Therapeutic combinations of drugs and methods of using them

Abstract

Provided are therapeutic combinations or formulations of drugs comprising a Glucagon-Like Peptide-1(GLP-1) receptor agonist, a dual GLP-1 / GIP (glucose-dependent insulinotropic peptide) -agonist-, a dual GLP-1 / Glucagon (GCG) receptor agonist, a GLP-1 / GIP / GCG receptor tri-agonist, or an amylin / GLP-1 dual agonist with a monoamine reuptake inhibitor or drugs with complimentary mechanism of actions to a GLP-1 agonists. In alternative embodiments, provided are therapeutic drug combinations for use in treating or ameliorating depression, treatment-resistant depression, hyperphagia (optionally hyperphagia associated with Prader-Willi Syndrome), binge eating disorder, and a substance addiction (wherein the substance addiction comprises addiction to cocaine, an amphetamine, an opioid, alcohol or nicotine).

Description

[0001] THERAPEUTIC COMBINATIONS OF DRUGS AND METHODS OF USING THEM

[0002] RELATED APPLICATIONS

[0003] This Patent Convention Treaty (PCT) International Application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Serial No. (USSN) 63 / 626,658, Jan. 30, 2024. The aforementioned application is expressly incorporated herein by reference in its entirety and for all purposes. All publications, patents, patent applications cited herein are hereby expressly incorporated by reference for all purposes.

[0004] TECHNICAL FIELD

[0005] This invention pertains to the field of pharmaceutical compositions and therapeutic combinations. Specifically, it relates to novel therapeutic combinations designed for the treatment or management of diseases including affective disorders and reward system-related disorders. These disorders include, but are not limited to, depression, treatment-resistant depression, hyperphagia (including hyperphagia associated with Prader-Willi Syndrome (PWS)), binge eating disorder, and various substance addictions such as those to cocaine, amphetamines, opioids, alcohol, and nicotine. The inventive pharmaceutical combinations comprise an oral dosage of either a monoamine reuptake inhibitor, its deuterated variants, or an agent that possesses a complementary mechanism of action to a GLP-1 agonist. These components are used in combination with a GLP-1 agonist, offering a unique therapeutic approach to the aforementioned conditions.

[0006] BACKGROUND

[0007] Despite the availability of numerous medications for treating affective disorders such as depression, there remains a significant unmet medical need, particularly in treatment-resistant or refractory depression. A considerable portion of patients either do not respond to existing treatments or experience a prolonged onset time before the effects of medication become apparent.

[0008] For reward system-related disorders, including binge eating disorder (BED), cocaine, amphetamine, opioid, alcohol, and nicotine addiction, the efficacy of current medications is limited, highlighting the need for more effective treatments. Serotonin, dopamine, and norepinephrine are crucial neurotransmitters that regulate key functions in the central nervous system, including mood control and the sense of reward and craving. Monoamine reuptake inhibitors, such as SSRIs and SNRIs, are commonly prescribed for affective disorders like depression and anxiety. Lisdexamfetamine, a dopamine and norepinephrine reuptake inhibitor, is approved for BED. A triple monoamine reuptake inhibitor (TRI), inhibiting the reuptake of serotonin, dopamine, and norepinephrine, is anticipated to be more effective for depression than SSRIs or SNRIs, with added benefits in regulating reward pathways. TRIs are also proposed to benefit reward system-related disorders, given the roles of these neurotransmitters in reward and impulsivity control.

[0009] GLP-1, an incretin hormone derived from preproglucagon and primarily released by intestinal L-cells, influences several peripheral and central processes, including insulin secretion, gut emptying, and glucagon inhibition. Its analogs are used in treating type 2 diabetes mellitus (T2DM). GLP-l's ability to cross the bloodbrain barrier indicates its potential impact on the nervous system.

[0010] Recent research points to the neuroprotective and pro-cognitive properties of GLP-1 agonists, traditionally used in T2DM and obesity treatment. These findings suggest a potential role for GLP-1 receptor agonists in treating depression by modulating immune, endocrine, and metabolic processes in the central nervous system. Additionally, growing evidence links GLP-1 and its receptors to reward system regulation, indicating that GLP-1 agonists could be beneficial in managing disorders related to the reward system, such as substance abuse and eating disorders.

[0011] The standalone use of GLP-lRAs is limited by several factors. While GLP- IRAs are effective in promoting weight loss, a portion of this weight loss has been reported to involve the reduction of lean muscle mass. The preservation of lean muscle is critical for maintaining metabolic health, physical mobility, and overall long-term weight management, particularly in older adults or individuals with comorbidities, where muscle loss could exacerbate existing health challenges. Moreover, their efficacy may be insufficient to address the complex and multifactorial nature of many metabolic and neurodegenerative disorders. Weight loss benefits often plateau over time, and variability in individual responses limits their applicability in heterogeneous populations. Furthermore, GLP-lRAs are associated with gastrointestinal side effects, such as nausea, vomiting, and diarrhea, which may reduce patient adherence and tolerability. In certain populations, including those with type 1 diabetes, these side effects occur at lower doses and with greater frequency, further limiting their standalone utility.

[0012] SUMMARY

[0013] In alternative embodiments, provided are therapeutic combinations, pharmaceutical dosage forms, drug delivery devices or products of manufacture, comprising one or more of any of the active agents or drugs comprising:

[0014] In alternative embodiments, provided are therapeutic combinations, pharmaceutical dosage forms or formulations drug delivery devices or products of manufacture, comprising:

[0015] (a) an active agent comprising:

[0016] (i) a Glucagon-Like Peptide-l(GLP-l) receptor agonist, wherein optionally the GLP-1 receptor agonist comprises: liraglutide or VICTOZA™ or SAXEND A™; exenatide or BYETTA™, BYDUREON™, B YDUREON™ or BCISE™); dulaglutide (or TRULICITY™), lixisenatide (or ADLYXIN™), a semaglutide injection (or OZEMPIC™ or WEGOVY™), a semaglutide tablet (or RYBELSUS™), albiglutide (or TANZEUM™ or EPERZAN™),

[0017] CT-996™ (Carmot Therapeutics, Inc.),

[0018] ECC5004™ (Eccogene, Inc.),

[0019] GSBR-1290™ (Structure Therapeutics),

[0020] LY-307161™ (a 31 amino acid analog of glucagonlike peptide- 1(7-37)OH), danuglipron (PF-06882961™),

[0021] LY2189265 (Eli Lilly), ecnoglutide (XW003, Sciwind Biosciences),

[0022] XW014 (Sciwind Biosciences), efpeglenatide (or HM11260C) (Hanmi Pharm Co., Ltd), beinaglutide or benaglutide,

[0023] JY09 (Beijing Dongfang Baitai Biotechnology Co., Ltd), HRS-7535 (Hercules CM NewCo), aleniglipron (GSBR-1290) or CAS Number 2685823-26-9 (Structure Therapeutics), dapiglutide or CAS Number 2296814-85-0 (Zealand Pharma), GZR18 (Gan & Lee Pharmaceuticals), HDM1002 (Huadong Medicine Co., Ltd.), NN9926, lotiglipron or CAS Number 2401892-75-7 (Pfizer), taspoglutide or CAS Number 275371-94-3 (Ipsen and Roche), and / or orforglipron (LY-3502970);

[0024] (ii) a dual GLP-l / GIP agonist, wherein optionally the GLP-l / GIP agonist comprises: tirzepatide (or MOUNJARO™ or ZEPBOUND™), maridebart cafraglutide, CAS Number 2760218-55-9, or AMG- 133™ (Amgen),

[0025] AZD9550 (AstraZeneca),

[0026] VK2735 (Viking Therapeutics, Inc.),

[0027] SCO-094 (Scohia Pharma, Inc.),

[0028] HRS-9531 (Hercules CM NewCo), CT-388™ (Carmot Therapeutics, Inc.), and / or CT-868™ (Carmot Therapeutics, Inc.),

[0029] (iii) a GLP-1 / Glucagon (GCG) receptor dual agonist, wherein optionally the GLP-l / GCG receptor dual agonist comprises:

[0030] AZD-9550™ or BI-456906™, mazdutide (or IB 1362, or LY-3305677) (Eli Lilly and Company), DD01 (D&D Pharmatech),

[0031] RGT-075 (Regor Therapeutics Group), efinopegdutide (or MK-6024) (Merck & Co., Inc.), pemvidutide (Altimmune, Inc.), and / or survodutide (or BI-456906) (C.H. Boehringer Sohn AG & Co.

[0032] KG),

[0033] (iv) a GLP-l / GIP / GCG receptor tri-agonist, wherein optionally the GLP-l / GIP / GCG receptor tri-agonist comprises: retatrutide (LY3437943™),

[0034] SAR425899 (Sanofi) or SAR441255™,

[0035] HM15275, efocipegtrutide (or HM15211, Hanmi Pharm Co., Ltd), and / or

[0036] MEDI0382 (AstraZeneca),

[0037] (v) an amylin / GLP-1 dual agonist, wherein optionally the amylin / GLP-1 dual agonist comprises NNC- 0487-0111™, or

[0038] (vi) any combination of (i) to (v), or the combination of (i) and (ii), (i) and (iii), (i) and (vi), (i) and (v), (i) and (iv), (ii) and (iii), (ii) and (iv), (ii) and (v), (ii) and (vi), (iii) and (iv), (iii) and (v) and (v), or (iv) and (vi) or

[0039] (vii) a combination of (i), (ii) and (vi); (i), (ii) and (v); (i), (ii) and (iv); (i), (ii) and (iii); (i), (ii) and (vi); (ii), (iii) and (iv); (ii), (iii) and (v); (ii), (iii) and (vi); (iii), (vi) and (v);, (iii), (iv) and (vi); (iii) (vi) and (vi); (iv), (v) and (vi); (i), (v) and (vi); (i), (iii), (v) and (vi); or, (iv), (v) and (vi); and

[0040] (b) one, or a combination of two, three, four, five, six or several of the following drugs, active agents, or small molecules:

[0041] (1) carbetocin, or DURATOCIN™, PABAL™ or LONACTENE™,

[0042] (2) oxytocin and / or the precursor oxytocin-neurophysin,

[0043] (3) diazoxide (or PROGLYCEM™) or a diazoxide Choline Controlled-Release (DCCR formulation);

[0044] (4) setmelanotide, BIM-22493, IRC-022493 or RM-493 (CAS Number 920014-72-8), or lMCIVREE™,

[0045] 0,

[0046] (5) N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D- phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide),

[0047] (6) a bitter taste receptor (TAS2R) agonist, wherein optionally the bitter taste receptor (TAS2R) agonist comprises denatonium acetate or ARD-101, (7) rimonabant (also known as SR141716) and / or ACOMPLIA™, ZIMULTI™,

[0048] (8) a melatonin receptor agonist, wherein optionally the melatonin receptor agonist is or comprises: melatonin or N-acetyl-5-methoxy tryptamine, ramelteon (or ROZEREM™) and / or tesimelteon (or HETLIOZ™), or any combination thereof,

[0049] (9) modafinil (or PRO VIGIL™, ALERTEC™ or MODAVIGIL™), and / or amodafonil (or NUVIGIL™),

[0050] (10) metformin (or GLUCOPHAGE™) and / or repaglinide (or PRANDIN)™,

[0051] (11) a mood stabilizer, wherein optionally the mood stabilizer is or comprises: gabapentin (or NEURONTIN™); clonazepam (or KLONOPIN™ or RIVOTRILF™); valproate, valproic acid, sodium valproate or valproate semisodium (or CONVULEX™, DEPAKOTE™, EPILIM™ or STAVZOR™); oxcarbazepine (or TRILEPTAL™ or OXTELLAR XR™); lithium or lithium carbonate (or LITHOBID™ or LITHOMAX™); topiramate (or TOPAMAX™, TROKENDI XR™ or QUDEXY XR™) and / or lamotrigine (or LAMICTAL™), or any combination thereof,

[0052] (12) a neuroleptic, wherein optionally the neuroleptic comprises: risperidone (or Risperdal), aripiprazole (or ABILI Y™), quetiapine (or SEROQUEL™), olanzapine (or ZYPREXA™), ziprasidone (or GEODON™) and / or haloperidol (or HALDOL™ or SERENACE™), or any combination thereof,

[0053] (13) quetiapine, or SEROQUEL™ or TEMPROLIDE™,

[0054] (14) naltrexone (or FEBIA™ or VIVITROL™),

[0055] (15) solriamfetol or SUNOS™,

[0056] (16) a selective norepinephrine reuptake inhibitor (NRI), or a selective serotonin reuptake inhibitor (SSRI), or a selective serotonin norepinephrine inhibitor (SNRI), wherein optionally the SSRI or SNRI inhibitor is or comprises reboxetine (or AXS-12, or Edronax™), atomoxetine (or Strattera™), venlafaxine (Effexor™ or Effexor XR™), fluoxetine (Prozac™), citalopram (Celexa™), escitalopram (Lexapro), paroxetine (Paxil™), sertraline (Zoloft™), or duloxetine (Cymbalta™),

[0057] (17) an amphetamine, wherein optionally the amphetamine or comprises amphetamine, dextroamphetamine (or Adderall™), dextroamphetamine-amphetamine (Mydayis™) or lisdexamfetamine (or Vyvanse™).

[0058] (18) methylphenidate or Ritalin, Ritalin LA, Concerta, Metadate CD, Methylin, Methylin ER, Daytrana, Quillivant XR, Quillichew ER, Aptensio XR, Cotempla XR-ODT, Jomay PM, Adhansia XR, or serdexmethylphenidate.

