Transdermal administration of PDE4 inhibitors for reduction in adverse events

Abstract

The present disclosure relates to a method of reducing adverse events due to systemic administration of a PDE4 inhibitor to a patient. The method comprises transdermally administering to the patient a PDE4 inhibitor, for example, over at least about 12 hours.

Description

TRANSDERMAL ADMINISTRATION OF PDE4 INHIBITORS FOR REDUCTION INADVERSE EVENTS

[0001] The application claims the benefit of U.S. Provisional Application No. 63 / 634,844, filed April 16, 2024, and U.S. Provisional Application No. 63 / 650,845, filed May 22, 2024, each of which is hereby incorporated by reference.FIELD OF THE INVENTION

[0002] The present invention relates to a method of a patient in need of systemic administration of a PDE4 inhibitor while minimizing adverse events. The method comprises transdermally administering to the patient a PDE4 inhibitor, for example, over at least about 12 hours.BACKGROUND OF THE INVENTION

[0003] PDE4 inhibitors have well-known class-related dose-limiting side effects of nausea and vomiting. Robichaud et al., Neuropharmacology, 1999, 38:289-297; Robichaud et al., Br J Pharmacol., 2002, 135: 113-118; Mori et al., J Chem Neuroanatomy, 2010, 40:36-42; Robichaud et al., Neuropharmacology, 2001, 40:262-269. It has been hypothesized that the nausea and vomiting are, at least in part, due to direct stimulation of emetic centers in the brain. Mori, supra.

[0004] There is therefore a continuing need for improved treatments that reduce adverse events due to systemic administration of a PDE4 inhibitor. The present invention addresses such needs.SUMMARY OF THE INVENTION

[0005] The present inventors have surprisingly found that adverse events due to systemic (e.g., oral) administration of a PDE4 inhibitor to patient can be reduced by transdermally administering the PDE4 inhibitor to the patient.

[0006] Accordingly, in one aspect, the invention relates to a method of treating a patient in need of systemic administration of a PDE4 inhibitor while minimizing adverse events. The method comprises transdermally administering to the patient the PDE4 inhibitor, such as over at least 12 hours.

[0007] In another aspect, the present invention relates to a method of reducing adverse events due to systemic administration of a PDE4 inhibitor to a patient, the method comprising transdermally administering to the patient a PDE4 inhibitor.

[0008] In one embodiment, the method comprises transdermally administering to the patient a PDE4 inhibitor, for example, over at least about 12 hours.

[0009] In one embodiment of any of the methods described herein, the adverse event is nausea, dizziness, vomiting, diarrhea, a gastrointestinal disorder, neuralgia, abdominal pain, dyspepsia, or any combination thereof.

[0010] In one embodiment of any of the methods described herein, the adverse event is nausea, dizziness, vomiting, diarrhea, or any combination thereof.

[0011] In one embodiment of any of the methods described herein, the PDE4 inhibitor is administered via a transdermal patch. In one embodiment of any of the methods described herein, the PDE4 inhibitor is administered via applying a transdermal patch to the skin of the patient. In one embodiment of any of the methods described herein, the patch is replaced once a day or twice a day. In one embodiment of any of the methods described herein, the patch is replaced once a day. In another embodiment of any of the methods described herein, the patch is replaced onceevery two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0012] In one embodiment of any of the methods described herein, the PDE4 inhibitor is selected from tilivapram, zatolmilast, roflumilast, apremilast, nerandomilast, crisaborole, rolipram, cilomilast, ibudilast, piclamilast, and pharmaceutically acceptable salts of any of the foregoing.

[0013] In one embodiment of any of the methods described herein, the PDE4 inhibitor is a PDE4B inhibitor.

[0014] In one embodiment of any of the methods described herein, the PDE4 inhibitor is a PDE4D inhibitor, such as zatolmilast.

[0015] In one embodiment of any of the methods described herein, the PDE4 inhibitor crosses the blood-brain barrier.

[0016] In one embodiment of any of the methods described herein, the PDE4 inhibitor is selected from tilivapram, zatolmilast, roflumilast, and pharmaceutically acceptable salts of any of the foregoing.

[0017] In one embodiment of any of the methods described herein, the PDE4 inhibitor is nerandomilast or a pharmaceutically acceptable salt thereof.

[0018] In one embodiment, any of the methods described herein may be used to treat a patient suffering from any disease or disorder for which administration of a PDE4 inhibitor may be effective.

