Peringatan Keamanan

Toxicity information regarding pirtobrutinib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hemorrhage, cytopenias, atrial fibrillation and atrial flutter.L44863 Symptomatic and supportive measures are recommended. In vivo carcinogenicity studies have not been conducted with pirtobrutinib. A bacterial mutagenicity (Ames) assay found that pirtobrutinib was not mutagenic, and in vitro micronucleus assays using human peripheral blood lymphocytes found that pirtobrutinib was aneugenic. Up to 2000 mg/kg, pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay.L44863

Pirtobrutinib

DB17472

small molecule approved investigational

Deskripsi

Pirtobrutinib is a small molecule and a highly selective non-covalent inhibitor of Bruton’s tyrosine kinase (BTK). Its high selectivity has been associated with lower discontinuation rates due to adverse events and a lower incidence of atrial fibrillation.A256758 Unlike BTK covalent inhibitors, such as ibrutinib, that bind to the cysteine 481 (Cys481) amino acid within the active site of BTK, the inhibitory activity of pirtobrutinib is maintained even in the presence of Cys481 mutations. Although the mechanisms of resistance to covalent BTK inhibitors have not been fully elucidated, it appears that the presence of Cys481 mutations is the most common reason for resistance to covalent BTK inhibitors.A256758,A256773,L44863 However, other mutations may confer resistance to non-covalent BTK inhibitors such as pirtobrutinib.A256788

In January 2023, the use of pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy was approved under the FDA's Accelerated Approval pathway.L44863,L44873

Struktur Molekul 2D

Berat 479.436
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Pirtobrutinib has an effective half-life of approximately 19 hours.[L44863]
Volume Distribusi Pirtobrutinib has an apparent central volume of distribution of 32.8 L.[L44863]
Klirens (Clearance) Pirtobrutinib has an apparent clearance of 2.02 L/h.[L44863]

Absorpsi

With single oral doses between 300 mg and 800 mg (1.5 to 4 times the approved recommended dose) and once daily doses between 25 mg and 300 mg (0.125 to 1.5 times the recommended dose), pirtobrutinib follows a dose-proportional pharmacokinetic profile. Within 5 days of once-daily dosing, pirtobrutinib reached steady-state concentration, with an accumulation ratio of 1.63 based on AUC after 200 mg dosages. With the recommended dose, pirtobrutinib has a steady-state AUC and Cmax of 91300 h?ng/mL and 6460 ng/mL, respectively. On day 8 of cycle 1, pirtobrutinib had an AUC0-24 of 81800 h?ng/mL and a Cmax of 3670 ng/mL. After approximately 2 hours, pirtobrutinib reaches peak plasma concentration (tmax).L44863 After a single oral dose of 200 mg, pirtobrutinib reaches an absolute bioavailability of 85.5%. The administration of a high-fat, high-calorie meal to healthy subjects did not have a clinically significant effect on the pharmacokinetics of pirtobrutinib. A high-fat meal decreased the Cmax of pirtobrutinib by 23%, delayed tmax by 1 hour and had no effects on the AUC.L44863

Metabolisme

In vitro studies suggest that pirtobrutinib is mainly metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9.L44863

Rute Eliminasi

Pirtobrutinib is mainly excreted in urine and feces. In healthy subjects given a single dose of 200 mg of radiolabeled pirtobrutinib, 57% of the dose was recovered in urine (10% unchanged), and 37% was recovered in feces (18% unchanged).L44863

Interaksi Makanan

2 Data
  • 1. Take at the same time every day. Pirtobrutinib should be taken at approximately the same time each day with or without food.
  • 2. Take with or without food. High-fat, high-calorie meals do not have a clinically significant effect in the pharmacokinetics of pirtobrutinib.