[0059] (19) a tricyclic antidepressant (TCA), wherein optionally the TCA is or comprises imipramine (Tofranil™), or amitriptyline (Elavil™), clomipramine (Anafranil™) or another TCA,

[0060] (20) a monoamine oxidase inhibitor (MAOI), wherein optionally the MAOI is or comprises selegiline (Emsam™), isocarboxazid (Marplan™), phenelzine (Nardil™), and tranylcypromine (Parnate™) or another MAOI,

[0061] (21) an anti-obesity medication, wherein optionally the anti-obesity medication comprises lorcaserin (Belviq™), orlistat (Alli™), phentermine and topiramate (Qsymia™), ornaltrexone HC1 or bupropion HC1 (Contrave™),

[0062] (22) a famesoid X receptor (FXR) agonist, wherein optionally the FXR agonist comprises Obeticholic Acid (OCA), EYP001 (ENYO Pharma), TQA3526, Px-102, Px-104, or tropifexor,

[0063] (23) a PPAR agonist, optionally a PPAR a / 5 agonist, or a PPAR-a / y agonist, wherein optionally the PPAR-a / y agonist comprises pioglitazone, elafibranor or lanifibranor (or IVA337, Inventiva),

[0064] (24) a CC chemokine receptor CCR2 / CCR5 inhibitor, wherein optionally the CC chemokine receptor comprises tropifexor, a combination of tropifexor and cenicriviroc, or cenicriviroc,

[0065] (25) a mitochondrial pyruvate carrier (MPC) inhibitor, wherein optionally the MPC inhibitor comprises MSDC-0602K (Cirius Therapeutics),

[0066] (26) a Fibroblast Growth Factor 19 (FGF19) analogue, wherein optionally the FGF19 analogue comprises aldafermin (or

[0067] NGM282, NGM Biopharmaceuticals)

[0068] (27) a Fibroblast Growth Factor 21 (FGF21) analogue, wherein optionally the FGF21 analogue comprises a PEGylated Fibroblast Growth Factor 21 analogue, optionally pegbelfermin,

[0069] (28) a thyroid hormone receptor beta (THR-P) agonist, wherein optionally the THR-P agonist comprises resmetirom (MGL-3196, Magrigal Pharmaceuticals) or VK-2890,

[0070] (29) a Stearoyl-CoA desaturase- 1 (SCD1) inhibitor, wherein optionally the SCD1 inhibitor comprises aramchol (Galmed Pharmaceuticals),

[0071] (30) an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, wherein optionally the ASK1 inhibitor comprises selonsertib (Gilead Sciences),

[0072] (31) an acetyl-CoA carboxylase (ACC) inhibitor, wherein optionally the ACC inhibitor comprises firsocostat (GS-0976) or MK-4074,

[0073] (32) a triple monoamine reuptake inhibitor, wherein optionally the triple monoamine reuptake inhibitor comprises:

[0074] 7-([ 1 , 2, 4]tri azolof 1 , 5-a]pyridin-6-yl)-4-(3 ,4-dichlorophenyl)- 1,2,3,4-tetrahydroisoquinoline, tesofensine (also known as tesomet or tesofen) (Saniona, Ballerup, Denmark), centanafadine or CAS Number 924012-43-1 (Otsuka Pharmaceutical), liafensine or CAS Number 1198790-53-2 (Bristol-Myers Squibb), toludesvenlafaxine or CAS Number 916918-84-8 or

[0075] RUOXINLIN™, amitifadine or CAS Number 410074-73-6 (Euthymics Bioscience), and / or

[0076] NOE-115 (Noema Pharma AG),

[0077] (33) a [l,2,4]triazolo[l,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative as described in USPN 8,802,696, or 7- ([ 1,2, 4]tri azolof 1, 5-a]pyridin-6-yl)-4-(3,4-di chlorophenyl)- 1,2, 3,4- tetrahydroisoquinoline, or a deuterated form thereof (optionally as described in WO 2021 / 142395), or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)-stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)-stereoisomer or a (R)(-)-stereoisomer thereof;

[0078] (34) a compound having the formula (Formula I):

[0079] Formula I or a pharmaceutically acceptable salt thereof, or an S-enantiomer, (+)- stereoisomer or a (-)-stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)-stereoisomer or a (R)(-)-stereoisomer thereof; or

[0080] (35) any combination of two, three, four, five or six or more of 1 to 34.

[0081] In alternative embodiments of therapeutic combinations, pharmaceutical dosage forms or formulations drug delivery devices or products of manufacture as provided herein: - the active agent or agents of (a) as described above and the drugs, active agents, or small molecules of (b) as described above are formulated as separate compositions, or are formulated into one composition or drug formulation;

[0082] - one or two or more of the drugs or active agents are packaged individually, or are packaged together, or packaged in any combination, in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap;

[0083] - the one or two or more or all of the drugs or active agent or agents are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a spray, a sachet, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof, and optionally the drug delivery device or product of manufacture is or comprises an implant;

[0084] - the one or two or more or all of the drugs or active agent or agents are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository;

[0085] - the one or two or more or all of the drugs or active agent or agents are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day; and / or

[0086] - the drugs or active agents comprise:

[0087] (a) a Glucagon-Like Peptide- l(GLP-l) receptor agonist, a dual GLP-l / GIP (agonist), a GLP-l / Glucagon (GCG) receptor dual agonist, a GLP-l / GIP / GCG receptor tri -agonist or an amylin / GLP-1 dual agonist, or a combination of any two, three or more of: Glucagon-Like Peptide- 1(GLP- 1) receptor agonist, a dual GLP-l / GIP (agonist), a GLP-1 / Glucagon (GCG) receptor dual agonist, a GLP-l / GIP / GCG receptor tri-agonist, and an amylin / GLP-1 dual agonist, and: (b) (i) a triple monoamine reuptake inhibitor or a [l,2,4]triazolo[l,5- a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I,;

[0088] (ii) a triple monoamine reuptake inhibitor or a [l,2,4]triazolo[l,5- a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I , and a diazoxide (or PROGLYCEM™) or a diazoxide Choline Controlled-Release (DCCR formulation);

[0089] (iii) a triple monoamine reuptake inhibitor or a [l,2,4]triazolo[l,5- a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a beta blocker, optionally, atenolol (TENORMIN™), bisoprolol (CARDICOR™, EMCOR™), or metoprolol (BETALOC™, LOPRESOR™, TOPROL XL™), or any combination thereof; and / or

[0090] (iv) any combination of (i) to (iii), or (i) and (ii), or (i) and (iii), or (ii) and (iii).

[0091] In alternative embodiments, provided are pharmaceutical compositions, drugs or formulations comprising a therapeutic combination or pharmaceutical dosage form as provided herein, wherein optionally the pharmaceutical composition, drug or formulation is formulated for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

[0092] In alternative embodiments, provided are drug delivery devices or products of manufacture comprising or having contained therein a therapeutic combination or pharmaceutical dosage form as provided herein. wherein optionally the pharmaceutical dosage form is formulated for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

[0093] In alternative embodiments, provided are methods for treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing, a disease or condition comprising or associated with: hyperphagia in PWS (optionally as assessed by Hyperphagia Questionnaire for Clinical Trials (HQ-CT), moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity, optionally further comprising management of weight loss and maintenance of weight loss, or optionally further comprising as an adjunct to a reduced-calorie diet or for increased physical activity for chronic weight management, early onset morbid obesity, non- Alcoholic Steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH) non-alcoholic fatty liver disease (NAFLD), type II diabetes, hypothalamic injury-induced obesity, obsessive-compulsive disorder (OCD), disruptive mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), irritability in autism, irritability in autistic spectrum disorder, excoriation, trichotillomania, intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders-Third Edition (ICSD-3), narcolepsy with cataplexy, narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, cataplexy, idiopathic hypersomnia, rapid eye movement (REM) sleep behavior disorder, major depressive disorder (MDD), treatment resistant depression (TRD), negative symptoms of schizophrenia, MDD Associated with Parkinson’s Disease, Parkinson’s Disease, general anxiety, Social Anxiety Disorder (Social Phobia), Fibromyalgia (FM), diabetic neuropathy. lower back pain, chronic fatigue syndrome, cognitive inflexibility cocaine addiction, amphetamines addiction, opioids addiction, alcohol addiction, nicotine addiction attention deficit hyperactivity disorder (ADHD), autism,

[0094] Asperger spectrum, a genetically confirmed disease or syndrome, wherein optionally the genetically confirmed disease or syndrome is or comprises Prader-Willi Syndrome, Bardet Biedl Syndrome, Smith- Magenis Syndrome, lp36 deletion syndrome, 16pl 1.2 deletion Syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, Melanocortin 4 Receptor (MC4R) Pathway Heterozygous Obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman’s Syndrome, Schaff-Yang Syndrome, Albright Hereditary Osteodystroph, Silver-Russell Syndrome, Maternal Disomy 14, Alstrbm Syndrome, Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation or WAGR or WAGRO Syndrome; Dravet Syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Doose Syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick type C disease, or Norrie disease, or Coffin-Lowry disease, wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural orthostatic tachycardia syndrome, the method comprising:

[0095] (a) (i) providing or having provided a pharmaceutical composition, drug or formulation comprising a therapeutic combination or pharmaceutical dosage form as provided herein, or a drug delivery device or product of manufacture as provided herein, and

[0096] (ii) administering to or implanting into an individual in need thereof the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture, or

[0097] (b) administering to or implanting into an individual in need thereof a therapeutic combination or pharmaceutical dosage form as provided herein, or a drug delivery device or product of manufacture as provided herein.

[0098] In alternative embodiments or methods as provided herein:

[0099] - the drug, or therapeutic combination, pharmaceutical dosage form, is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally;

[0100] - the parenteral administration comprises administration intrathecally, intracerebrally or epidurally (into an intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially;

[0101] - the drug, or therapeutic combination, pharmaceutical dosage form, or active agent or agents, is or are administered to achieve a therapeutic level range of plasma concentration at a steady state, and wherein: the therapeutic level range of plasma concentration for Formula I, is between about: 50 to 4000 ng / ml; 100 to 3000 ng / ml; 250 to 1600 ng / ml; 500 to 1400 ng / ml, 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml, 1500 to 2000 ng / ml, 2000 to 2500 ng / ml; 2500 to 3000 ng / ml; 3000 to 3500 ng / ml; or, 3500 to 4000 ng / ml; the therapeutic level range of plasma concentration for formula I, is between about: 5 to 4000 ng / ml, 10 to 1000 ng / ml, 10 to 500 ng / ml, 25 to 500 ng / ml, 25 to 250 ng / ml, 50 to 500 ng / ml, 50 to 1000 ng / ml, 50 to 500 ng / ml, 100 to 1000 ng / ml, 100 to 500 ng / ml, 200 to 1000 ng / ml, 500 to 1000 ng / ml, 1000 to 2000 ng / ml, 2000 to 3000 ng / ml, or 3000 to 4000 ng / ml, the therapeutic level range of plasma concentration for tesofensine is between about: 2 ng to 50 ng / ml, 5 to 20 ng / ml, 6.5 to 15 ng / ml, 8 to 12 ng / ml, or about 10 ng / ml, or the therapeutic level range of plasma concentration for diazoxide is between about: 10 ng / ml to 100 ng / ml, 20 to 80 ng / ml, 30 to 50 ng / ml, or about 40 ng / ml;

[0102] - the drug, therapeutic combination, or pharmaceutical dosage form, or active agent or agents, is or are administered to achieve a therapeutic level range of plasma concentration (optionally human plasma concentration) at a steady state, and wherein:

[0103] (a) the therapeutic level range of plasma concentration for use of the Formula I is between about: 250 to 1600 ng / ml; 500 to 1400 ng / ml, 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml, 1500 to 2000 ng / ml, 2000 to 2500 ng / ml; or 2500 to 3000 ng / ml;

[0104] (b) the therapeutic level range of plasma concentration for use of the Formula I is between about: 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml, 1500 to 2000 ng / ml, or 2000 to 2500 ng / ml; or

[0105] (c) the therapeutic level range of plasma concentration for use of Formula

[0106] I, is between about: 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to

[0107] 1250 ng / ml, 1250 to 1500 ng / ml.; the steady state is achieved after:

[0108] (a) between about 3 to 5 times the elimination half-life (Tl / 2) of the drug, therapeutic combination, or pharmaceutical dosage form in a subject or a patient, or (b) between about 7 to 14 days after periodic or regular administration to a optionally once-a-day dosing of the drug, or therapeutic combination, pharmaceutical dosage form.

[0109] - the plasma concentration for the drug, or therapeutic combination, pharmaceutical dosage form is:

[0110] (a) the trough level or trough concentration (Ctrough), or the lowest concentration reached by the drug, or therapeutic combination or pharmaceutical dosage form before a second or next dose is administered, or

[0111] (b) determined from blood samples taken between about 2 hours to 24 hours, or 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hours, after the last dose or administration of the drug, or therapeutic combination, pharmaceutical dosage form; and / or

[0112] - each drug, or therapeutic combination, pharmaceutical dosage form or active agent or agents of the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture is delivered to the individual simultaneously, or separately, wherein optionally one or each or several drug or active agent of the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture is administered in a chronodosed regimen.