[0019] In one embodiment, the PDE4 inhibitor is administered to treat a disorder selected from, but not limited to, Parkinson's disease, cognitive impairment associated with Parkinson's disease, anxiety disorders, Huntington’s disease, memory impairment associated with Parkinson'sdisease, or information processing speed and / or psychomotor speed impairment associated with Parkinson’s disease, schizophrenia, cognitive impairment associated with schizophrenia, memory impairment associated with schizophrenia, information processing speed and / or psychomotor speed impairment associated with schizophrenia, mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD), multiple sclerosis, allergic encephalomyelitis, amyotrophic lateral sclerosis (ALS), migraine, glioblastoma, depression, cerebrovascular disorder, developmental delay, learning disabilities, bipolar disorder, post-traumatic stress disorder (PTSD), autism, Fragile X disorder, cognitive impairment associated with Fragile X disorder, idiopathic pulmonary fibrosis (IPF), substance dependence, Angelman’s syndrome, cognitive impairment, Alzheimer's disease (AD), frontotemporal dementia, vascular dementia, dementia with Lewy bodies (DLB), asthma, chronic obstructive pulmonary disease (COPD), psoriasis, eczema, rosacea, psoriatic arthritis, palmoplantar pustulosis, nummular eczema, pruritus, rheumatoid arthritis, lupus (such as systematic lupus erythematosus, SLE), Crohn’s disease, SARS-COV-2 (COVID), long- COVID, diabetes (e.g., type I diabetes and type II diabetes), obesity, antipsychotic medication- induced weight gain, insulin resistance, metabolic syndrome, hypertension, atopic dermatitis, plaque psoriasis, oral ulcers associated with Behcet disease, spinal muscular atrophy (SMA) and other muscle wasting, Duchenne's muscular dystrophy (DMD) and other muscular dystrophies, Friedreich's ataxia (FA) and other ataxias, diabetic nephropathy, chronic kidney disease (CKD), and substance use disorders (such as due to alcohol, opiate, stimulant, cannabis, cocaine, methamphetamine, sedative, hypnotic, or hallucinogen).

[0020] In one embodiment, the PDE4 inhibitor is administered to treat a non- neuropsychiatric disorder (i.e., the PDE4 inhibitor is not administered to treat a neuropsychiatric disorder).

[0021] For example, in one embodiment, the PDE4 inhibitor is not administered to treat Parkinson's disease or schizophrenia, cognitive impairment associated with Parkinson's disease or schizophrenia, memory impairment associated with Parkinson's disease or schizophrenia, or information processing speed and / or psychomotor speed impairment associated with Parkinson’sdisease or schizophrenia, mild cognitive impairment (MCI), or attention deficit hyperactivity disorder (ADHD).BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figures 1A (linear scale) and IB (semi-log scale) show the mean plasma concentration of tilivapram versus time after administration with an oral solution or transdermal patch as described in Example 1.

[0023] Figures 2A (linear scale) and 2B (semi-log scale) show the mean plasma concentration of tilivapram versus time for the 24 hours relevant to that dosing period (i.e. 0-24 hours for P1D1 and P2D1 and 24-48hr for P2D2) after administration with an oral solution or transdermal patch as described in Example 1.DETAILED DESCRIPTION OF THE INVENTION

[0024] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.

[0025] Unless specifically stated or obvious from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural.

[0026] Ranges provided herein are understood to be shorthand for all of the values within the range.

[0027] 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 can be understood as within 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 context, all numerical values provided herein can be modified by the term about.

[0028] The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel character! stic(s)” of the claimed invention.

[0029] Unless indicated otherwise, the term “tilivapram” (AVE8112) refers to 4- (cyclopropylmethoxy)-N-(3,5-dichloro-l-oxidopyridin-4-yl)-5-methoxypyridine-2-carboxamide (otherwise referred to as 4-(cyclopropylmethoxy)-N-(3,5-dichloro-l-oxido-4-pyridyl)-5- methoxypyridine-2-carboxamide), which has the structure:

[0030] Tilivapram and pharmaceutically acceptable salts thereof can be prepared as described in U.S. Patent No. 9,611,250 and International Publication No. WO 95 / 04045, each of which is incorporated by reference in its entirety.