Interaksi Obat

970 Data
Clozapine The risk or severity of neutropenia can be increased when Pirtobrutinib is combined with Clozapine.
Darbepoetin alfa The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Pirtobrutinib.
Erythropoietin The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Pirtobrutinib.
Peginesatide The risk or severity of Thrombosis can be increased when Peginesatide is combined with Pirtobrutinib.
Methoxy polyethylene glycol-epoetin beta The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Pirtobrutinib.
Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Pirtobrutinib.
Propacetamol The serum concentration of Propacetamol can be increased when it is combined with Pirtobrutinib.
Metamizole The risk or severity of myelosuppression can be increased when Metamizole is combined with Pirtobrutinib.
Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Pirtobrutinib.
Eptifibatide The risk or severity of bleeding can be increased when Eptifibatide is combined with Pirtobrutinib.
Ticlopidine The metabolism of Ticlopidine can be decreased when combined with Pirtobrutinib.
Anagrelide The risk or severity of bleeding can be increased when Anagrelide is combined with Pirtobrutinib.
Clopidogrel The metabolism of Clopidogrel can be decreased when combined with Pirtobrutinib.
Tirofiban The risk or severity of bleeding can be increased when Tirofiban is combined with Pirtobrutinib.
Pentoxifylline The risk or severity of bleeding can be increased when Pentoxifylline is combined with Pirtobrutinib.
Acetylsalicylic acid The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Pirtobrutinib.
Dipyridamole The risk or severity of bleeding can be increased when Dipyridamole is combined with Pirtobrutinib.
Sulfinpyrazone The risk or severity of bleeding can be increased when Sulfinpyrazone is combined with Pirtobrutinib.
Cilostazol The risk or severity of bleeding can be increased when Cilostazol is combined with Pirtobrutinib.
Ridogrel The risk or severity of bleeding can be increased when Ridogrel is combined with Pirtobrutinib.
Epoprostenol The risk or severity of bleeding can be increased when Epoprostenol is combined with Pirtobrutinib.
Resveratrol The risk or severity of bleeding can be increased when Resveratrol is combined with Pirtobrutinib.
Nimesulide The risk or severity of bleeding can be increased when Nimesulide is combined with Pirtobrutinib.
Tesmilifene The risk or severity of bleeding can be increased when Tesmilifene is combined with Pirtobrutinib.
Defibrotide The risk or severity of bleeding can be increased when Defibrotide is combined with Pirtobrutinib.
Beraprost The metabolism of Beraprost can be decreased when combined with Pirtobrutinib.
Ibudilast The risk or severity of bleeding can be increased when Ibudilast is combined with Pirtobrutinib.
Andrographolide The risk or severity of bleeding can be increased when Andrographolide is combined with Pirtobrutinib.
Caplacizumab The risk or severity of bleeding can be increased when Caplacizumab is combined with Pirtobrutinib.
Prasugrel The risk or severity of bleeding can be increased when Prasugrel is combined with Pirtobrutinib.
Cangrelor The risk or severity of bleeding can be increased when Cangrelor is combined with Pirtobrutinib.
Tranilast The risk or severity of bleeding can be increased when Tranilast is combined with Pirtobrutinib.
Triflusal The risk or severity of bleeding can be increased when Triflusal is combined with Pirtobrutinib.
Ticagrelor The serum concentration of Ticagrelor can be increased when it is combined with Pirtobrutinib.
Icosapent ethyl The risk or severity of bleeding can be increased when Icosapent ethyl is combined with Pirtobrutinib.
Vorapaxar The risk or severity of bleeding can be increased when Vorapaxar is combined with Pirtobrutinib.
Trapidil The risk or severity of bleeding can be increased when Trapidil is combined with Pirtobrutinib.
Naftopidil The risk or severity of bleeding can be increased when Naftopidil is combined with Pirtobrutinib.
Sarpogrelate The risk or severity of bleeding can be increased when Sarpogrelate is combined with Pirtobrutinib.
Ifetroban The risk or severity of bleeding can be increased when Ifetroban is combined with Pirtobrutinib.
Nitroaspirin The risk or severity of bleeding can be increased when Nitroaspirin is combined with Pirtobrutinib.
Indobufen The risk or severity of bleeding can be increased when Indobufen is combined with Pirtobrutinib.
Butylphthalide The risk or severity of bleeding can be increased when Butylphthalide is combined with Pirtobrutinib.
Hydroxytyrosol The risk or severity of bleeding can be increased when Hydroxytyrosol is combined with Pirtobrutinib.
Ramatroban The risk or severity of bleeding can be increased when Ramatroban is combined with Pirtobrutinib.
Picotamide The risk or severity of bleeding can be increased when Picotamide is combined with Pirtobrutinib.