[0113] In alternative embodiments, provided are uses of: a therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture as provided herein, or a therapeutic combination or pharmaceutical dosage form as provided herein, or a drug delivery device or product of manufacture as provided herein, for treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing, a disease or condition comprising or associated with: hyperphagia in PWS (optionally as assessed by HQ-CT), moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity, optionally further comprising management of weight loss and maintenance of weight loss, or optionally further comprising as an adjunct to a reduced-calorie diet or for increased physical activity for chronic weight management, early onset morbid obesity, non- Alcoholic Steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH) non-alcoholic fatty liver disease (NAFLD), type II diabetes, hypothalamic injury-induced obesity, obsessive-compulsive disorder (OCD), disruptive mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), irritability in autism, irritability in autistic spectrum disorder, excoriation, trichotillomania, intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders-Third Edition (ICSD-3), narcolepsy with cataplexy, narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, cataplexy, idiopathic hypersomnia, rapid eye movement (REM) sleep behavior disorder, major depressive disorder (MDD), treatment resistant depression (TRD), negative symptoms of schizophrenia, MDD Associated with Parkinson’s Disease,

[0114] Parkinson’s Disease, general anxiety, Social Anxiety Disorder (Social Phobia), Fibromyalgia (FM), diabetic neuropathy, lower back pain, chronic fatigue syndrome, cognitive inflexibility cocaine addiction, amphetamines addiction, opioids addiction, alcohol addiction, nicotine addiction attention deficit hyperactivity disorder (ADHD), autism,

[0115] Asperger spectrum, a genetically confirmed disease or syndrome, wherein optionally the genetically confirmed disease or syndrome is or comprises Prader-Willi Syndrome, Bardet Biedl Syndrome, Smith- Magenis Syndrome, lp36 deletion syndrome, 16pl 1.2 deletion Syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, Melanocortin 4 Receptor (MC4R) Pathway Heterozygous Obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman’s Syndrome, Schaff-Yang Syndrome, Albright Hereditary Osteodystroph, Silver-Russell Syndrome, Maternal Disomy 14, Alstrbm Syndrome, Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation or WAGR or WAGRO Syndrome; Dravet Syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Doose Syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick type C disease, or Norrie disease, or Coffin-Lowry disease, wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural orthostatic tachycardia syndrome.

[0116] In alternative embodiments, provided are therapeutic combinations, pharmaceutical dosage forms, drug delivery devices or products of manufacture for use in treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing, a disease or a condition comprising or associated with: hyperphagia in PWS (optionally as assessed by HQ-CT), moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity, optionally further comprising management of weight loss and maintenance of weight loss, or optionally further comprising as an adjunct to a reduced-calorie diet or for increased physical activity for chronic weight management, early onset morbid obesity, non- Alcoholic Steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH) non-alcoholic fatty liver disease (NAFLD), type II diabetes, hypothalamic injury-induced obesity, obsessive-compulsive disorder (OCD), disruptive mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), irritability in autism, irritability in autistic spectrum disorder, excoriation, trichotillomania, intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, narcolepsy type 1 (NT1) according to the International Classification of

[0117] Sleep Disorders-Third Edition (ICSD-3), narcolepsy with cataplexy, narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, cataplexy, idiopathic hypersomnia, rapid eye movement (REM) sleep behavior disorder, major depressive disorder (MDD), treatment resistant depression (TRD), negative symptoms of schizophrenia, MDD Associated with Parkinson’s Disease, Parkinson’s Disease, general anxiety,

[0118] Social Anxiety Disorder (Social Phobia), Fibromyalgia (FM), diabetic neuropathy. lower back pain, chronic fatigue syndrome, cognitive inflexibility cocaine addiction, amphetamines addiction, opioids addiction, alcohol addiction, nicotine addiction attention deficit hyperactivity disorder (ADHD), autism,

[0119] Asperger spectrum, a genetically confirmed disease or syndrome, wherein optionally the genetically confirmed disease or syndrome is or comprises Prader-Willi Syndrome, Bardet Biedl Syndrome, Smith- Magenis Syndrome, lp36 deletion syndrome, 16pl 1.2 deletion Syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, Melanocortin 4 Receptor (MC4R) Pathway Heterozygous Obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman’s Syndrome, Schaff-Yang Syndrome, Albright Hereditary Osteodystroph, Silver-Russell Syndrome, Maternal Disomy 14, Alstrbm Syndrome, Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation or WAGR or WAGRO Syndrome; Dravet Syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Doose Syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick type C disease, or Norrie disease, or Coffin-Lowry disease, wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural orthostatic tachycardia syndrome, and the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture comprises or has contained therein: a therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture as provided herein, or a therapeutic combination or pharmaceutical dosage form as provided herein, or a drug delivery device or product of manufacture as provided herein.

[0120] In alternative embodiment, provided are methods for administering a therapeutic combination or pharmaceutical dosage form as provided herein, or a drug delivery device or product of manufacture as provided herein, wherein the dosaging is determined by a method comprising:

[0121] (a) an empirical method for safe and predictable titration and to determine the initial therapeutic dose, or to determine the lowest therapeutic dose, or to determine an optimal effective dose; the method comprising:

[0122] 1. administrating a test dose (for example, a no adverse events observed dose amount or a minimal adverse events observed dose amount or a safe dose amount) daily until a patient achieves a steady state plasma drug concentration, rior to the next scheduled dose, drawing a blood sample and assessing the test plasma drug concentration, alculating the initial therapeutic dose / day by:

[0123] A. for drugs with a linear dose to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, and then multiply the dividend by the test dose amount, and

[0124] B. for drugs with a non-linear dose to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiply the dividend by the test dose amount and then multiply the product by a non-linear index factor, optionally, the initial target therapeutic plasma drug concentration is the concentration corresponding to: (i) certain pharmacodynamic efficacy marker levels, such as occupancy of serotonin transporter (SERT or 5- HTT), dopamine transporter (DAT) or norepinephrine transporter (NET) determined by imaging method such as positron emission tomography (PET); or, (ii) the lowest effective therapeutic dose determined by a clinical study. ptionally comprising: i. administrating the initial therapeutic dose, daily, until a patient achieves a steady state plasma drug concentration, ii. prior to the next scheduled dose, drawing a blood sample and assessing the current therapeutic plasma drug concentration, iii. Calculating the next therapeutic target dose / day by:

[0125] A. For drugs with a linear dose to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount, and

[0126] B. For drugs with a non-linear dose to plasma concentration, divide next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the dividend by the current therapeutic dose amount and then multiply the product by a non-linear index factor, and iv. continuing the process until the lowest therapeutic dose or optimal effective dose is achieved; or

[0127] (b) a model-based method for safe and predictable titration, and to determine the initial therapeutic dose and to determine the lowest therapeutic dose, or to determine an optimal effective dose, and method comprising:

[0128] 1. Administrating a test dose amount daily for between about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day,

[0129] 2. Drawing a first blood sample at between about 1 hour to 3 days, 6 hours to 2 days or about 1 day after administering the first test dose,

[0130] 3. Drawing a second or subsequent blood samples at between about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or at about 2 days, after drawing of the first blood samples or subsequent blood samples,

[0131] 4. calculating the initial therapeutic starting dose / day by: i. using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose(s), the plasma concentration of the blood samples and the time the draws of the blood samples and a pharmacometric model, ii. and optionally, using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose(s), the plasma concentration of the blood samples, the time of the draws of the blood samples, human PK data and a Bayesian pharmacometric model, iii. and optionally, using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose, the plasma concentration of the blood samples, the time of the draws of the blood samples, human PK data, a patient’s geneti c information, a patient’s non-heritable host factors, a patient’s other medications, and a Bayesian pharmacometric model,

[0132] 5. and optionally comprising: i. administrating the initial therapeutic starting dose, daily until a patient achieves a steady state plasma drug concentration, ii. Prior to the next scheduled dose, drawing a blood sample and assessing the current therapeutic plasma drug concentration, iii. calculating the next therapeutic target dose / day:

[0133] A. For drugs with a linear dose to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount, and

[0134] B. For drugs with a non-linear dose to plasma concentration, divide he next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount and then multiply the product by a non-linear index factor, and iv. Continuing the process until the lowest therapeutic dose or optimal effective dose is achieved.

[0135] In alternative embodiments of these methods, the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture comprises Formula I, or a deuterated derivative of Formula I.

[0136] In alternative embodiments, provided are methods for treating or ameliorating, or decreasing the symptoms of: depression, treatment-resistant depression, hyperphagia (optionally hyperphagia associated with Prader-Willi Syndrome), binge eating disorder, and a substance addiction (wherein the substance addiction comprises addiction to cocaine, an amphetamine, an opioid, alcohol or nicotine), comprising administering to an individual in need thereof a therapeutic combination or pharmaceutical dosage form as provided herein, or a drug delivery device or product of manufacture as provided herein., wherein optionally the pharmaceutical composition, drug or formulation is formulated and administered for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

[0137] In alternative embodiments, provided are methods for treating or ameliorating, or decreasing the symptoms of: depression, treatment-resistant depression, hyperphagia (optionally hyperphagia associated with Prader-Willi Syndrome), binge eating disorder, and a substance addiction (wherein the substance addiction comprises addiction to cocaine, an amphetamine, an opioid, alcohol or nicotine), with a dosage form of a therapeutic combination or pharmaceutical dosage form as provided herein, and the method comprises administering an oral dosage form that provides trough plasma concentration, a 24-hour time-averaged plasma concentration, or a daytime 12-hour time-averaged plasma concentration between 250 ng / mL to 500 ng / ml, 500 to 1000 ng / ml, 1000 to 1500 ng / ml, 1500 to 2000 ng / ml, or 1500 to 2500 ng / ml of a therapeutic combination or pharmaceutical dosage form as provided herein, when administered once daily, or twice daily, and measured at about one week, about two weeks, or steady state, wherein optionally the dosage form is formulated and administered for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

[0138] In alternative embodiments, the pharmaceutical combinations as described herein are specifically intended for use in patients diagnosed with the aforementioned diseases or conditions, where the use of such combinations is restricted based on the patient's body mass index (BMI). The application of these therapeutic combinations is tailored to patients whose BMI falls within specific ranges, as follows:

[0139] (a) BMI Equal to or Greater Than 25: This embodiment encompasses patients with a BMI of 25 or above. This range typically indicates overweight individuals, where the use of the pharmaceutical combinations is anticipated to be particularly beneficial, considering the potential interplay between the disorders being treated and the patient's weight status.

[0140] (b) BMI Between 25 to 30: This specific embodiment applies to patients whose BMI falls in the range of 25 to 30. This subset of patients, classified as overweight, might exhibit different responses or require unique considerations in treatment when compared to patients with a higher or lower BMI; and

[0141] (c ) BMI Greater Than 30: In this embodiment, the pharmaceutical combinations are specifically designated for patients with a BMI exceeding 30, categorizing them as obese. This group might present distinct clinical features or treatment.

[0142] The details of one or more exemplary embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description, and from the claims.

[0143] All publications, patents, patent applications cited herein are hereby expressly incorporated by reference in their entireties for all purposes.

[0144] DETAILED DESCRIPTION

[0145] In alternative embodiments, provided are therapeutic combinations or formulations of drugs comprising a Glucagon-Like Peptide- l(GLP-l) receptor agonist, a dual GLP-l / GIP (glucose-dependent insulinotropic peptide) agonist, a GLP-1 / GCG (Glucagon) receptor dual agonist, a GLP-l / GIP / GCG receptor triagonist, and / or an amylin / GLP-1 dual agonist.

[0146] Combining a triple monoamine reuptake inhibitor with a GLP-1 agonist addresses both the monoaminergic and metabolic aspects of depression, offering a more comprehensive treatment strategy for refractory depression. In alternative embodiments, this exemplary combination provides synergistic benefits in treating reward system-related disorders by leveraging the role of GLP-1 in modulating reward pathways and enhancing the broad-spectrum action of a triple monoamine reuptake inhibitor.

[0147] In alternative embodiments, this invention addresses the unmet need for more effective therapies by leveraging the synergistic mechanisms of GLP-lRAs and TRIs. In alternative embodiments, this combination strategy is used to enhance therapeutic efficacy, reduce side effects, and provide consistent benefits across diverse patient populations. By targeting both neurochemical and structural aspects of CNS disorders, this innovative approach represents a significant advancement in the treatment landscape for complex neuropsychiatric and metabolic diseases.

[0148] Achieving the optimal dose for individual patients is crucial to maximizing clinical benefit and minimizing adverse events. Variations in body weight, body composition, metabolic enzyme CYP P450 polymorphism, drug transporters like PGP polymorphism, and drug-drug interactions present challenges in prescribing optimal doses. This is particularly difficult in pediatric, intellectually disabled, and clinically fragile patients. To address these challenges, provided herein are methods comprising use of individualized dosing strategies for certain pharmaceutical components in the therapeutic compositions, addressing these challenges. Furthermore, the combination of a GLP-1 agonist with either a single or dual monoamine reuptake inhibitor, or other drug classes described herein, could offer added or synergistic benefits in treating the disorders outlined herein.

[0149] In alternative embodiments, CT 996™ has the formula: and the term CT 996™ also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)- stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)- stereoisomer or a (R)(-)-stereoisomer thereof.

[0150] In alternative embodiments, danuglipron or CAS Number 2230198-02-2 (also called PF-06882961™ (Pfizer)) has the formula: and the term danuglipron also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)- stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)- stereoisomer or a (R)(-)-stereoisomer thereof.

[0151] In alternative embodiments, retatrutide, CAS Number 2381089-83-2 or LY3437943™ (Eli Lilly and Company) is a 39 amino acid single peptide engineered from a GIP peptide backbone to achieve triple agonist activity at the GCGR, GIPR, and GLP1R. The peptide back bone sequence of LY contains three non-coded amino acid residues at positions 2, 20, and 13. Aib2(a-aminoisobutyric acid) provides stability against DPP4 cleavage. Aib20 contributes to optimal GIP activity, PK profile, and developability. aMeL13 (a-methyl-L-leucine) contributes to optimal glucagon and GIP activity. The backbone is conjugated to a C20 fatty acid moiety via a linker at the position 17 lysine residue, enabling albumin binding as a pharmacokinetic half-life extension strategy while providing desired pharmacological properties, and has the formula and structure: and the term LY3437943™ also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof.

[0152] In alternative embodiments, BI 456906™ is a 29-amino-acid peptide optimized to balance the degree of agonism for the human GCGR and GLP-1R by introducing various modifications to the human glucagon sequence, and has the sequence and structure: and the term survodutide, CAS Number 2805997-46-8 or BI 456906™ (Boehringer Ingelheim) also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof. maridebart cafraglutide, MariTide or AMG-133™ consists of two GLP-1 agonist peptides conjugated to an anti-GIP antibody backbone, and also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof.