[0031] The term “zatolmilast” (BPN14770) refers to 2-(4-((2-(3-chlorophenyl)-6- (trifluoromethyl)pyridin-4-yl)methyl)phenyl)- 1 -(11 -oxidaneyl)ethan- 1 -one (or 2-[4-[[2-(3 - chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl]methyl]phenyl]acetic acid), which has the structureshown below and is described in U.S. Patent No. 10,093,686 (see Example 142), which is hereby incorporated by reference.

[0032] Roflumilast has the chemical name N-(3,5-dichloropyridin-4-yl)-3- cyclopropylmethoxy-4-difluoromethoxy-benzamide. The roflumilast can be in the form of roflumilast free base, an N-oxide of roflumilast, or a pharmaceutically acceptable salt thereof. Exemplary salts of roflumilast are salt described in U.S. Patent Publication No. 2006 / 0084684, the entire disclosure of which is incorporated herein by reference.

[0033] Pharmaceutically acceptable salts include, but are not limited to, those derived from the following acids as well as acid addition salts: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. The corresponding acid addition salts comprise the following: hydrohalides, such as hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfamate and quinate, respectively.

[0034] The terms "treat," "treatment," and "treating" in the context of the administration of a therapy to a patient refers to the reduction or inhibition of the progression and / or duration of a disease or condition, the reduction or amelioration of the severity of a disease or condition, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. PDE4 inhibitors have shown activity for treating obesity and diabetes (Gyldenlove et al., J Am Acad Dermatol., 2024 Mar 1 : SO 190-9622(24)00426-2; Wouters et al., J Clin Endocrinol Metab, September 2012, 97(9):E1720-E1725; Jensterle et al., J Ovarian Res., 2015, 8:32; Lugnier, Int J Mol Sci., 2022, 23 (18): 10616, PMID 36142518), hypertension (Fan et al., Communications Biology, 2022, 5:81), muscular atrophy (Arcaro et al., Life Sciences, 2021, 278: 119563; Hinkle et al., Muscle Nerve, 2005, 32(6):775-81), Friedreich's ataxia (FA) (Molla et al., Neur other apeutics, 2019, 16(2):432-449), diabetic nephropathy (Ookawara et al., Cell Signal,2022, 90: 110185, PMID 34785349), chronic kidney disease (CKD) (Tao et al., Cell Death Dis.,2023, 14(4):273, PMID 37072403), substance use disorders (Grodin et al., Transl. Psychiatry, 2021, 11 :355; Hatoum et al., Nat Ment Health, 2023, l(3):210-223), as well as improving cognition in patients with Fragile X disorder (Berry-Kravis et al., Nat Med., 2021, 27(5):862-870, PMID 33927413). PDE4 inhibitors have also shown the ability to enhance sensory processing in patients with schizophrenia (L. Scott etal., Abstract A22, Br. Assoc. Psychopharmacology, 30(8), Aug. 2016).

[0035] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, delay, inhibition, suppression, or reduction of a symptom or symptoms of a disease or disorder, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). An “effective amount” of a drug can be an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g.,preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pi ckar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose may also be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner.

[0036] As used herein, the terms "subject," “participant,” and "patient" are used interchangeably and refer to a human patient unless indicated otherwise.

[0037] The term “transdermal administration” refers to a route of administration in which the pharmaceutical dosage form is taken up through the skin. Similarly, a “transdermal delivery device” is intended to mean any apparatus or system that administers a drug to be taken up through the skin.

[0038] Transdermal delivery devices are known in the art. Thus, any device suitable for delivery of drug across the skin of a patient may be used. Devices known in the art include reservoir type devices involving membranes that control the rate of drug release to the skin and devices where the drug is dispersed or dissolved in a matrix such as a pressure sensitive adhesive. Transdermal delivery devices may be made in the form of an article such as a tape, a patch, a sheet,a dressing or any other form known in the art. Generally, the device may in the form of a patch of a size suitable to deliver a preselected amount of drug through the skin. In one embodiment, the device has a surface area of about 5 cm2to about 100 cm2, such as about 10 cm2to about 40 cm2.

