Peringatan Keamanan

During clinical trials, the highest single dose of ritlecitinib was 800 mg. No specific toxicities were identified at this dose, and the adverse reactions detected were comparable to those seen at lower doses. Pharmacokinetic studies indicate that in healthy adult volunteers given a single oral dose of 800 mg, more than 90% of ritlecitinib is expected to be eliminated within 48 hours. There is no specific antidote for overdose with ritlecitinib. In patients experiencing a ritlecitinib overdose, provide symptomatic and supportive treatment, and monitor for signs and symptoms of adverse reactions.L47092

In rats given 100 mg/kg/day of ritlecitinib (29 times the maximum recommended human dose based on AUC comparison), females had an increased incidence of combined benign and malignant thymomas, while males had a higher incidence of thyroid follicular adenomas and combined follicular adenomas and carcinomas. Ritlecitinib was negative in the bacterial reverse mutation assay and positive in an in vitro micronucleus assay in TK6 cells; however, mechanistic studies suggest that ritlecitinib is aneugenic and does not present a clinically relevant genotoxic concern.L47092

Ritlecitinib

DB14924

small molecule approved investigational

Deskripsi

Ritlecitinib (PF-06651600) is a highly selective inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family. In June 2023, it was approved by the FDA for the treatment of severe alopecia areata in adults and adolescents 12 years and older.L47092,L47127 It was further approved by the EMA in September 2023.L48181 Ritlecitinib is administered orally and is the first member of its class.A260122,A260127

Ritlecitinib binds covalently to Cys-909 of JAK3, a site where other JAK isoforms have a serine residue. This makes ritlecitinib a highly selective and irreversible JAK3 inhibitor.A260122,A260127 Other kinases have a cysteine at a position equivalent to Cys-909 in JAK3, and several of them belong to the TEC kinase family. It has been suggested that the dual activity of ritlecitinib toward JAK3 and the TEC kinase family block cytokine signaling as well as the cytolytic activity of T cells, both implicated in the pathogenesis of alopecia areata.A260122

Struktur Molekul 2D

Berat 285.351
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Ritlecitinib has a terminal half-life that ranges from 1.3 to 2.3 hours.[L47092]
Volume Distribusi Ritlecitinib is predicted to have a volume of distribution of 1.3 L/kg.[A260127]
Klirens (Clearance) Ritlecitinib is predicted to have a blood clearance of 5.6 mL/min/kg.[A260127]

Absorpsi

Up to 200 mg, the AUC0-tau and Cmax of ritlecitinib increase in an approximately dose-proportional manner, and steady state is reached approximately by day 4. Ritlecitinib has an absolute oral bioavailability of approximately 64%, and 1 hour after an oral dose is administered, peak plasma concentrations are achieved. Food does not have a clinically significant impact on the systemic exposures of ritlecitinib. The co-administration of a high-fat meal and a 100 mg ritlecitinib capsule reduced Cmax by 32% and increased AUCinf by 11%. Ritlecitinib was administered without regard to meals during clinical trials.L47092

Metabolisme

Ritlecitinib is metabolized by cytochrome P450 (CYP) and glutathione-S-transferase (GST) enzymes. The GST enzymes participating in the metabolism of ritlecitinib include cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3, and the CYP enzymes participating in this process include CYP3A, CYP2C8, CYP1A2, and CYP2C9. No single route contributes to more than 25% of the total metabolism of ritlecitinib.L47092

Rute Eliminasi

Ritlecitinib is mainly excreted through urine and feces. Approximately 66% and 20% of radiolabeled ritlecitinib are excreted in the urine and feces, respectively. Approximately 4% of the ritlecitinib dose is excreted unchanged drug in urine.L47092

Interaksi Makanan

1 Data
  • 1. Take with or without food. The coadministration of ritlecitinib and a high-fat meal reduced the Cmax and AUC; however, food does not have a clinically significant impact on the systemic exposures of ritlecitinib.