[0153] In alternative embodiments, ECC5004™ (a GLP-1 receptor agonist, or GLP-1 RA) has the formula: and the term ECC5004™ also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)- stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)- stereoisomer or a (R)(-)-stereoisomer thereof. In alternative embodiments, orforglipron or CAS Number 2212020-52-3 (LY- 3502970™) (Eli Lilly and Company) has the formula: and the term orforglipron also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)- stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)- stereoisomer or a (R)(-)-stereoisomer thereof.

[0154] In alternative embodiments, SAR441255™ (see Bossart et al, Cell Metab. 2022 Jan 4; 34(l):59-74; Epub 2021 Dec 20) is triple GLP-1R / GCGR / GIPR agonist with the following amino acid sequence, H - Aib - H - G - T - F - T - S - D - L - S - K - [K(GluA5-GluA6-GluA7-Palm)] - Q - Aib - E - F - 1 - W - L - K - aDala - G - P - P - S - Aib - K - P - P - K (Aib is Alpha-aminoisobutyric acid, and aDala is Alphadiaminobutyric acid. Palm is palmitoyl, and the term SAR441255™ also comprises or encompasses a deuterated form thereof, or a pharmaceutically acceptable salt thereof.

[0155] Pharmaceutical Compositions and Formulations

[0156] In alternative embodiments, drugs or compounds are provided herein, or drugs or compounds used to practice methods are provided herein, are formulated for administration by any or a variety of means including orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally. Drugs or compounds are provided herein, or drugs or compounds used to practice methods are provided herein, can further comprise pharmaceutically acceptable carriers, adjuvants and vehicles. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated for parenteral administration, including administration intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially; for example, by injection routes but also including a variety of infusion techniques. Intraarterial, intrathecal, intracranial, epidural, intravenous and other injections as used in some embodiments can include administration through catheters or pumps, for example, an intrathecal pump, or an implantable medical device (which can be an intrathecal pump or catheter).

[0157] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be formulated in accordance with a routine procedure(s) adapted for a desired administration route. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated or manufactured as lyophilates, powders, lozenges, liposomes, suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0158] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Suitable alternative and exemplary formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0159] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be formulations for parenteral administration comprising any common excipient, for example, sterile water or saline, a polyalkylene glycol such as a polyethylene glycol, an oil of synthetic or vegetable origin, a hydrogenated naphthalene and the like. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be a biocompatible, biodegradable lactide polymer, a lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are administered using parenteral delivery systems such as ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, intrathecal catheters, pumps and implants, and / or use of liposomes. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.

[0160] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are administered intranasally. When given by this route, examples of appropriate dosage forms are a nasal spray or dry powder, as is known to those skilled in the art. For example, a nasal formulation can comprise a conventional surfactant, generally a non-ionic surfactant. When a surfactant is employed in a nasal formulation, the amount present will vary depending on the particular surfactant chosen, the particular mode of administration (for example drop or spray) and the effect desired.

[0161] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In alternative embodiments, sterile fixed oils are conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In alternative embodiments, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule (ampoule) or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0162] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, further comprise aqueous and non-aqueous sterile injection solutions that can contain (comprise) antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and / or aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.

[0163] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated for topical administration, for example, in the form of a liquid, lotion, cream or gel. Topical administration can be accomplished by application directly on the treatment area. For example, such application can be accomplished by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by a spray application of a liquid formulation onto the application or treatment area.

[0164] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise a bioimplant or a bioimplant material, and also can be coated with a compound of the invention or other compounds so as to improve interaction between cells and the implant.

[0165] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise minor amounts of wetting or emulsifying agents, or pH buffering agents. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0166] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise oral formulations such as tablets, pills, troches, lozenges (see, for example, as described in USPN 5,780,055), aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules or geltabs, gels, jellies, syrups and / or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, taste-masking agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrrolidone, sodium saccharine, cellulose, magnesium carbonate, etc. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0167] In alternative embodiments, formulations for oral use are hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0168] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise aqueous suspensions comprising the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Exemplary excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (for example, lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example, heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n- propyl p-hydroxy -benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0169] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise oil suspensions that can be formulated by suspending the active ingredient (for example, a compound of this invention) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0170] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, include an agent which controls release of the compound, thereby providing a timed or sustained release compound.

[0171] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated or made as a multiparticulate and / or a solid dispersion formulation, for example, as described in, for example, U.S. Patent App. Pub. No. 20080118560, for example, comprising a hydrophobic matrix former which is a water-insoluble, non-swelling amphiphilic lipid; and a hydrophilic matrix former which is a meltable, water-soluble excipient. In one embodiment, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are contained in tablets, pills, capsules, troches, and the like comprising any combination of a binder, for example, as a starch, polyvinyl pyrrolidone, gum tragacanth or gelatin; a filler, such as microcrystalline cellulose or lactose; a disintegrating agent, such as crospovidone, sodium starch glycolate, corn starch, and the like; a lubricant, such as magnesium stearate, stearic acid, glyceryl behenate; a glidant, such as colloidal silicon dioxide and talc; a sweetening agent, such as sucrose or saccharin, aspartame, acesulfame-K; and / or flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it also can comprise a liquid carrier, such as a fatty oil.

[0172] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations having a coating, for example, a coat comprising a sugar, shellac, sustained and / or other enteric coating agents, or any pharmaceutically pure and / or nontoxic agents.

[0173] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations, wherein each different compound of the composition or product of manufacture is contained in a different layer of a pill, tablet or capsule, for example, as described in USPN 7,384,653, for example, having an outer base-soluble layer and an inner acid-soluble layer. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations, wherein each different compound of the composition or product of manufacture is contained in a liquid or a gel of different viscosity, for example, described in U.S. Patent App. Pub. No. 20050214223. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations having reduced abuse potential, for example, as described in U.S. Patent App. Pub. No. 20040228802, for example, comprising a bittering agent, a bright deterrent / indicator dye, or a fine insoluble particulate matter.

[0174] Carriers

[0175] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise or are formulated with or as aqueous or non-aqueous solutions, suspensions, emulsions and solids. Examples of non-aqueous solvents suitable for use as disclosed herein include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. In alternative embodiments, aqueous carriers can comprise water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions and / or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.

[0176] In alternative embodiments, liquid carriers are used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including carriers for preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can comprise other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.

[0177] In alternative embodiments, liquid carriers used to manufacture or formulate compounds of this invention comprise water (partially containing additives as above, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0178] In alternative embodiments, solid carriers are used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including solid carriers comprising substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (for example, povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0179] In alternative embodiments, parenteral carriers are used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including parenteral carriers suitable for use as disclosed herein include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers can comprise fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also comprise, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

[0180] In alternative embodiments, carriers used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.

[0181] The invention also provides articles of manufacture and kits containing (comprising) drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including pharmaceutical compositions and formulations. By way of example only a kit or article of manufacture can include a container (such as a bottle) with a desired amount of a compound (or pharmaceutical composition of a compound) described herein. Such a kit or article of manufacture can further include instructions for using the compound (or pharmaceutical composition of a compound) described herein. The instructions can be attached to the container, or can be included in a package (such as a box or a plastic or foil bag) holding the container.

[0182] The drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be delivered to the body or targeted to a specific tissue or organ (for example, a muscle or a brain) by any method or protocol, for example, including ex vivo “loading of cells” with drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, where the “loaded cell” is the administered intramuscularly, or intrathecally, intracerebrally, or epidurally into the central nervous system (CNS), for example, as described in U.S. Pat. App. Pub. No. 20050048002.

[0183] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are first lyophilized and then suspended in a hydrophobic medium, for example, comprising aliphatic, cyclic or aromatic molecules, for example, as described in U.S. Pat. App. Pub. No. 20080159984.

[0184] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise or are formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts can include suitable acid addition or base salts thereof. In alternative embodiments, compounds can be formulated as described in Berge et al, J Pharm Sci, 66, 1-19 (1977).

[0185] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated as salts that are formed, for example, with strong inorganic acids such as mineral acids, for example hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (for example, by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with amino acids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or arylsulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Compounds of the invention also encompass salts which are not pharmaceutically acceptable, for example, a salt may still be valuable as an intermediate in a synthetic or analytical process or protocol.

[0186] In alternative embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, comprise any acceptable salt for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3 -phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. Pharmaceutical compositions as disclosed herein can be prepared in accordance with methods well known and routinely practiced in the art. See, for example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20thed., 2000; and Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0187] In some embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, are provided in the form of pharmaceutically acceptable salts comprising an amine that is basic in nature and can react with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt; for example, such salts comprise inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids; or optionally such pharmaceutically acceptable salts comprise sulfate, pyrosulfate, bi sulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene- 1 -sulfonate, naphthal ene-2- sulfonate, mandelate, hippurate, gluconate, lactobionate, methylene-bis-b- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like salts.

[0188] In alternative embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, comprise compositions manufactured under “Good manufacturing practice” or GMP, or "current good manufacturing practices" (cGMP), conditions.

[0189] Derivatized and Deuterated Compounds

[0190] In alternative embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, are derivatized analogs, for example, metabolically blocked or otherwise altered derivatives, including deuterated, hydroxylated, fluorinated or methylated analogs or derivatives, or any combination thereof.

[0191] With regard to deuterated compounds as provided herein, or as used to practice methods as provided herein, it will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of a compound will inherently contain small amounts of deuterated isotopologues. For compounds as provided herein, or as used to practice methods as provided herein, which include pharmaceutical preparations and formulations, when a particular position is designated as having deuterium (“-D”), it is understood that the abundance of deuterium at that position is greater than, or substantially greater than, the natural abundance of deuterium, which is 0.015%. For example, alternative embodiments of the invention comprise analogs of drugs or compounds as provided herein, or drugs or compounds used to practice methods as provided herein, having greater than 0.02%, or greater than about 0.1% deuterium. In one embodiment, the deuterium substitution, or “enrichment”, occurs at a specific position or positions. In one embodiment, the deuterium enrichment is no less than about 1%, 10%, 20%, 50%, 70%, 80%, 90% or 95% or more or between about 1% and 100%.

[0192] In one embodiment, the deuterated (or otherwise substituted) compounds as provided herein, or as used to practice methods as provided herein have a slower rate of metabolism, for example, slower rate of hydroxylation, than a corresponding protonated (non-deuterated, non- substituted) compound.

[0193] In alternative embodiments, pharmaceutical compositions, drug or formulations as provided here, or as used in a method or use as provided herein, comprise a compound having the formula: wherein at least one of Ri through Ris is -D (deuterium), or all of Ri through Ris is -D, and optionally the carbon atom designated * is in an R or an S configuration if it is a stereocenter; or a pharmaceutically acceptable salt thereof.

[0194] In alternative embodiments, pharmaceutical compositions, drug or formulations as provided here, or as used in a method or use as provided herein, comprise a compound having the formula:

[0195] (a) a 7-([ 1 , 2, 4]tri azolof 1 ,5-a]pyridin-6-yl)-4-(3 ,4-di chlorophenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline-l,l,3,3,4,8-d6 compound having the formula: (b) a 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline-l,l,3,3,4-d5 compound having the formula:

[0196] (c) a7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline-l,l-d2 compound having the formula: (d) a 7-([ 1 , 2, 4]tri azolof 1 ,5-a]pyridin-6-yl)-4-(3 ,4-di chlorophenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline-3,3-d2 compound having the formula:

[0197] (e) a 7-([ 1 , 2, 4]tri azolof 1 ,5-a]pyridin-6-yl)-4-(3 ,4-di chlorophenyl)- 1 ,2,3,4- tetrahydroisoquinoline-4-d compound having the formula:

[0198] (f) a 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline-8-d compound having the formula: (g) a 7-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydroisoquinoline-3,3,4-d3 compound having the formula:

[0199] Stereoisomers

[0200] In alternative embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, exist as (comprise) individual respective stereoisomers that are substantially free from another possible stereoisomer. In alternative embodiments, the term "substantially free of other stereoisomers" as used herein means less than about 15%, 20%, 25%, 30%, 35%, 40%, 50% or 55% of other stereoisomers, or less than about 10% of other stereoisomers, or less than about 5% of other stereoisomers, or less than about 2% of other stereoisomers, or less than about 1% or less of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present. Methods of obtaining or synthesizing an individual enantiomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[0201] Methods of administration

[0202] In alternative embodiments, drugs or compounds are provided herein, or drugs or compounds used to practice methods are provided herein, are administered by any or a variety of means including orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally. Drugs or compounds are provided herein, or drugs or compounds used to practice methods are provided herein, are administered with pharmaceutically acceptable carriers, adjuvants and vehicles. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are administered intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially; for example, by injection routes but also including a variety of infusion techniques. Intraarterial, intrathecal, intracranial, epidural, intravenous and other injections can include administration through catheters or pumps, for example, an intrathecal pump, or an implantable medical device (which can be an intrathecal pump or catheter).

[0203] In alternative embodiments, therapeutic combinations of drugs, pharmaceutical compositions, preparations and kits, can be administered by any known method or route, including by intranasal, intramuscular, intravenous, topical or oral, or combinations thereof, routes.

[0204] One embodiment comprises a product of manufacture comprising a pharmaceutical composition or a formulation, a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, comprising: therapeutic combinations of drugs, pharmaceutical compositions or preparations as provided herein for oral administration.

[0205] In alternative embodiments, although all ingredients can be in one blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, separate ingredients can be formulated for example, for topical application, for oral or for topical application. Each ingredient can be either separately packaged, or can be formulated as one unit dose, for example, as one tube (for example, with gel, lotion etc.), ampoule, blister packette and the like.

