33537 Inhibitory effects of ME3183, a novel phosphodiesterase-4 inhibitor, on stimulants-induced production of proinflammatory cytokines and chemokines in whole blood cell cultures of patients with plaque psoriasis

Kaji, Chizuko; Suzuki, Kenji; Kano, Akiko

doi:10.1016/j.jaad.2022.06.321

Cited by 2 publications

(6 citation statements)

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“…In the MAD part, 2.5 mg twice‐daily administration was the minimal dosage of ME3183, giving C min = 10.3 ng/mL in plasma at steady state. This value was above the IC 50 (13 nM = 5.5 ng/mL) that was determined as the potency of the drug to inhibit TNF‐α production in the human whole‐blood assay 7 . Plasma levels of apremilast were found to be above the human whole‐blood TNF IC 50 value identified in the nonclinical studies when patients with psoriasis were dosed with 20 mg of apremilast, suggesting that when the plasma levels of a PDE4 inhibitor exceed the IC 50 value for TNF‐α production in the human whole‐blood assay, it is believed to show efficacy in patients with psoriasis 14 .…”

Section: Discussionmentioning

confidence: 85%

“…This value was above the IC 50 (13 nM = 5.5 ng/mL) that was determined as the potency of the drug to inhibit TNF-α production in the human whole-blood assay. 7 Plasma levels of apremilast were found to be above the human wholeblood TNF IC 50 value identified in the nonclinical studies when patients with psoriasis were dosed with 20 mg of apremilast, suggesting that when the plasma levels of a PDE4 inhibitor exceed the IC 50 value for TNF-α production in the human whole-blood assay, it is believed to show efficacy in patients with psoriasis. 14 Therefore, 2.5 mg twice-daily administration of ME3183, the lowest dose used in the MAD part, may demonstrate efficacy in patients with psoriasis.…”

Section: Estimated Clinical Effective Dosementioning

confidence: 90%

“…The molecular formula of ME3183 (1‐((2‐(3,6‐diazabicyclo[3.1.1]heptan‐3‐yl)‐7‐(thiazol‐2‐yl)benzo[d]oxazol‐4‐yl)oxy)‐1,1‐difluoro‐2‐methylpropan‐2‐ol; structure shown in Figure 1) is C 19 H 20 F 2 N 4 O 3 S (molecular weight = 422.5 g/mol). The compound strongly inhibits stimulant‐induced production of psoriasis‐related cytokines such as TNF‐α and interleukin‐17A in human blood cells, compared to other PDE4 inhibitors 7 . Nonclinical data have shown that ME3183 is notably stable in human hepatocytes and liver microsomes.…”

Section: Figurementioning

confidence: 97%

“…The molecular formula of ME3183 ( 1 The compound strongly inhibits stimulant-induced production of psoriasis-related cytokines such as TNF-α and interleukin-17A in human blood cells, compared to other PDE4 inhibitors. 7 Nonclinical data have shown that ME3183 is notably stable in human hepatocytes and liver microsomes. After oral administration of radio-labeled ME3183 to rats, the excretion ratios of the radioactivity into urine and feces were <5% and >90% of the dose, respectively, suggesting that the primary route of elimination for ME3183 would be through biliary excretion (unpublished in-house data, Meiji Seika Pharma Co., Ltd.).…”

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confidence: 99%

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Safety, Tolerability, and Pharmacokinetics of a Novel Oral Phosphodiesterase 4 Inhibitor, ME3183: First‐in‐Human Phase 1 Study

Kato,

Cho,

Koresawa

et al. 2023

Clinical Pharm in Drug Dev

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A novel, oral phosphodiesterase 4 (PDE4) inhibitor, ME3183, is under development for the treatment of psoriasis, atopic dermatitis, and other inflammatory diseases. To evaluate its safety, tolerability, and pharmacokinetics, double‐blind, placebo‐controlled, single ascending dose (SAD), and multiple ascending dose (MAD) phase 1 studies were conducted in 126 healthy adults. The food effect was evaluated in a randomized, open‐label, crossover manner (n = 5). ME3183 was safe and tolerable up to 25 mg in the SAD part and up to 10 mg twice daily in the MAD part. Frequently observed treatment‐emergent adverse events included diarrhea and headache, as commonly reported for approved PDE4 inhibitors, providing no novel safety concerns. Pharmacokinetic analysis showed dose‐dependent increases in Cmax and AUC, with later tmax and longer t1/2 than apremilast, an approved PDE4 inhibitor. The food effect study showed slightly decreased systemic exposure. In the MAD part, plasma exposure levels of ME3183 were higher even at the minimal dose (2.5 mg twice daily) than the estimated therapeutically effective level. These results show the safe profile of ME3183 and support further studies to confirm the safety and efficacy of the drug in patients with psoriasis and other inflammatory diseases.

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Section: Discussionmentioning

confidence: 85%

Section: Estimated Clinical Effective Dosementioning

confidence: 90%

Section: Figurementioning

confidence: 97%

mentioning

confidence: 99%

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Safety, Tolerability, and Pharmacokinetics of a Novel Oral Phosphodiesterase 4 Inhibitor, ME3183: First‐in‐Human Phase 1 Study

Kato,

Cho,

Koresawa

et al. 2023

Clinical Pharm in Drug Dev

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“…ME3183 is an orally available selective PDE4 inhibitor developed by Meiji Seika Pharma Co. Ltd., Osaka, Japan [ 57 , 58 ]. In preclinical studies, ME3183 was 5- to 40-fold more potent than apremilast in inhibiting inflammatory cytokine production, specifically IL-10, TNF, and interferon (IFN)-γ [ 57 ].…”

Section: Phosphodiesterase-4 Inhibitorsmentioning

confidence: 99%

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

Drakos,

Torres,

Vender

2024

Pharmaceutics

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The introduction of biologic agents for the treatment of psoriasis has revolutionized the current treatment landscape, targeting cytokines in the interleukin (IL)-23/IL-17 pathway and demonstrating strong efficacy and safety profiles in clinical trials. These agents however are costly, are associated with a risk of immunogenicity, and require administration by intravenous or subcutaneous injection, limiting their use among patients. Oral therapies, specifically small molecule and microbiome therapeutics, have the potential to be more convenient and cost-effective agents for patients and have been a focus of development in recent years, with few targeted oral medications available for the disease. In this manuscript, we review pipeline oral therapies for psoriasis identified through a search of ClinicalTrials.gov (30 June 2022–1 October 2023). Available preclinical and clinical trial data on each therapeutic agent are discussed. Small molecules under development include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early phase studies. As new oral therapies emerge for the treatment of psoriasis, real-world data and comparative trials are needed to better inform their use among patients.

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33537 Inhibitory effects of ME3183, a novel phosphodiesterase-4 inhibitor, on stimulants-induced production of proinflammatory cytokines and chemokines in whole blood cell cultures of patients with plaque psoriasis

Cited by 2 publications

References 0 publications

Safety, Tolerability, and Pharmacokinetics of a Novel Oral Phosphodiesterase 4 Inhibitor, ME3183: First‐in‐Human Phase 1 Study

Safety, Tolerability, and Pharmacokinetics of a Novel Oral Phosphodiesterase 4 Inhibitor, ME3183: First‐in‐Human Phase 1 Study

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

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