Interaksi Obat

1147 Data
Denosumab The risk or severity of adverse effects can be increased when Denosumab is combined with Ritlecitinib.
Etanercept The risk or severity of adverse effects can be increased when Etanercept is combined with Ritlecitinib.
Peginterferon alfa-2a The risk or severity of adverse effects can be increased when Peginterferon alfa-2a is combined with Ritlecitinib.
Interferon alfa-n1 The risk or severity of adverse effects can be increased when Interferon alfa-n1 is combined with Ritlecitinib.
Interferon alfa-n3 The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Ritlecitinib.
Peginterferon alfa-2b The risk or severity of adverse effects can be increased when Peginterferon alfa-2b is combined with Ritlecitinib.
Anakinra The risk or severity of adverse effects can be increased when Anakinra is combined with Ritlecitinib.
Interferon gamma-1b The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Ritlecitinib.
Interferon alfa-2a The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Ritlecitinib.
Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Ritlecitinib.
Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Ritlecitinib.
Gemtuzumab ozogamicin The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Ritlecitinib.
Pegaspargase The risk or severity of adverse effects can be increased when Pegaspargase is combined with Ritlecitinib.
Infliximab The risk or severity of adverse effects can be increased when Infliximab is combined with Ritlecitinib.
Interferon beta-1b The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Ritlecitinib.
Interferon alfacon-1 The risk or severity of adverse effects can be increased when Interferon alfacon-1 is combined with Ritlecitinib.
Trastuzumab The risk or severity of neutropenia can be increased when Trastuzumab is combined with Ritlecitinib.
Rituximab The risk or severity of adverse effects can be increased when Rituximab is combined with Ritlecitinib.
Basiliximab The risk or severity of adverse effects can be increased when Basiliximab is combined with Ritlecitinib.
Muromonab The risk or severity of adverse effects can be increased when Muromonab is combined with Ritlecitinib.
Ibritumomab tiuxetan The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Ritlecitinib.
Tositumomab The risk or severity of adverse effects can be increased when Tositumomab is combined with Ritlecitinib.
Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ritlecitinib.
Cyclosporine Ritlecitinib may increase the immunosuppressive activities of Cyclosporine.
Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Ritlecitinib.
Efalizumab The risk or severity of adverse effects can be increased when Efalizumab is combined with Ritlecitinib.
Antithymocyte immunoglobulin (rabbit) The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Ritlecitinib.
Interferon alfa-2b The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Ritlecitinib.
Natalizumab The risk or severity of immunosuppression can be increased when Ritlecitinib is combined with Natalizumab.
Daclizumab The risk or severity of adverse effects can be increased when Daclizumab is combined with Ritlecitinib.
Phenylalanine The risk or severity of adverse effects can be increased when Phenylalanine is combined with Ritlecitinib.
Flunisolide The serum concentration of Flunisolide can be increased when it is combined with Ritlecitinib.
Bortezomib The serum concentration of Bortezomib can be increased when it is combined with Ritlecitinib.
Cladribine Ritlecitinib may increase the immunosuppressive activities of Cladribine.
Carmustine The serum concentration of Carmustine can be increased when it is combined with Ritlecitinib.
Amsacrine The risk or severity of adverse effects can be increased when Amsacrine is combined with Ritlecitinib.
Bleomycin The risk or severity of adverse effects can be increased when Bleomycin is combined with Ritlecitinib.
Chlorambucil The risk or severity of adverse effects can be increased when Chlorambucil is combined with Ritlecitinib.
Raltitrexed The risk or severity of adverse effects can be increased when Raltitrexed is combined with Ritlecitinib.
Mitomycin The risk or severity of adverse effects can be increased when Mitomycin is combined with Ritlecitinib.
Bexarotene The serum concentration of Bexarotene can be increased when it is combined with Ritlecitinib.
Vindesine The serum concentration of Vindesine can be increased when it is combined with Ritlecitinib.
Floxuridine The risk or severity of adverse effects can be increased when Floxuridine is combined with Ritlecitinib.
Fluorometholone The serum concentration of Fluorometholone can be increased when it is combined with Ritlecitinib.
Indomethacin The risk or severity of adverse effects can be increased when Indomethacin is combined with Ritlecitinib.
Tioguanine The risk or severity of adverse effects can be increased when Tioguanine is combined with Ritlecitinib.
Vinorelbine The serum concentration of Vinorelbine can be increased when it is combined with Ritlecitinib.
Dexrazoxane The risk or severity of adverse effects can be increased when Dexrazoxane is combined with Ritlecitinib.
Beclomethasone dipropionate The serum concentration of Beclomethasone dipropionate can be increased when it is combined with Ritlecitinib.
Sorafenib The serum concentration of Sorafenib can be increased when it is combined with Ritlecitinib.
Streptozocin The risk or severity of adverse effects can be increased when Streptozocin is combined with Ritlecitinib.