[0206] Dosages

[0207] In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated and administered in a variety of different dosages and treatment regimens, depending on the disease or condition to be ameliorated, the condition of the individual to be treated, the goal of the treatment, and the like, as to be routinely determined by the clinician, see for example, the latest edition of Remington: The Science and Practice of Pharmacy, Mack Publishing Co., supra.

[0208] In alternative embodiments, an effective amount of a drug or compound as provided herein, or a composition used to practice the methods as provided herein, including a stereoisomer, salt, hydrate or solvate, is between about 0.1 mg and about 20.0 mg per kg of body weight of the individual or subject (for example, patient). In another variation, the effective amount is between about 0.1 mg and about 10.0 mg per kg of body weight of the individual or subject (for example, patient) or between about 0.1 mg and about 5.0 mg per kg of body weight of the patient. Alternately, the effective amount is between about 0.2 mg and about 2 mg per kg of body weight of the individual or subject (for example, patient).

[0209] In alternative embodiments, an effective amount of a drug or compound as provided herein, or a composition used to practice the methods as provided herein (for example, as a solid dosage, such as a pill, tablet or lozenge) is between about 0.1 mg and about 2.0 mg per kg of body weight of said individual, subject or patient; or is between about 0.1 mg and about 1.0 mg per kg of body weight; or is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, or about 1.0 mg, per kg of body weight; or an effective amount of a drug or compound as provided herein, or a composition used to practice the methods as provided herein, is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg or about 0.3 mg per kg of body weight.

[0210] In alternative embodiment, an effective amount (for example, as a solid dosage, such as a pill, tablet or lozenge) of a drug or compound as provided herein, or a composition used to practice the methods as provided herein, is between about 1 mg and about 400 mg; or is a solid dosage form comprising between about 1 mg and about 250 mg; or the solid dosage form comprises between about 5 mg and about 150; or the solid dosage form (for example, as a pill, tablet or lozenge) comprises between about 1 mg and about 75; or the solid dosage form comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

[0211] Methods for safe and predictable titration to an effective dose

[0212] In alternative embodiments, provided is an empirical method for safe and predictable titration and to determine the initial therapeutic dose, or to determine the lowest therapeutic dose, or to determine an optimal effective dose for any individual drug as used in methods as provided herein (for example, as when that drug is used alone), or for any combination of drugs as provided herein; the method comprises: a. Administrating a test dose (for example, a no adverse events observed dose amount or a minimal adverse events observed dose amount or a safe dose amount) daily until a patient achieves a steady state plasma drug concentration, b. Prior to the next scheduled dose, drawing a blood sample and assessing the test plasma drug concentration, c. Calculating the initial therapeutic dose / day by:

[0213] 1. For drugs with a linear dose to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, and then multiply the dividend by the test dose amount, and

[0214] 2. For drugs with a non-linear dose to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiply the dividend by the test dose amount and then multiply the product by a non-linear index factor, optionally, the initial target therapeutic plasma drug concentration is the concentration corresponding to: (i) certain pharmacodynamic efficacy marker levels, such as occupancy of serotonin transporter (SERT or 5- HTT), dopamine transporter (DAT) or norepinephrine transporter (NET) determined by imaging method such as positron emission tomography (PET); or, (ii) the lowest effective therapeutic dose determined by a clinical study. d. Optionally comprising: i. administrating the initial therapeutic dose, daily, until a patient achieves a steady state plasma drug concentration, ii. prior to the next scheduled dose, drawing a blood sample and assessing the current therapeutic plasma drug concentration, iii. Calculating the next therapeutic target dose / day by:

[0215] 1. For drugs with a linear dose to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount, and

[0216] 2. For drugs with a non-linear dose to plasma concentration, divide next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the dividend by the current therapeutic dose amount and then multiply the product by a non-linear index factor, and iv. continuing the process until the lowest therapeutic dose or optimal effective dose is achieved.

[0217] In alternative embodiments, provided is a model-based method for safe and predictable titration, and to determine the initial therapeutic dose and to determine the lowest therapeutic dose, or to determine an optimal effective dose, and method comprising: a. Administrating a test dose amount daily for between about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day, b. Drawing a first blood sample at between about 1 hour to 3 days, 6 hours to 2 days or about 1 day after administering the first test dose, c. Drawing a second or subsequent blood samples at between about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or at about 2 days, after drawing of the first blood samples or subsequent blood samples, d. calculating the initial therapeutic starting dose / day by: i. using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose(s), the plasma concentration of the blood samples and the time the draws of the blood samples and a pharmacometric model, ii. and optionally, using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose(s), the plasma concentration of the blood samples, the time of the draws of the blood samples, human PK data and a Bayesian pharmacometric model, iii. and optionally, using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose, the plasma concentration of the blood samples, the time of the draws of the blood samples, human PK data, a patient’s genetic information, a patient’s non-heritable host factors, a patient’s other medications, and a Bayesian pharmacometric model, e. and optionally comprising: i. administrating the initial therapeutic starting dose, daily until a patient achieves a steady state plasma drug concentration, ii. Prior to the next scheduled dose, drawing a blood sample and assessing the current therapeutic plasma drug concentration, iii. calculating the next therapeutic target dose / day:

[0218] 1. For drugs with a linear dose to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount, and

[0219] 2. For drugs with a non-linear dose to plasma concentration, divide he next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount and then multiply the product by the a non-linear index factor, and iv. Continuing the process until the lowest therapeutic dose or optimal effective dose is achieved.

[0220] In alternative embodiments, provided is a method to maintain an effective dose, wherein the method comprises:

[0221] (a) recording the maintenance dose amount and the maintenance therapeutic plasma drug concentration associated with the lowest effective therapeutic dose or optimal therapeutic dose,

[0222] (b) at the early of between about 1 to 12 months, 3 to 9 month 4 to 8 months or 6 months or change in body weight, medication or health status then:

[0223] 1. prior to the next scheduled dose, draw a blood sample and assess the current plasma drug concentration

[0224] 2. if the current plasma drug concentration is different from the maintenance therapeutic plasma drug concentration by more than about 20%, optionally more than about 50%, then calculate a new therapeutic dose / day by a method comprising: i. For drugs with a linear dose to plasma concentration, divide the maintenance therapeutic plasma drug concentration by the current plasma drug concentration, and then and multiple the dividend by the maintenance dose amount, and ii. For drugs with a non-linear dose to plasma concentration, divide the maintenance therapeutic plasma drug concentration by the current plasma drug concentration, then multiply the dividend by the maintenance dose amount, and then multiply the product by a non-linear index, or iii. optionally, reaching steady state after two subsequent measured plasma drug concentration results at least one week apart and within about 20% of the maintenance therapeutic plasma concentration, pr iv. optionally, continuing the process until a maintenance therapeutic dose at steady state is achieved.

[0225] In alternative embodiments, there is need for rounding of the lowest therapeutic dose or optimal effective dose amount to the closest available dosage amount. For example, the calculation might determine the optimal effective dose amount is 23 mg / day, however the closest available dosage amount might be only 20 mg. Therefore the patient would be administered only 20 mg / day.

[0226] In alternative embodiments, provided are PK-guided, precision dosing methods using the above-mentioned pharmacokinetic modeling and simulation methods, or similar modeling and simulation methods, and a population PK / PD model of formula I and a GLP-1 agonist to treat or manage diseases including, but are not limited to, affective disorders and reward system-related disorders. These disorders include, but are not limited to, depression, treatment-resistant depression, hyperphagia (including hyperphagia associated with Prader-Willi Syndrome), binge eating disorder, and various substance addictions such as those to cocaine, amphetamines, opioids, alcohol, and nicotine, optionally with an injectable (optionally intramuscular, intravenous, subcutaneous) and / or oral or inhaled dosage (or combination thereof, as appropriate) of therapeutic combinations, preparations, formulations and / or kits, comprising combinations of ingredients, as described herein.

[0227] Packaging and Drug Delivery Systems

[0228] In alternative embodiments, provided are therapeutic combinations, preparations, formulations and / or kits, comprising combinations of ingredients, as described herein. In one aspect, each member of the combination of ingredients is manufactured in a separate package, kit or container; or, all or a subset of the combinations of ingredients are manufactured in a separate package or container. In alternative aspects, the package, kit or container comprises a blister package, a clamshell, a tray, a shrink wrap and the like.

[0229] In one aspect, the package, kit or container comprises a “blister package” (also called a blister pack, or bubble pack). In alternative embodiments, provided are therapeutic combinations, preparations, formulations and / or kits manufactured as “blister packages” or as a plurality of packettes, including as lidded blister packages, lidded blister or blister card or packets or packettes, or a shrink wrap.

[0230] In one aspect, the blister package is made up of two separate elements: a transparent or occlusive plastic cavity shaped to the product and its blister foil backing. These two elements are then sealed together into a blister strip of one or more blister with each blister an environmentally (for example moisture, pathogen, light) protected unit dose. One or more blister strips can be further joined with board material which allows the product to be package, handled, hung, displayed or shipped without damaging the blister seal and provided child resistant features. Exemplary types of “blister packages” include: Face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, slide blister packages.

[0231] Blister packs, clamshells or trays are forms of packaging used for goods; thus, provided are blister packs, clamshells or trays comprising a composition (for example, a (the multi-ingredient combination of drugs as provided herein) combination of active ingredients) as provided herein. Blister packs, clamshells or trays can be designed to be non-reclosable, so consumers can tell if a package has already opened. They are used to package for sale goods where product tampering is a consideration, such as the pharmaceuticals as provided herein. In one aspect, a blister pack as provided herein comprises a molded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc. comprising the combinations as provided herein, covered by a foil laminate. Tablets, pills, etc. are removed from the pack either by peeling the foil back or by pushing the blister to force the tablet to break the foil. In one aspect, a specialized form of a blister pack is a strip pack. In one aspect, in the United Kingdom, blister packs adhere to British Standard 8404.

[0232] In alternative embodiments, laminated aluminum foil blister packs are used, for example, for the preparation of drugs designed to dissolve immediately in the mouth of a patient. This exemplary process comprises having the drug combinations, therapeutic combinations and pharmaceutical dosage forms as provided herein prepared as an aqueous solution(s) which are dispensed (for example, by measured dose) into an aluminum (for example, alufoil) laminated tray portion of a blister pack. This tray is then freeze-dried to form tablets which take the shape of the blister pockets. The alufoil laminate of both the tray and lid fully protects any highly hygroscopic and / or sensitive individual doses. In one aspect, the pack incorporates a child-proof peel open security laminate. In one aspect, the system gives tablets an identification mark by embossing a design into the alufoil pocket that is taken up by the tablets when they change from aqueous to solid state. In one aspect, individual 'push-through' blister packs / packettes are used, for example, using hard temper aluminum (for example, alufoil) lidding material. In one aspect, hermetically-sealed high barrier aluminum (for example, alufoil) laminates are used. In one aspect, any products of manufacture as provided herein, including kits or blister packs, use foil laminations and strip packs, stick packs, sachets and pouches, peelable and non- peelable laminations combining foil, paper, and film for high barrier packaging.

[0233] In alternative embodiments, any products of manufacture as provided herein, including kits or blister packs, include memory aids to help remind patients when and how to take the drug. This safeguards the drug's efficacy by protecting each pill until it's taken; gives the product or kit portability, makes it easy to take a dose anytime or anywhere.

[0234] In alternative embodiments, drug combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein, use child resistant and elderly friendly packaging, for example, packaging compliant to U.S. Government child resistant packaging regulation that requires minimal finger and grip strength. For example, in alternative embodiments foil-only containment of pills is used.

[0235] In alternative embodiments, drug combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein, please tablets, capsules, pills or equivalents on a blister card or equivalent to track usage. By tracking usage, the blister card monitor can remind the patient and / or the primary care-giver to take medication (or that medication has been taken) at the correct time, for example, in AM and / or PM; and can facilitate discussion with health care professionals to identify and overcome barriers to adherence.

[0236] In alternative embodiments, patient usage is monitored by use of customized blister cards or equivalents using an Electronic Compliance Monitor (ECM) system (Intelligent Devices SEZC Inc. (IDI), Grand Cayman, Cayman Islands), or equivalents. For example, in alternative embodiments, the blister cards or equivalents comprise an electronic component that detects, records, safeguards and / or transmits medication removal from the blister cards or equivalents. For example, a sensor detects medication removal from the blister cards or equivalents, and this information can be transferred to a remote location for review by for example, the drug provider and / or the primary care institution or individuals. The data transfer can be by hard contact downloading of data to a transmitting and / or storage device, and can be scanned and data downloaded remotely using a radio-frequency identification (RFID) chip, tag or device or equivalent, which can be operatively connected to a computer and / or a mobile phone or other device. Radio-frequency identification uses electromagnetic fields to automatically identify and track tags attached to objects, where the tags contain electronically stored information, which in this embodiment is transmitting whether and / or when medication is removed from each compartment of the blister cards or equivalents, or by Near-Field Communication (NFC) to a NFC- enabled mobile device or mobile phone. The NFC is a set of communication protocols that enable two electronic devices, one of which is usually a portable device such as a smartphone, to establish communication by bringing them within 4 cm (1.6 in) of each other.

[0237] In alternative embodiments, multi-drug delivery systems as used in methods as provided herein can comprise use of a box to house or enclose drug delivery devices or packages, blister packages, clamshells or trays, as provided herein, where in this exemplary delivery system a week of pharmaceutical dosage form (for example, one, two or three or more tablets, pills, capsules, geltabs or equivalents) are stored on four rows, two rows for administration (for opening and self-administering by user, for example, patient) are for morning or breakfast, or AM administration, and two rows are for evening, dinnertime or PM administration; morning or breakfast, or AM administration rows are clearly separated from the evening, dinnertime or PM administration rows, and each day, and the spare dose, are arranged in column form. In alternative embodiments the blister packages, clamshells or trays are physical linked to a storage box, wherein the blister packages, clamshells or trays slide into and out of the storage box, and in alternative embodiments if needed the PM set of rows can be folded over the AM set of rows for reinsertion of the blister packages, clamshells or trays into the storage box. In alternative embodiments, the storage box comprises sensors to detect medication removal from each of the compartments (for example, which compartment is opened and when), and this information can be transferred to a remote location, for example, by Near-Field Communication (NFC) to a NFC-enabled mobile device or mobile phone, for review by for example, the drug provider and / or the primary care institution or individuals.