[0039] Transdermal drug delivery devices typically involve a carrier (such as a liquid, gel, or solid matrix, or a pressure sensitive adhesive) into which the PDE4 inhibitor (such as, e.g., tilivapram, zatolmilast, rofhimilast, or a pharmaceutically acceptable salt of any of the foregoing) is incorporated. In one embodiment, transdermal administration is by a sustained release or extended release transdermal formulation and / or device. In some embodiments, sustained release transdermal administration of the PDE4 inhibitor includes multi-day delivery of a therapeutically effective amount of the PDE4 inhibitor that is applied to the skin of a subject. By multi-day delivery is meant that the transdermal composition is formulated to provide a therapeutically effective amount to a subject when the transdermal delivery device is applied to the skin of a subject for a period of time that is 1 day or longer, such as 2 days or longer, such as 4 days or longer, such as 7 days or longer, such as 14 days and including 30 days or longer. In certain embodiments, transdermal delivery devices provide a therapeutically effective amount of the PDE4 inhibitor to a subject for a period of 10 days or longer. For multi-day delivery, an upper limit period of time is, in some instances, 30 days or shorter, such as 28 days or shorter, such as 21 days or shorter, such as 14 days or shorter, such as 7 days or shorter and including 3 days or shorter. In certain embodiments, multi-day transdermal delivery ranges such as from 2 days to 30 days, such as from 3 days to 28 days, such as from 4 days to 21 days, such as from 5 days to 14 days and including from 6 days to 10 days.

[0040] Methods for making formulations suitable for transdermal administration are known in the art, such as in, for example, Remington: The Science and Practice of Pharmacy, 23rdEd. (Academic Press), 2020.

[0041] Suitable doses of tilivapram or a pharmaceutically acceptable salt thereof for transdermal administration include from about 0.01 to about 50 mg / kg body weight per day, suchas about 0.1 to about 40 mg / kg body weight per day or about 0.5 to about 10 mg / kg body weight per day. In one embodiment, about 1 mg to about 700 mg of tilivapram or a pharmaceutically acceptable salt thereof is transdermally administered daily.

[0042] Suitable doses of zatolmilast or a pharmaceutically acceptable salt thereof for transdermal administration include from about 0.01 to about 100 mg / kg body weight per day, such as about 0.1 to about 70 mg / kg body weight per day or about 0.5 to about 10 mg / kg body weight per day. In one embodiment, about 10 to about 700 mg of zatolmilast or a pharmaceutically acceptable salt thereof are transdermally administered daily.

[0043] Suitable doses of roflumilast or a pharmaceutically acceptable salt thereof for transdermal administration include from about 0.01 to about 100 mg / kg body weight per day, such as about 0.1 to about 70 mg / kg body weight per day or about 0.5 to about 10 mg / kg body weight per day. In one embodiment, about 0.5 to about 700 mg (e.g., about 1 to about 10 mg or about 1 to about 5 mg) of roflumilast or a pharmaceutically acceptable salt thereof are transdermally administered daily.

[0044] PDE4 inhibitors have well-known class-related dose-limiting side effects of nausea and vomiting at higher doses. This is thought to be due to its action in the brainstem at the area postrema (also known as the chemoreceptor trigger zone). In an immediate release formulation, the maximum drug dose is achieved at Cmax (the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given). In contrast, the effective dose of a drug relates more so to the AUC (area under the curve), and more meaningfully to the time over which a pharmacodynamic and therapeutically relevant blood level of the drug is achieved. As such, in the service of maximizing the time of exposure to the pharmacodynamic and therapeutically relevant blood level, giving a patient a higher dose of the drug will end up also achieving a higher Cmax, and thereby a higher likelihood of dose-related nausea / vomiting and related adverse events such as dizziness or lightheadedness. By giving the drug transdermally, the time at thepharmacodynamic and therapeutically relevant blood level can be maximized while simultaneously minimizing Cmax, and thereby diminishing dose-limiting side effects.

[0045] Transdermal patches for long term use (such as weekly, biweekly, or monthly use) can also provide improved patient compliance and consistent and continuous treatment. An immediate release dosage form would have to be administered at a significantly greater frequency than that provided transdermally over a sustained period in order to achieve the same time during which a pharmacodynamically relevant concentration of the drug remains in the blood. Such an immediate release dosage form would also result in greater side effects (and possibly render the dosage form intolerable) due to the higher Cmax which is achieved and / or the frequency with which Cmax spikes are induced due to taking an individual oral immediate release dosage.

[0046] In one embodiment of any of the methods described herein, the rate of increase of the PDE4 inhibitor administered transdermally in the blood of the patient is less than that observed following oral administration of the PDE4 inhibitor, while maintaining a similar pharmacodynamic and therapeutically relevant blood level of the PDE4 inhibitor.