Trifluridine The risk or severity of adverse effects can be increased when Trifluridine is combined with Ritlecitinib.
Gemcitabine The risk or severity of adverse effects can be increased when Gemcitabine is combined with Ritlecitinib.
Betamethasone The serum concentration of Betamethasone can be increased when it is combined with Ritlecitinib.
Teniposide The serum concentration of Teniposide can be increased when it is combined with Ritlecitinib.
Epirubicin The risk or severity of adverse effects can be increased when Epirubicin is combined with Ritlecitinib.
Chloramphenicol The risk or severity of adverse effects can be increased when Chloramphenicol is combined with Ritlecitinib.
Lenalidomide The risk or severity of adverse effects can be increased when Lenalidomide is combined with Ritlecitinib.
Altretamine The risk or severity of adverse effects can be increased when Altretamine is combined with Ritlecitinib.
Zidovudine The serum concentration of Zidovudine can be increased when it is combined with Ritlecitinib.
Cisplatin The risk or severity of adverse effects can be increased when Cisplatin is combined with Ritlecitinib.
Oxaliplatin The risk or severity of adverse effects can be increased when Oxaliplatin is combined with Ritlecitinib.
Cyclophosphamide The serum concentration of Cyclophosphamide can be increased when it is combined with Ritlecitinib.
Vincristine The serum concentration of Vincristine can be increased when it is combined with Ritlecitinib.
Fluorouracil The serum concentration of Fluorouracil can be increased when it is combined with Ritlecitinib.
Desoximetasone The risk or severity of adverse effects can be increased when Desoximetasone is combined with Ritlecitinib.
Propylthiouracil The risk or severity of adverse effects can be increased when Propylthiouracil is combined with Ritlecitinib.
Pentostatin The risk or severity of adverse effects can be increased when Pentostatin is combined with Ritlecitinib.
Methotrexate The serum concentration of Methotrexate can be increased when it is combined with Ritlecitinib.
Carbamazepine The serum concentration of Ritlecitinib can be decreased when it is combined with Carbamazepine.
Vinblastine The serum concentration of Vinblastine can be increased when it is combined with Ritlecitinib.
Fluticasone propionate The serum concentration of Fluticasone propionate can be increased when it is combined with Ritlecitinib.
Fluocinolone acetonide The serum concentration of Fluocinolone acetonide can be increased when it is combined with Ritlecitinib.
Linezolid The risk or severity of adverse effects can be increased when Linezolid is combined with Ritlecitinib.
Imatinib The serum concentration of Imatinib can be increased when it is combined with Ritlecitinib.
Triamcinolone The serum concentration of Triamcinolone can be increased when it is combined with Ritlecitinib.
Clofarabine The risk or severity of adverse effects can be increased when Clofarabine is combined with Ritlecitinib.
Prednisone The serum concentration of Prednisone can be increased when it is combined with Ritlecitinib.
Pemetrexed The serum concentration of Pemetrexed can be increased when it is combined with Ritlecitinib.
Fludrocortisone The serum concentration of Fludrocortisone can be increased when it is combined with Ritlecitinib.
Mycophenolate mofetil The serum concentration of Mycophenolate mofetil can be increased when it is combined with Ritlecitinib.
Daunorubicin The risk or severity of adverse effects can be increased when Daunorubicin is combined with Ritlecitinib.
Irinotecan The serum concentration of Irinotecan can be increased when it is combined with Ritlecitinib.
Methimazole The metabolism of Ritlecitinib can be decreased when combined with Methimazole.
Mometasone The serum concentration of Mometasone can be increased when it is combined with Ritlecitinib.
Etoposide The serum concentration of Etoposide can be increased when it is combined with Ritlecitinib.
Sulfasalazine The risk or severity of adverse effects can be increased when Sulfasalazine is combined with Ritlecitinib.
Dacarbazine The serum concentration of Dacarbazine can be increased when it is combined with Ritlecitinib.
Temozolomide The risk or severity of adverse effects can be increased when Temozolomide is combined with Ritlecitinib.
Penicillamine The risk or severity of adverse effects can be increased when Penicillamine is combined with Ritlecitinib.
Prednisolone The serum concentration of Prednisolone can be increased when it is combined with Ritlecitinib.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Ritlecitinib.
Sirolimus The serum concentration of Sirolimus can be increased when it is combined with Ritlecitinib.
Mechlorethamine The risk or severity of adverse effects can be increased when Mechlorethamine is combined with Ritlecitinib.
Azacitidine The risk or severity of adverse effects can be increased when Azacitidine is combined with Ritlecitinib.
Carboplatin The risk or severity of adverse effects can be increased when Carboplatin is combined with Ritlecitinib.
Methylprednisolone The serum concentration of Methylprednisolone can be increased when it is combined with Ritlecitinib.
Dactinomycin The risk or severity of adverse effects can be increased when Dactinomycin is combined with Ritlecitinib.
Cytarabine The risk or severity of adverse effects can be increased when Cytarabine is combined with Ritlecitinib.
Azathioprine The serum concentration of Azathioprine can be increased when it is combined with Ritlecitinib.

