decreased weight gain as a result of exposure to Solliam fetol.

23. The method according to claim 20, wherein the adverse event is one or more of restlessness, insomnia, or decreased weight gain.

24. The method according to claim 20, wherein the subject is 1 day to 24 months postpartum.

25. The method according to claim 20, wherein the subject is 10 days to 12 months postpartum.

26. The method according to claim 20, wherein the subject is a woman between the ages of 18 and 45.

27. A method for treating excessive daytime sleepiness, attention deficit hyperactivity disorder, bulimia disorder, or cognitive impairment in lactating human mothers who breastfeed their infants, the following: Administer solliamfetol orally to the mother at a dose of approximately 150 mg once daily; and The infant is given breast milk obtained from the mother at least approximately 5 hours after the administration of Solliamfetol to the mother. Includes, The daily infant dose of Solliamufetol has decreased to approximately 0.1 mg / kg or less, and The infant's exposure to Solriamfetol derived from breast milk is reduced. The aforementioned method.

28. The method according to claim 27, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to the sorriam fetol derived from the breast milk.

29. The method according to claim 27, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work disorder, or Parkinson's disease.

30. The method according to claim 27, wherein the mother who is lactating is between 1 day and 24 months postpartum.

31. The method according to claim 27, wherein the mother who is lactating is 10 to 12 months postpartum.

32. The method according to claim 27, wherein the mother who is lactating is between 18 and 45 years of age.

33. A method for treating excessive daytime sleepiness, attention deficit hyperactivity disorder, bulimia disorder, or cognitive impairment in lactating human mothers who breastfeed their infants, the following: Administer soluriamfetol orally to the mother at a dose of approximately 75 mg once daily; and The infant is given breast milk obtained from the mother at least approximately 5 hours after the administration of Solliamfetol to the mother. Includes, The daily infant dose of Solliamufetol has decreased to approximately 0.05 mg / kg or less, and The infant's exposure to Solriamfetol derived from breast milk is reduced. The aforementioned method.

34. The method according to claim 33, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to sorriam fetol derived from breast milk.

35. The method according to claim 33, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work disorder, or Parkinson's disease.

36. The method according to claim 33, wherein the mother who is lactating is between 1 day and 24 months postpartum.

37. The method according to claim 33, wherein the mother who is lactating is 10 to 12 months postpartum.

38. The method according to claim 33, wherein the mother who is lactating is between 18 and 45 years of age.

39. A method for treating postpartum human subjects who produce breast milk for disorders for which treatment with sorriamfetor is appropriate, the following: Oral administration of approximately 150 mg of souliamfetol once daily to the subject; and The infant should be given breast milk obtained from the subject at least approximately 5 hours after administering Solliamfetol to the subject. Includes, The daily infant dose of Solliamufetol has decreased to approximately 0.1 mg / kg or less, and The infant's exposure to Solriamfetol derived from breast milk is reduced. The aforementioned method.

40. The method according to claim 39, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to sorriam fetol derived from breast milk.

41. The method according to claim 39, wherein the subject is 1 day to 24 months postpartum.

42. The method according to claim 39, wherein the subject is 10 days to 12 months postpartum.

43. The method according to claim 39, wherein the subject is being treated with sourium fetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, bulimia disorder, or cognitive impairment.

44. The method according to claim 43, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

45. The method according to claim 43, wherein the cognitive impairment is caused by narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

46. A method for treating postpartum human subjects who produce breast milk for disorders for which treatment with sorriamfetor is appropriate, the following: Oral administration of approximately 75 mg of souliamfetol once daily to the subject; and The infant should be given breast milk obtained from the subject at least approximately 5 hours after administering Solliamfetol to the subject. Includes, The daily infant dose of Solliamufetol has decreased to approximately 0.05 mg / kg or less, and The infant's exposure to Solriamfetol derived from breast milk is reduced. The aforementioned method.

47. The method according to claim 46, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to the sorriam fetol derived from the breast milk.

48. The method according to claim 46, wherein the subject is 1 day to 24 months postpartum.

49. The method according to claim 46, wherein the subject is 10 to 12 months postpartum.

50. The method according to claim 46, wherein the subject is being treated with sourium fetol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, bulimia disorder, or cognitive impairment.

51. The method according to claim 50, wherein the excessive daytime sleepiness is caused by narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

52. The method according to claim 50, wherein the cognitive impairment is caused by narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

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