[0238] In any embodiment of methods as provided herein, the plasma concentration for the drug, or therapeutic combination, pharmaceutical dosage form is: (a) the trough level or trough concentration (Ctrough), or the lowest concentration reached by the drug, or therapeutic combination or pharmaceutical dosage form before a second or next dose is administered, or (b) determined from blood samples taken between about 0.5 hours to 24 hours, or 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hours, after the last dose or administration of the drug, or therapeutic combination, pharmaceutical dosage form.

[0239] In alternative embodiments, “Individualized dosing” and “PK -guided dosing”, “precision dosing” are interchangeable terms, mean administering each patient by a drug’s PK properties in the patient.

[0240] In alternative embodiments, terms of “plasma concentration”, “plasma drug concentration”, “serum concentration”, “serum drug concentration”, “plasma level”, “level” in the context of drug concentration, are interchangeable, and mean drug concentration in humans or animals, and measured by and interpreted by skilled in the art see Loftsson T. Essential Pharmacokinetics - 1st Edition. Elsevier. 2015.

[0241] In alternative embodiments, “target therapeutic plasma drug concentration”, or a similar term, is within the therapeutic plasma range, optionally about the mid-point of a therapeutic level range of plasma concentration. For example, if the therapeutic, ie, the effective or efficacious plasma concentration range of Formula I in a combination therapy with a GLP-1 agonist for treating binge eating disorder (BED) or treatment resistant depression is between 1000 ng / ml to 1400 ng / ml, the target therapeutic plasma drug concentration can be about 1000 ng / ml, about 1300 ng / ml, or optionally the mid-point about 1200 ng / ml.

[0242] In alternative embodiments, therapeutic in the context of plasma concentration means effective or efficacious in treating a medical condition(s).

[0243] In alternative embodiments, the term "GLP-1 receptor agonist" may also refer to agents with broader activity, including dual GLP-l / GIP receptor agonists, GLP- 1 / Glucagon (GCG) receptor dual agonists, GLP-l / GIP / GCG receptor tri-agonists, and amylin / GLP-1 dual agonists.

[0244] Exemplary mechanisms of action

[0245] While the invention is not limited by any particular mechanism of action:

[0246] Glucagon-like peptide-1 receptor agonists (GLP-lRAs) are a well-established class of therapeutics primarily indicated for the treatment of metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. GLP-lRAs mimic the incretin hormone GLP-1, stimulating glucose-dependent insulin secretion, inhibiting glucagon release, and delaying gastric emptying. These mechanisms result in improved glycemic control and significant weight loss. In addition to their metabolic actions, GLP-lRAs have been shown to exert pleiotropic effects on cardiovascular, immune, and central nervous system (CNS) functions. GLP-lRAs regulate appetite and energy expenditure, while also demonstrating potential neuroprotective properties.

[0247] The presence of GLP-1 receptors in key CNS regions, including the arcuate nucleus (ARC) of the hypothalamus, hippocampus, and cortical areas, underscores the broad central actions of GLP-lRAs. Activation of these receptors influences neuronal circuits responsible for appetite control, reward-driven behaviors, and energy homeostasis. Experimental evidence indicates that GLP-lRAs enhance the activity of brown adipose tissue via hypothalamic pathways, reduce gliosis, and improve leptin sensitivity. These findings highlight the dual metabolic and neuroprotective potential of GLP-lRAs.

[0248] Emerging research further suggests that GLP-lRAs modulate functional connectivity in the CNS, particularly within brain networks such as the default mode network (DMN), salience network, and visuospatial and frontal-parietal networks (Zheng et al 2024). These networks are critical for cognition, emotion, and attention regulation. Functional imaging studies have shown that GLP-lRAs, such as liraglutide and exenatide, enhance connectivity in the hippocampus and hypothalamic-thalamic circuits, respectively (Zheng et al, 2024). Such region-specific effects suggest a targeted role for GLP-lRAs in addressing neurodegenerative and psychiatric disorders.

[0249] Preclinical studies have demonstrated the neuroprotective and neuroregenerative effects of GLP-lRAs in models of Parkinson’s disease, stroke, and Alzheimer’s disease. In Parkinson’s disease models, exenatide reversed neurotoxin- induced nigrostriatal damage. In rodent stroke models, exenatide reduced microglial infiltration and promoted stem cell proliferation. In Alzheimer’s disease models, liraglutide reduced amyloid plaque deposition, improved memory, and enhanced hippocampal neurogenesis. Mechanistically, GLP-lRAs activate pathways such as PI3K / AKT and ERK / MAPK, promoting neurogenesis, synaptic plasticity, and neuronal survival.

[0250] Despite these promising outcomes, the standalone use of GLP-lRAs is limited by several factors. While GLP-lRAs are effective in promoting weight loss, a portion of this weight loss has been reported to involve the reduction of lean muscle mass. The preservation of lean muscle is critical for maintaining metabolic health, physical mobility, and overall long-term weight management, particularly in older adults or individuals with comorbidities, where muscle loss could exacerbate existing health challenges. Moreover, their efficacy may be insufficient to address the complex and multifactorial nature of many metabolic and neurodegenerative disorders. Weight loss benefits often plateau over time, and variability in individual responses limits their applicability in heterogeneous populations. Furthermore, GLP-lRAs are associated with gastrointestinal side effects, such as nausea, vomiting, and diarrhea, which may reduce patient adherence and tolerability. In certain populations, including those with type 1 diabetes, these side effects occur at lower doses and with greater frequency, further limiting their standalone utility.

[0251] Triple monoamine reuptake inhibitors (TRIs) provide a complementary therapeutic approach by simultaneously targeting serotonin (SERT), norepinephrine (NET), and dopamine (DAT) transporters. This mechanism increases synaptic concentrations of these neurotransmitters, addressing mood dysregulation, cognitive impairments, and behavioral disturbances. Unlike conventional monoaminergic therapies that act on one or two neurotransmitter pathways, TRIs leverage the interplay of all three systems, providing broader therapeutic efficacy. TRIs are particularly promising for conditions such as treatment-resistant depression (TRD), binge eating disorder (BED), and neuropsychiatric disorders with overlapping metabolic and reward-related components.

[0252] In alternative embodiments, TRIs are combined with GLP-lRAs to offer a novel and synergistic therapeutic strategy. GLP-lRAs modulate neural circuits involved in appetite regulation, reward sensitivity, and emotional processing, while TRIs address neurotransmitter imbalances critical for mood stabilization and cognitive function. Together, these agents can target both structural and chemical dysfunctions underlying CNS disorders, providing a robust and holistic treatment approach. GLP-lRAs reduce appetite and food-seeking behaviors via hypothalamic and caudate nucleus pathways, whereas TRIs enhance reward sensitivity and reduce cravings by modulating dopamine and norepinephrine signaling. Both classes also improve cognitive function, with GLP-lRAs enhancing hippocampal connectivity and TRIs addressing deficits in executive function and memory.

[0253] In one embodiment, the combination of TRIs and GLP-lRAs is used to treat or ameliorate neuroinflammation, a contributing factor in metabolic and psychiatric disorders. By reducing neuroinflammation through distinct but complementary pathways, exemplary therapeutic combinations as provided herein enhance neuroprotection and improve long-term outcomes. Furthermore, combining these agents allows for dose reductions, mitigating adverse effects such as GLP- IRA- associated nausea and monoaminergic overstimulation.

[0254] Accordingly, in alternative embodiments, this invention addresses the unmet need for more effective therapies by leveraging the synergistic mechanisms of GLP- lRAs and TRIs. This exemplary combination strategy offers the potential to enhance therapeutic efficacy, reduce side effects, and provide consistent benefits across diverse patient populations. By targeting both neurochemical and structural aspects of CNS disorders, the innovative approach as provided herein represents a significant advancement in the treatment landscape for complex neuropsychiatric and metabolic diseases.

[0255] Any of the above aspects and embodiments can be combined with any other aspect or embodiment as disclosed here in the Summary, Figures and / or Detailed Description sections. As used in this specification and the claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0256] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and”.

[0257] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About (use of the term “about”) can be understood as within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12% 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

[0258] Unless specifically stated or obvious from context, as used herein, the terms “substantially all”, “substantially most of’, “substantially all of’ or “majority of’ encompass at least about 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 99.5%, or more of a referenced amount of a composition. For example, in alternative embodiments, the term “substantially pure” refers to chemical purity, for example, a “substantially pure” compounds as provided or used in a therapeutic formulation or combination as provided herein is at least about 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 99.5%, pure or free of contaminants or other forms, for example, free of any form but the S-enantiomer of Formula I.

[0259] The entirety of each patent, patent application, publication and document referenced herein hereby is incorporated by reference. Citation of the above patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. Incorporation by reference of these documents, standing alone, should not be construed as an assertion or admission that any portion of the contents of any document is considered to be essential material for satisfying any national or regional statutory disclosure requirement for patent applications. Notwithstanding, the right is reserved for relying upon any of such documents, where appropriate, for providing material deemed essential to the claimed subject matter by an examining authority or court.

[0260] Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, and yet these modifications and improvements are within the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of, and "consisting of' may be replaced with either of the other two terms. Thus, the terms and expressions which have been employed are used as terms of description and not of limitation, equivalents of the features shown and described, or portions thereof, are not excluded, and it is recognized that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.

[0261] A number of embodiments of the invention have been described.