Target Protein

Tyrosine-protein kinase JAK3 JAK3
Tyrosine-protein kinase Tec TEC
Tyrosine-protein kinase ITK/TSK ITK
Tyrosine-protein kinase TXK TXK
Tyrosine-protein kinase BTK BTK
Cytoplasmic tyrosine-protein kinase BMX BMX

Referensi & Sumber

Synthesis reference: Thorarensen, A., et al. (2023). Pyrrolo2,3-dpyrimidinyl, pyrrolo2,3-bpyrazinyl and pyrrolo2,3-dpyridinyl acrylamides (U.S. Patent No. 2023/0009153 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/fb/75/3e/68ad4603d518f9/US20230009153A1.pdf
Artikel (PubMed)
  • PMID: 35210753
    Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022.
  • PMID: 27791347
    Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10.
  • PMID: 36091777
    Yan D, Fan H, Chen M, Xia L, Wang S, Dong W, Wang Q, Niu S, Rao H, Chen L, Nie X, Fang Y: The efficacy and safety of JAK inhibitors for alopecia areata: A systematic review and meta-analysis of prospective studies. Front Pharmacol. 2022 Aug 24;13:950450. doi: 10.3389/fphar.2022.950450. eCollection 2022.
  • PMID: 30100707
    Triyangkulsri K, Suchonwanit P: Role of janus kinase inhibitors in the treatment of alopecia areata. Drug Des Devel Ther. 2018 Jul 27;12:2323-2335. doi: 10.2147/DDDT.S172638. eCollection 2018.

Contoh Produk & Brand

Produk: 6 • International brands: 1
Produk
  • Litfulo
    Capsule • 50 mg/1 • Oral • US • Approved
  • Litfulo
    Capsule • 50 mg/1 • Oral • US • Approved
  • Litfulo
    Capsule • 50 mg • Oral • EU • Approved
  • Litfulo
    Capsule • 50 mg • Oral • EU • Approved
  • Litfulo
    Capsule • 50 mg • Oral • EU • Approved
  • Litfulo
    Capsule • 50 mg • Oral • Canada • Approved
International Brands
  • Litfulo — Pfizer Inc.

Sekuens Gen/Protein (FASTA)

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