[0047] In one embodiment of any of the methods described herein, the concentration of the PDE4 inhibitor (such as, e.g., tilivapram, zatolmilast, roflumilast, or a pharmaceutically acceptable salt of any of the foregoing) at 2 hours after initiating administration with the PDE4 inhibitor for the first time is less than about 20%, such as less than about 15%, less than about 10%, or less than about 5% of Cmax for the first 24 hours (from the time administration is initiated). In one embodiment of any of the methods described herein, the concentration of the PDE4 inhibitor (such as, e.g., tilivapram, zatolmilast, roflumilast, or a pharmaceutically acceptable salt of any of the foregoing) at 2 hours after initiating administration with the PDE4 inhibitor for the first time is less than about 5% of Cmax for the first 24 hours (from the time administration is initiated). In one embodiment, after 1-4 hours from initiating administration with the drug for the first time, the plasma concentration of the PDE inhibitor rises at a zero order rate over the next 10 to 24 hours.

[0048] In one embodiment of any of the methods described herein, the PDE4 inhibitor is transdermally administered over at least about 12 hours, at least about 18 hours, at least about 20 hours, or at least about 24 hours.

[0049] In one embodiment of any of the methods described herein, the PDE4 inhibitor is transdermally administered with a transdermal delivery device (such as a patch) which is replaced daily, once every two days, once every three days, or once a week.

[0050] At steady state, the transdermal delivery device (even when replaced with a new device) provides low fluctuation and swing of the PDE4 inhibitor blood or plasma levels. In one embodiment, the fluctuation (for example, over a 24 hour period at steady state) is less than 100%, 90%, 80%, 70%, 60%, 50% or 40%. In another embodiment, the swing (for example, over a 24 hour period at steady state) is less than 120%, 110%, 100%, 90%, 80%, 70%, 60%, 50%, or 40%. Swing denotes (CmaX-Cmin) / Cmin and fluctuation denotes (Cmax-Cmin) / Caverage.

[0051] The transdermal drug delivery device, such as a transdermal patch, may remain on the patient for extended periods of time to provide continuous delivery of the PDE4 inhibitor. For instance, the patch may be work for 1 week or 2 weeks (e.g., a new patch may replace a currently worn patch once a week or biweekly).Example 1Clinical Study

[0052] A phase I, open-label, fixed period, 2-way cross-over study was performed to establish the pharmacokinetics and safety of a transdermal delivery system containing tilivapram. In Period 1 Day 1 (P1D1), participants were dosed with 1.5 mg of tilivapram in a liquid oral solution in a fasted state. After a 7-day washout period, participants were dosed with the first set of 4 patches applied by study staff on Period 2 Day 1 (P2D1), which were then removed after 24hours and 4 new patches applied for an additional 24 hours on Period 2 Day 2 (P2D2) for a total of 48 hours. All but one of the 15 subjects completed the study. One subject withdrew after receiving the oral solution.

[0053] The mean plasma concentration of tilivapram administered orally and transdermally versus time is shown in a linear scale in Figure 1A and a semi-log scale in Figure IB. The mean plasma concentration of tilivapram administered orally and transdermally versus time for the 24 hours relevant to that dosing period (i.e. 0-24 hours for P1D1 and P2D1 and 24- 48hr for P2D2) is shown in a linear scale in Figure 2A and a semi-log scale in Figure 2B.

[0054] The related adverse events resulting from the oral solution and transdermal patches are provided in the table below.

[0055] All publications, patents and patent applications cited herein are hereby incorporated by reference as if set forth in their entirety herein. While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications and combinations of illustrative embodiments,as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to the description. It is therefore intended that the appended claims encompass such modifications and enhancements.

Claims

CLAIMS1. A method of treating a patient in need of systemic administration of a PDE4 inhibitor while minimizing adverse events, the method comprising transdermally administering to the patient the PDE4 inhibitor, such as over at least 12 hours.

2. The method of claim 1, wherein the adverse event is nausea, dizziness, vomiting, or diarrhea.

3. The method of claim 1, wherein the rate of increase of the PDE4 inhibitor in the blood of the patient is less than that observed following oral administration of the PDE4 inhibitor, while maintaining a similar therapeutically relevant blood level of the PDE4 inhibitor.

4. The method of any one of the preceding claims, wherein on the first day of transdermally administering the PDE4 inhibitor, the concentration of the PDE4 inhibitor at 2- hours after initiating administration with the PDE4 inhibitor for the first time is less than 20% of Cmax for the first 24 hours (from the time administration is initiated).