[0262] Nevertheless, it can be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A therapeutic combination, a pharmaceutical dosage form or formulation, a drug delivery device or a product of manufacture, comprising:(a) an active agent comprising:(i) a Glucagon-Like Peptide-l(GLP-l) receptor agonist, wherein optionally the GLP-1 receptor agonist comprises: liraglutide or VICTOZA™ or SAXEND A™; exenatide or BYETTA™, BYDUREON™, BYDUREON™ or BCISE™); dulaglutide (or TRULICITY™), lixisenatide (or ADLYXIN™), a semaglutide injection (or OZEMPIC™ or WEGOVY™), a semaglutide tablet (or RYBELSUS™), albiglutide (or TANZEUM™ or EPERZAN™),CT-996™ (Carmot Therapeutics, Inc.),ECC5004™ (Eccogene, Inc.),GSBR-1290™ (Structure Therapeutics),LY-307161™ (a 31 amino acid analog of glucagonlike peptide- 1(7-37)OH), danuglipron (PF-06882961™),LY2189265 (Eli Lilly), ecnoglutide (XW003, Sciwind Biosciences),XW014 (Sciwind Biosciences), efpeglenatide (or HM11260C) (Hanmi Pharm Co., Ltd), beinaglutide or benaglutide,JY09 (Beijing Dongfang Baitai Biotechnology Co., Ltd),HRS-7535 (Hercules CM NewCo),aleniglipron (GSBR-1290) or CAS Number 2685823-26-9 (Structure Therapeutics), dapiglutide or CAS Number 2296814-85-0 (Zealand Pharma),GZR18 (Gan & Lee Pharmaceuticals),HDM1002 (Huadong Medicine Co., Ltd.),,NN9926, lotiglipron or CAS Number 2401892-75-7 (Pfizer), taspoglutide or CAS Number 275371-94-3 (Ipsen and Roche), and / or orforglipron (LY-3502970);(ii) a dual GLP-l / GIP agonist, wherein optionally the GLP-l / GIP agonist comprises: tirzepatide (or MOUNJARO™ or ZEPBOUND™), maridebart cafraglutide, CAS Number 2760218-55-9, or AMG-133™ (Amgen),AZD9550 (AstraZeneca),VK2735 (Viking Therapeutics, Inc.),SCO-094 (Scohia Pharma, Inc.),HRS-9531 (Hercules CM NewCo),CT-388™ (Carmot Therapeutics, Inc.), and / orCT-868™ (Carmot Therapeutics, Inc.),(iii) a GLP-1 / Glucagon (GCG) receptor dual agonist, wherein optionally the GLP-l / GCG receptor dual agonist comprises:AZD-9550™ or BI-456906™, mazdutide (or IB 1362, or LY-3305677) (Eli Lilly and Company),DD01 (D&D Pharmatech),RGT-075 (Regor Therapeutics Group),efinopegdutide (or MK-6024) (Merck & Co., Inc.), pemvidutide (Altimmune, Inc.), and / or survodutide (or BI-456906) (C.H. Boehringer Sohn AG & Co.KG),(iv) a GLP-l / GIP / GCG receptor tri-agonist, wherein optionally the GLP-l / GIP / GCG receptor tri-agonist comprises: retatrutide (LY3437943™),SAR425899 (Sanofi) or SAR441255™,HM15275, efocipegtrutide (or HM15211, Hanmi Pharm Co., Ltd), and / orMEDI0382 (AstraZeneca),(v) an amylin / GLP-1 dual agonist, wherein optionally the amylin / GLP-1 dual agonist comprises NNC- 0487-0111™, or(vi) any combination of (i) to (v), or the combination of (i) and (ii), (i) and (iii), , (i) and (v), (i) and (iv), (ii) and (iii), (ii) and (iv), (ii) and (v), , (iii) and (iv), (iii) and (v), (iv) and (v), or (v) and (vi); or(vii) a combination of (i), (ii) and (iii); (i), (ii) and (v); (i), (ii) and (iv); (i), (ii) and (iii); (i), (ii) and (vi); (ii), (iii) and (iv); (ii), (iii) and (v); (ii), (iii) and (vi); (iii), (vi) and (v);, (iii), (iv) and (vi); (iii) (vi) and (vi); (iv), (v) and (vi); (i), (v) and (vi); (i), (iii), (v) and (vi); or, (iv), (v) and (vi); and(b) one, or a combination of two, three, four, five, six or several of the following drugs, active agents, or small molecules:(1) carbetocin, or DURATOCIN™, PABAL™ or LONACTENE™,(2) oxytocin and / or the precursor oxytocin-neurophysin,(3) diazoxide (or PROGLYCEM™) or a diazoxide Choline Controlled-Release (DCCR formulation);(4) setmelanotide, BIM-22493, IRC-022493 or RM-493 (CAS Number 920014-72-8), or lMCIVREE™,(5) N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D- phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide),(6) a bitter taste receptor (TAS2R) agonist, wherein optionally the bitter taste receptor (TAS2R) agonist comprises denatonium acetate or ARD-101,(7) rimonabant (also known as SR141716) and / or ACOMPLIA™, ZIMULTI™,(8) a melatonin receptor agonist, wherein optionally the melatonin receptor agonist is or comprises: melatonin or N-acetyl-5-methoxy tryptamine, ramelteon (or ROZEREM™) and / or tesimelteon (or HETLIOZ™), or any combination thereof,(9) modafinil (or PRO VIGIL™, ALERTEC™ or MODAVIGIL™), and / or amodafonil (or NUVIGIL™),(10) metformin (or GLUCOPHAGE™) and / or repaglinide (or PRANDIN)™,(11) a mood stabilizer, wherein optionally the mood stabilizer is or comprises: gabapentin (or NEURONTIN™); clonazepam (or KLONOPIN™ or RIVOTRILF™); valproate, valproic acid, sodium valproate or valproate semisodium (or CONVULEX™, DEPAKOTE™, EPILIM™ or STAVZOR™); oxcarbazepine (or TRILEPTAL™ or OXTELLAR XR™); lithium or lithium carbonate (or LITHOBID™ or LITHOMAX™); topiramate (or TOPAMAX™, TROKENDI XR™ or QUDEXY XR™) and / or lamotrigine (or LAMICTAL™), or any combination thereof,(12) a neuroleptic,wherein optionally the neuroleptic comprises: risperidone (or Risperdal), aripiprazole (or ABILIFY™), quetiapine (or SEROQUEL™), olanzapine (or ZYPREXA™), ziprasidone (or GEODON™) and / or haloperidol (or HALDOL™ or SERENACE™), or any combination thereof,(13) quetiapine, or SEROQUEL™ or TEMPROLIDE™,(14) naltrexone (or FEBIA™ or VIVITROL™),(15) solriamfetol or SUNOS™,(16) a selective norepinephrine reuptake inhibitor (NRI), or a selective serotonin reuptake inhibitor (SSRI), or a selective serotonin norepinephrine inhibitor (SNRI), wherein optionally the SSRI or SNRI inhibitor is or comprises reboxetine (or AXS-12, or Edronax™), atomoxetine (or Strattera™), venlafaxine (Effexor™ or Effexor XR™), fluoxetine (Prozac™), citalopram (Celexa™), escitalopram (Lexapro), paroxetine (Paxil™), sertraline (Zoloft™), or duloxetine (Cymbalta™),(17) an amphetamine, wherein optionally the amphetamine or comprises amphetamine, dextroamphetamine (or Adderall™), dextroamphetamine-amphetamine (Mydayis™) or lisdexamfetamine (or Vyvanse™).(18) methylphenidate or Ritalin, Ritalin LA, Concerta, Metadate CD, Methylin, Methylin ER, Daytrana, Quillivant XR, Quillichew ER, Aptensio XR, Cotempla XR-ODT, lomay PM, Adhansia XR, or serdexmethylphenidate.(19) a tricyclic antidepressant (TCA), wherein optionally the TCA is or comprises imipramine (Tofranil™), or amitriptyline (Elavil™), clomipramine (Anafranil™) or another TCA,(20) a monoamine oxidase inhibitor (MAOI),wherein optionally the MAOI is or comprises selegiline (Emsam™), isocarboxazid (Marplan™), phenelzine (Nardil™), and tranylcypromine (Parnate™) or another MAOI,(21) an anti-obesity medication, wherein optionally the anti-obesity medication comprises lorcaserin (Belviq™), orlistat (Alli™), phentermine and topiramate (Qsymia™), ornaltrexone HC1 or bupropion HC1 (Contrave™),(22) a famesoid X receptor (FXR) agonist, wherein optionally the FXR agonist comprises Obeticholic Acid (OCA), EYP001 (ENYO Pharma), TQA3526, Px-102, Px-104, or tropifexor,(23) a PPAR agonist, optionally a PPAR a / 5 agonist, or a PPAR-a / y agonist, wherein optionally the PPAR-a / y agonist comprises pioglitazone, elafibranor or lanifibranor (or IVA337, Inventiva),(24) a CC chemokine receptor CCR2 / CCR5 inhibitor, wherein optionally the CC chemokine receptor comprises tropifexor, a combination of tropifexor and cenicriviroc, or cenicriviroc,(25) a mitochondrial pyruvate carrier (MPC) inhibitor, wherein optionally the MPC inhibitor comprises MSDC-0602K (Cirius Therapeutics),(26) a Fibroblast Growth Factor 19 (FGF19) analogue, wherein optionally the FGF19 analogue comprises aldafermin (or NGM282, NGM Biopharmaceuticals)(27) a Fibroblast Growth Factor 21 (FGF21) analogue, wherein optionally the FGF21 analogue comprises a PEGylated Fibroblast Growth Factor 21 analogue, optionally pegbelfermin,(28) a thyroid hormone receptor beta (THR-P) agonist, wherein optionally the THR-P agonist comprises resmetirom (MGL-3196, Magrigal Pharmaceuticals) or VK-2890,(29) a Stearoyl-CoA desaturase- 1 (SCD1) inhibitor, wherein optionally the SCD1 inhibitor comprises aramchol (Galmed Pharmaceuticals),(30) an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, wherein optionally the ASK1 inhibitor comprises selonsertib (Gilead Sciences),(31) an acetyl-CoA carboxylase (ACC) inhibitor, wherein optionally the ACC inhibitor comprises firsocostat (GS-0976) or MK-4074,(32) a triple monoamine reuptake inhibitor, wherein optionally the triple monoamine reuptake inhibitor comprises:7-([ 1 , 2, 4]tri azolof 1 , 5-a]pyridin-6-yl)-4-(3 ,4-dichlorophenyl)- 1,2,3,4-tetrahydroisoquinoline, tesofensine (also known as tesomet or tesofen) (Saniona, Ballerup, Denmark), centanafadine or CAS Number 924012-43-1 (Otsuka Pharmaceutical), liafensine or CAS Number 1198790-53-2 (Bristol-Myers Squibb), toludesvenlafaxine or CAS Number 916918-84-8 or RUOXINLIN™, amitifadine or CAS Number 410074-73-6 (Euthymics Bioscience), and / orNOE-115 (Noema Pharma AG),(33) a [l,2,4]triazolo[l,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative as described in USPN 8,802,696, or 7-([ 1,2, 4]tri azolof 1, 5-a]pyridin-6-yl)-4-(3,4-di chlorophenyl)- 1,2, 3,4- tetrahydroisoquinoline, or a deuterated form thereof (optionally as described in WO 2021 / 142395), or a pharmaceutically acceptable salt thereof, or a (+)-stereoisomer or a (-)-stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)-stereoisomer or a (R)(-)-stereoisomer thereof;(34) a compound having the formula (Formula I):Formula I or a pharmaceutically acceptable salt thereof, or an S-enantiomer, (+)- stereoisomer or a (-)-stereoisomer thereof, or a compound in the S or R configuration, or a (S)(+)-stereoisomer or a (R)(-)-stereoisomer thereof; or(35) any combination of two, three, four, five or six or more of 1 to 34.

2. The therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of claim 1, wherein the active agent or agents of (a) and the drugs, active agents, or small molecules of (b) are formulated as separate compositions, or are formulated into one composition or drug formulation.

3. The therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of claim 1 or claim 2, wherein one or two or more of the drugs or active agents are packaged individually, or are packaged together, or packaged in any combination, in a single package, a plurality of packagesor packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap.

4. The therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of any of claims 1 to 3, or any of the preceding claims, wherein the one or two or more or all of the drugs or active agent or agents are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a spray, a sachet, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof, and optionally the drug delivery device or product of manufacture is or comprises an implant.

5. The therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of any of claims 1 to 3, wherein the one or two or more or all of the drugs or active agent or agents are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository.

6. The therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of any of claims 1 to 5, or any of the preceding claims, wherein the one or two or more or all of the drugs or active agent or agents are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.

7. The therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of any of claims 1 to 6, or any of the preceding claims, wherein the drugs or active agents comprise:(a) a Glucagon-Like Peptide- l(GLP-l) receptor agonist, a dual GLP-l / GIP (agonist), a GLP-l / Glucagon (GCG) receptor dual agonist, a GLP-l / GIP / GCG receptor tri -agonist or an amylin / GLP-1 dual agonist, or a combination of any two, three or more of: Glucagon-Like Peptide- l(GLP-l) receptor agonist, a dual GLP-l / GIP (agonist), a GLP-l / Glucagon (GCG) receptor dual agonist, a GLP-l / GIP / GCG receptor tri-agonist, and an amylin / GLP-1 dual agonist, and:(b) (i) a triple monoamine reuptake inhibitor or a [l,2,4]triazolo[l,5- a]pyridinyl-6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I,;(ii) a triple monoamine reuptake inhibitor or a [l,2,4]triazolo[l,5-a]pyridinyl- 6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I , and a diazoxide (or PROGLYCEM™) or a diazoxide Choline Controlled-Release (DCCR formulation);(iii) a triple monoamine reuptake inhibitor or a [l,2,4]triazolo[l,5-a]pyridinyl- 6-yl-substituted tetrahydroisoquinoline derivative, optionally a compound of Formula I, and a beta blocker, optionally, atenolol (TENORMIN™), bisoprolol (CARDICOR™, EMCOR™), or metoprolol (BETALOC™, LOPRESOR™, TOPROL XL™), or any combination thereof; and / or(iv) any combination of (i) to (iii), or (i) and (ii), or (i) and (iii), or (ii) and (iii).

8. A pharmaceutical composition, drug or formulation comprising a therapeutic combination or pharmaceutical dosage form of any of claims 1 to 7. wherein optionally the pharmaceutical composition, drug or formulation is formulated for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

9. A drug delivery device or product of manufacture comprising or having contained therein a therapeutic combination or pharmaceutical dosage form of any of claims 1 to 8. wherein optionally the pharmaceutical dosage form is formulated for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

10. A method for treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing, a disease or condition comprising or associated with: hyperphagia in PWS (optionally as assessed by HQ-CT), moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity, optionally further comprising management of weight loss and maintenance of weight loss, or optionally further comprising as an adjunct to a reduced-calorie diet or for increased physical activity for chronic weight management, early onset morbid obesity, non- Alcoholic Steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH) non-alcoholic fatty liver disease (NAFLD), type II diabetes, hypothalamic injury-induced obesity, obsessive-compulsive disorder (OCD), disruptive mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), irritability in autism, irritability in autistic spectrum disorder,excoriation, trichotillomania, intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders-Third Edition (ICSD-3), narcolepsy with cataplexy, narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, cataplexy, idiopathic hypersomnia, rapid eye movement (REM) sleep behavior disorder, major depressive disorder (MDD), treatment resistant depression (TRD), negative symptoms of schizophrenia,MDD Associated with Parkinson’s Disease,Parkinson’s Disease, general anxiety,Social Anxiety Disorder (Social Phobia),Fibromyalgia (FM), diabetic neuropathy.lower back pain, chronic fatigue syndrome, cognitive inflexibility, cocaine addiction, amphetamines addiction, opioids addiction, alcohol addiction, nicotine addiction attention deficit hyperactivity disorder (ADHD), autism,Asperger spectrum, a genetically confirmed disease or syndrome, wherein optionally the genetically confirmed disease or syndrome is or comprises Prader-Willi Syndrome, Bardet Biedl Syndrome, Smith- Magenis Syndrome, lp36 deletion syndrome, 16pl 1.2 deletion Syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, Melanocortin 4 Receptor (MC4R) Pathway Heterozygous Obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman’s Syndrome, Schaff-Yang Syndrome, Albright Hereditary Osteodystroph, Silver-Russell Syndrome, Maternal Disomy 14, Alstrbm Syndrome, Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation or WAGR or WAGRO Syndrome; Dravet Syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Doose Syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick type C disease, or Norrie disease, or Coffin-Lowry disease, wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural orthostatic tachycardia syndrome, the method comprising:(b) (i) providing or having provided a pharmaceutical composition, drug or formulation comprising a therapeutic combination or pharmaceutical dosage form of claim 9, or a drug delivery device or product of manufacture of claim 10, and(ii) administering to or implanting into an individual in need thereof the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture, or(b) administering to or implanting into an individual in need thereof a therapeutic combination or pharmaceutical dosage form of claim 8, or a drug delivery device or product of manufacture of claim 9.

11. The method of claim 10, wherein the drug, or therapeutic combination, pharmaceutical dosage form, is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally.