5. The method of claim 4, wherein on the first day of transdermally administering the PDE4 inhibitor, the concentration of the PDE4 inhibitor at 2-hours after initiating administration with the PDE4 inhibitor for the first time is less than 10% of Cmax for the first 24 hours (from the time administration is initiated).

6. The method of claim 4, wherein on the first day of transdermally administering the PDE4 inhibitor, the concentration of the PDE4 inhibitor at 2-hours after initiating administration with the PDE4 inhibitor for the first time is less than 5% of Cmax for the first 24 hours (from the time administration is initiated).

7. The method of any one of the preceding claims, wherein after 1-4 hours from initiating administration with the PDE4 inhibitor for the first time, the plasma concentration of the PDE4 inhibitor rises at a zero order rate over the next 10 to 24 hours.

8. The method of any one of the preceding claims, wherein at steady state, the fluctuation (for example, over a 24 hour period at steady state) of the PDE4 inhibitor blood levels is less than 100%, 90%, 80%, 70%, 60%, 50% or 40%.

9. The method of any one of the preceding claims, wherein at steady state, the swing (for example, over a 24 hour period at steady state) of the PDE4 inhibitor blood levels is less than 120%, 110%, 100%, 90%, 80%, 70%, 60%, 50% or 40%.

10. The method of any one of the preceding claims, wherein the method comprises applying a transdermal patch to the skin of the patient.

11. The method of claim 10, wherein the patch is replaced once a day.

12. The method of any one of the preceding claims, wherein the PDE4 inhibitor is selected from tilivapram, zatolmilast, roflumilast, apremilast, nerandomilast, crisaborole, rolipram, cilomilast, ibudilast, piclamilast, and pharmaceutically acceptable salts of any of the foregoing.

13. The method of any one of claims 1-11, wherein the PDE4 inhibitor is a PDE4B inhibitor.

14. The method of any one of claims 1-11, wherein the PDE4 inhibitor is a PDE4D inhibitor.

15. The method of any one of the preceding claims, wherein the PDE4 inhibitor crosses the blood-brain barrier.

16. The method of any one of claims 1-15, wherein the PDE4 inhibitor is administered to treat Parkinson's disease, cognitive impairment associated with Parkinson's disease, anxiety disorders, Eluntington’s disease, memory impairment associated with Parkinson's disease, or information processing speed and / or psychomotor speed impairment associated with Parkinson’s disease, schizophrenia, cognitive impairment associated with schizophrenia, memory impairment associated with schizophrenia, information processing speed and / or psychomotor speed impairment associated with schizophrenia, mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD), multiple sclerosis, allergic encephalomyelitis, amyotrophic lateral sclerosis (ALS), migraine, glioblastoma, depression, cerebrovascular disorder, developmental delay, learning disabilities, cerebral metabolic inhibition, bipolar disorder, post-traumatic stress disorder (PTSD), autism, Fragile X disorder, cognitive impairment associated with Fragile X disorder, idiopathic pulmonary fibrosis (IPF), substance dependence, Angelman’s syndrome, cognitive impairment, Alzheimer's disease (AD), frontotemporal dementia, vascular dementia, dementia with Lewy bodies (DLB), asthma, chronic obstructive pulmonary disease (COPD), psoriasis, eczema, rosacea, psoriatic arthritis, palmoplantar pustulosis, nummular eczema, pruritus, rheumatoid arthritis, lupus, Crohn’s disease, SARS-COV-2 (COVID), long-COVID, diabetes (e g., type I diabetes and type II diabetes), obesity, antipsychotic medication-induced weight gain, insulin resistance, metabolic syndrome, hypertension, atopic dermatitis, plaque psoriasis, oral ulcers associated with Behcet disease, spinal muscular atrophy (SMA) and other muscle wasting, Duchenne's muscular dystrophy (DMD) and other muscular dystrophies, Friedreich's ataxia (FA) or other ataxias, diabetic nephropathy, chronic kidney disease (CKD), or a substance use disorder (such as due to alcohol, opiate, stimulant, cannabis, cocaine, methamphetamine, sedative, hypnotic, or hallucinogen).

17. The method of any one of claims 1-15, wherein the PDE4 inhibitor is administered to treat a non-neuropsychiatric disorder.

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