12. The method of claim 11, wherein the parenteral administration comprises administration intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

13. The method of any of claims 10 to 12, wherein the drug, or therapeutic combination, pharmaceutical dosage form, or active agent or agents, is or are administered to achieve a therapeutic level range of plasma concentration at a steady state, and wherein: the therapeutic level range of plasma concentration for Formula I, is between about: 50 to 4000 ng / ml; 100 to 3000 ng / ml; 250 to 1600 ng / ml; 500 to 1400 ng / ml, 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml, 1500 to 2000 ng / ml, 2000 to 2500 ng / ml; 2500 to 3000 ng / ml; 3000 to 3500 ng / ml; or, 3500 to 4000 ng / ml; the therapeutic level range of plasma concentration for formula I, is between about: 5 to 4000 ng / ml, 10 to 1000 ng / ml, 10 to 500 ng / ml, 25 to 500 ng / ml, 25 to 250 ng / ml, 50 to 500 ng / ml, 50 to 1000 ng / ml, 50 to 500 ng / ml, 100 to 1000 ng / ml, 100 to500 ng / ml, 200 to 1000 ng / ml, 500 to 1000 ng / ml, 1000 to 2000 ng / ml, 2000 to 3000 ng / ml, or 3000 to 4000 ng / ml, the therapeutic level range of plasma concentration for tesofensine is between about: 2 ng to 50 ng / ml, 5 to 20 ng / ml, 6.5 to 15 ng / ml, 8 to 12 ng / ml, or about 10 ng / ml, or the therapeutic level range of plasma concentration for diazoxide is between about: 10 ng / ml to 100 ng / ml, 20 to 80 ng / ml, 30 to 50 ng / ml, or about 40 ng / ml.

14. The method of any of claims 10 to 13, wherein the drug, therapeutic combination, or pharmaceutical dosage form, or active agent or agents, is or are administered to achieve a therapeutic level range of plasma concentration (optionally human plasma concentration) at a steady state, and wherein:(a) the therapeutic level range of plasma concentration for use of the Formula I is between about: 250 to 1600 ng / ml; 500 to 1400 ng / ml, 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml, 1500 to 2000 ng / ml, 2000 to 2500 ng / ml; or 2500 to 3000 ng / ml;(b) the therapeutic level range of plasma concentration for use of the Formula I is between about: 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml, 1500 to 2000 ng / ml, or 2000 to 2500 ng / ml; or(c) the therapeutic level range of plasma concentration for use of Formula I, is between about: 600 to 1300 ng / ml, 800 to 1250 ng / ml, 1000 ng / ml to 1250 ng / ml, 1250 to 1500 ng / ml.

15. The method of claim 14, wherein the steady state is achieved after:(a) between about 3 to 5 times the elimination half-life (Tl / 2) of the drug, therapeutic combination, or pharmaceutical dosage form in a subject or a patient, or(b) between about 7 to 14 days after periodic or regular administration to a optionally once-a-day dosing of the drug, or therapeutic combination, pharmaceutical dosage form.

16. The method of claim 10 to 15, wherein the plasma concentration for the drug, or therapeutic combination, pharmaceutical dosage form is:(a) the trough level or trough concentration (Ctrough), or the lowest concentration reached by the drug, or therapeutic combination or pharmaceutical dosage form before a second or next dose is administered, or(b) determined from blood samples taken between about 2 hours to 24 hours, or 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more hours, after the last dose or administration of the drug, or therapeutic combination, pharmaceutical dosage form.

17. The method of any of claims 1 to 16, or a method of any of the preceding claims, wherein each drug, or therapeutic combination, pharmaceutical dosage form or active agent or agents of the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture is delivered to the individual simultaneously, or separately, wherein optionally one or each or several drug or active agent of the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture is administered in a chronodosed regimen.

18. Use of: a therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of any of the preceding claims, or a therapeutic combination or pharmaceutical dosage form of claim 9, or a drug delivery device or product of manufacture of claim 10, for treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing, a disease or condition comprising or associated with: hyperphagia in PWS (optionally as assessed by HQ-CT), moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity, optionally further comprising management of weight loss and maintenance of weight loss, or optionally furthercomprising as an adjunct to a reduced-calorie diet or for increased physical activity for chronic weight management, early onset morbid obesity, non- Alcoholic Steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH) non-alcoholic fatty liver disease (NAFLD), type II diabetes, hypothalamic injury-induced obesity, obsessive-compulsive disorder (OCD), disruptive mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), irritability in autism, irritability in autistic spectrum disorder, excoriation, trichotillomania, intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders-Third Edition (ICSD-3), narcolepsy with cataplexy, narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy,cataplexy, idiopathic hypersomnia, rapid eye movement (REM) sleep behavior disorder, major depressive disorder (MDD), treatment resistant depression (TRD), negative symptoms of schizophrenia,MDD Associated with Parkinson’s Disease,Parkinson’s Disease, general anxiety,Social Anxiety Disorder (Social Phobia),Fibromyalgia (FM), diabetic neuropathy. lower back pain, chronic fatigue syndrome, cognitive inflexibility cocaine addiction, amphetamines addiction, opioids addiction, alcohol addiction, nicotine addiction attention deficit hyperactivity disorder (ADHD), autism,Asperger spectrum, a genetically confirmed disease or syndrome, wherein optionally the genetically confirmed disease or syndrome is or comprises Prader-Willi Syndrome, Bardet Biedl Syndrome, Smith- Magenis Syndrome, lp36 deletion syndrome, 16pl 1.2 deletion Syndrome, fragile X syndrome, proopiomelanocortin (POMC)deficiency obesity, leptin receptor (LEPR) deficiency obesity, Melanocortin 4 Receptor (MC4R) Pathway Heterozygous Obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman’s Syndrome, Schaff-Yang Syndrome, Albright Hereditary Osteodystroph, Silver-Russell Syndrome, Maternal Disomy 14, Alstrbm Syndrome, Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation or WAGR or WAGRO Syndrome; Dravet Syndrome, Lennox-Gastaut syndrome, Gillespie syndrome or cerebellar ataxia, or Doose Syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick type C disease, or Norrie disease, or Coffin-Lowry disease, wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural orthostatic tachycardia syndrome.

19. A therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture for use in treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing, a disease or a condition comprising or associated with: hyperphagia in PWS (optionally as assessed by HQ-CT), moderate to severe binge eating disorder (BED), bulimia nervosa, management of obesity, optionally further comprising management of weight loss and maintenance of weight loss, or optionally further comprising as an adjunct to a reduced-calorie diet or for increased physical activity for chronic weight management, early onset morbid obesity, non- Alcoholic Steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH) non-alcoholic fatty liver disease (NAFLD), type II diabetes,hypothalamic injury-induced obesity, obsessive-compulsive disorder (OCD), disruptive mood dysregulation disorder (DMDD), oppositional defiant disorder (ODD), irritability in autism, irritability in autistic spectrum disorder, excoriation, trichotillomania, intermittent explosive disorder (IED), excessive daytime sleepiness (EDS), excessive daytime sleepiness associated with narcolepsy and sleep apnea, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with central or obstructive sleep apnea, narcolepsy, narcolepsy type 1 (NT1) according to the International Classification of Sleep Disorders-Third Edition (ICSD-3), narcolepsy with cataplexy, narcolepsy type 2 (NT2) according to ICSD-3, narcolepsy without cataplexy, cataplexy, idiopathic hypersomnia, rapid eye movement (REM) sleep behavior disorder, major depressive disorder (MDD), treatment resistant depression (TRD), negative symptoms of schizophrenia,MDD Associated with Parkinson’s Disease,Parkinson’s Disease, general anxiety,Social Anxiety Disorder (Social Phobia),Fibromyalgia (FM), diabetic neuropathy. lower back pain, chronic fatigue syndrome, cognitive inflexibility cocaine addiction, amphetamines addiction, opioids addiction, alcohol addiction, nicotine addiction attention deficit hyperactivity disorder (ADHD), autism,Asperger spectrum, a genetically confirmed disease or syndrome, wherein optionally the genetically confirmed disease or syndrome is or comprises Prader-Willi Syndrome, Bardet Biedl Syndrome, Smith- Magenis Syndrome, lp36 deletion syndrome, 16pl 1.2 deletion Syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficiency obesity, leptin receptor (LEPR) deficiency obesity, Melanocortin 4 Receptor (MC4R) Pathway Heterozygous Obesity, trisomy 21, Rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disorder, Angelman’s Syndrome, Schaff-Yang Syndrome, Albright Hereditary Osteodystroph, Silver-Russell Syndrome, Maternal Disomy 14, Alstrbm Syndrome, Wilms' Tumor, Aniridia, Genitourinary Anomalies, Mental Retardation or WAGR or WAGRO Syndrome; Dravet Syndrome, Lennox-Gastaut syndrome,Gillespie syndrome or cerebellar ataxia, or Doose Syndrome or myoclonic atonic epilepsy (MAE), or Niemann-Pick type C disease, or Norrie disease, or Coffin-Lowry disease, wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural orthostatic tachycardia syndrome, and the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture comprises or has contained therein: a therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture of any of the preceding claims, or a therapeutic combination or pharmaceutical dosage form of claim 9, or a drug delivery device or product of manufacture of claim 10.

20. A method for administering a therapeutic combination or pharmaceutical dosage form of claim 8, or a drug delivery device or product of manufacture of claim 9, wherein the dosaging is determined by a method comprising:(a) an empirical method for safe and predictable titration and to determine the initial therapeutic dose, or to determine the lowest therapeutic dose, or to determine an optimal effective dose; the method comprising:

1. administrating a test dose (for example, a no adverse events observed dose amount or a minimal adverse events observed dose amount or a safe dose amount) daily until a patient achieves a steady state plasma drug concentration,2. prior to the next scheduled dose, drawing a blood sample and assessing the test plasma drug concentration,3. calculating the initial therapeutic dose / day by:A. for drugs with a linear dose to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, and then multiply the dividend by the test dose amount, andB. for drugs with a non-linear dose to plasma concentration, divide the initial target therapeutic plasma drug concentration by the test plasma drug concentration, then multiply the dividend by the test dose amount and then multiply the product by a non-linear index factor, optionally, the initial target therapeutic plasma drug concentration is the concentration corresponding to: (i) certain pharmacodynamic efficacy marker levels, such as occupancy of serotonin transporter (SERT or 5- HTT), dopamine transporter (DAT) or norepinephrine transporter (NET) determined by imaging method such as positron emission tomography (PET); or, (ii) the lowest effective therapeutic dose determined by a clinical study.

4. optionally comprising: i. administrating the initial therapeutic dose, daily, until a patient achieves a steady state plasma drug concentration, ii. prior to the next scheduled dose, drawing a blood sample and assessing the current therapeutic plasma drug concentration, iii. Calculating the next therapeutic target dose / day by:A. For drugs with a linear dose to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount, andB. For drugs with a non-linear dose to plasma concentration, divide next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration, then multiply the dividend by the current therapeutic dose amount and then multiply the product by a non-linear index factor, and iv. continuing the process until the lowest therapeutic dose or optimal effective dose is achieved; or(b)a model-based method for safe and predictable titration, and to determine the initial therapeutic dose and to determine the lowest therapeutic dose, or to determine an optimal effective dose, and method comprising:

1. Administrating a test dose amount daily for between about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day,2. Drawing a first blood sample at between about 1 hour to 3 days, 6 hours to 2 days or about 1 day after administering the first test dose,3. Drawing a second or subsequent blood samples at between about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or at about 2 days, after drawing of the first blood samples or subsequent blood samples,4. calculating the initial therapeutic starting dose / day by: i. using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose(s), the plasma concentration of the blood samples and the time the draws of the blood samples and a pharmacometric model, ii. and optionally, using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose(s), the plasma concentration of the blood samples, the time of the draws of the blood samples, human PK data and a Bayesian pharmacometric model, iii. and optionally, using the initial target therapeutic plasma drug concentration, the test dose amount, the time at the administration of the test dose, the plasma concentration of the blood samples, the time of the draws of the blood samples, human PK data, a patient's genetic information, a patient's non-heritable host factors, a patient’s other medications, and a Bayesian pharmacometric model,5. and optionally comprising: i. administrating the initial therapeutic starting dose, daily until a patient achieves a steady state plasma drug concentration,ii. Prior to the next scheduled dose, drawing a blood sample and assessing the current therapeutic plasma drug concentration, iii. calculating the next therapeutic target dose / day:A. For drugs with a linear dose to plasma concentration, divide the next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount, andB. For drugs with a non-linear dose to plasma concentration, divide he next target therapeutic plasma drug concentration by the current therapeutic plasma drug concentration and then multiply the dividend by the current therapeutic dose amount and then multiply the product by a non-linear index factor, and iv. Continuing the process until the lowest therapeutic dose or optimal effective dose is achieved.

21. The method of claim 21, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device or product of manufacture comprises Formula I, or a deuterated derivative of Formula I.

22. A method for treating or ameliorating, or decreasing the symptoms of: depression, treatment-resistant depression, hyperphagia (optionally hyperphagia associated with Prader-Willi Syndrome), binge eating disorder, and a substance addiction (wherein the substance addiction comprises addiction to cocaine, an amphetamine, an opioid, alcohol or nicotine), comprising administering to an individual in need thereof a therapeutic combination or pharmaceutical dosage form of claim 9, or a drug delivery device or product of manufacture of claim 10. wherein optionally the pharmaceutical composition, drug or formulation is formulated and administered for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

23. A method for treating or ameliorating, or decreasing the symptoms of: depression, treatment-resistant depression, hyperphagia (optionally hyperphagia associated with Prader-Willi Syndrome), binge eating disorder, and a substance addiction (wherein the substance addiction comprises addiction to cocaine, an amphetamine, an opioid, alcohol or nicotine), with a dosage form of a therapeutic combination or pharmaceutical dosage form of claim 9, and the method comprises administering an oral dosage form that provides trough plasma concentration, a 24- hour time-averaged plasma concentration, or a daytime 12-hour time-averaged plasma concentration between 250 ng / mL to 500 ng / ml, 500 to 1000 ng / ml, 1000 to 1500 ng / ml, 1500 to 2000 ng / ml, or 1500 to 2500 ng / ml of a therapeutic combination or pharmaceutical dosage form of claim 9, when administered once daily, or twice daily, and measured at about one week, about two weeks, or steady state, wherein optionally the dosage form is formulated and administered for parenteral administration, optionally formulated for administration orally, intrathecally, intracerebrally or epidurally (optionally into an intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially.

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