Cloricromen The risk or severity of bleeding can be increased when Cloricromen is combined with Pirtobrutinib.
Linsidomine The risk or severity of bleeding can be increased when Linsidomine is combined with Pirtobrutinib.
Buflomedil The risk or severity of bleeding can be increased when Buflomedil is combined with Pirtobrutinib.
Relcovaptan The risk or severity of bleeding can be increased when Relcovaptan is combined with Pirtobrutinib.
Maritime pine extract The risk or severity of bleeding can be increased when Maritime pine extract is combined with Pirtobrutinib.
Lipegfilgrastim Pirtobrutinib may increase the myelosuppressive activities of Lipegfilgrastim.
Palifermin The therapeutic efficacy of Palifermin can be decreased when used in combination with Pirtobrutinib.
Lepirudin The risk or severity of bleeding can be increased when Lepirudin is combined with Pirtobrutinib.
Bivalirudin The risk or severity of bleeding can be increased when Bivalirudin is combined with Pirtobrutinib.
Alteplase The risk or severity of bleeding can be increased when Alteplase is combined with Pirtobrutinib.
Urokinase The risk or severity of bleeding can be increased when Urokinase is combined with Pirtobrutinib.
Reteplase The risk or severity of bleeding can be increased when Reteplase is combined with Pirtobrutinib.
Anistreplase The risk or severity of bleeding can be increased when Anistreplase is combined with Pirtobrutinib.
Tenecteplase The risk or severity of bleeding can be increased when Tenecteplase is combined with Pirtobrutinib.
Drotrecogin alfa The risk or severity of bleeding can be increased when Drotrecogin alfa is combined with Pirtobrutinib.
Streptokinase The risk or severity of bleeding can be increased when Streptokinase is combined with Pirtobrutinib.
Dicoumarol The risk or severity of bleeding can be increased when Dicoumarol is combined with Pirtobrutinib.
Argatroban The risk or severity of bleeding can be increased when Argatroban is combined with Pirtobrutinib.
Ardeparin The risk or severity of bleeding can be increased when Ardeparin is combined with Pirtobrutinib.
Phenindione The risk or severity of bleeding can be increased when Phenindione is combined with Pirtobrutinib.
Fondaparinux The risk or severity of bleeding can be increased when Fondaparinux is combined with Pirtobrutinib.
Warfarin The metabolism of Warfarin can be decreased when combined with Pirtobrutinib.
Pentosan polysulfate The risk or severity of bleeding can be increased when Pentosan polysulfate is combined with Pirtobrutinib.
Phenprocoumon The metabolism of Phenprocoumon can be decreased when combined with Pirtobrutinib.
Edetic acid The risk or severity of bleeding can be increased when Edetic acid is combined with Pirtobrutinib.
Heparin The risk or severity of bleeding can be increased when Heparin is combined with Pirtobrutinib.
Enoxaparin The risk or severity of bleeding can be increased when Enoxaparin is combined with Pirtobrutinib.
Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Pirtobrutinib.
4-hydroxycoumarin The risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Pirtobrutinib.
Coumarin The risk or severity of bleeding can be increased when Coumarin is combined with Pirtobrutinib.
Ximelagatran The risk or severity of bleeding can be increased when Ximelagatran is combined with Pirtobrutinib.
Desmoteplase The risk or severity of bleeding can be increased when Desmoteplase is combined with Pirtobrutinib.
Ancrod The risk or severity of bleeding can be increased when Ancrod is combined with Pirtobrutinib.
SR-123781A The risk or severity of bleeding can be increased when SR-123781A is combined with Pirtobrutinib.
Rivaroxaban Pirtobrutinib may decrease the excretion rate of Rivaroxaban which could result in a higher serum level.
Sulodexide The risk or severity of bleeding can be increased when Sulodexide is combined with Pirtobrutinib.
Semuloparin The risk or severity of bleeding can be increased when Semuloparin is combined with Pirtobrutinib.
Idraparinux The risk or severity of bleeding can be increased when Idraparinux is combined with Pirtobrutinib.
Astaxanthin The risk or severity of bleeding can be increased when Astaxanthin is combined with Pirtobrutinib.
Apixaban The metabolism of Apixaban can be decreased when combined with Pirtobrutinib.
Otamixaban The risk or severity of bleeding can be increased when Otamixaban is combined with Pirtobrutinib.
Amediplase The risk or severity of bleeding can be increased when Amediplase is combined with Pirtobrutinib.
Dabigatran etexilate The serum concentration of Dabigatran etexilate can be increased when it is combined with Pirtobrutinib.
Danaparoid The risk or severity of bleeding can be increased when Danaparoid is combined with Pirtobrutinib.
Dalteparin The risk or severity of bleeding can be increased when Dalteparin is combined with Pirtobrutinib.
Tinzaparin The risk or severity of bleeding can be increased when Tinzaparin is combined with Pirtobrutinib.
(R)-warfarin The metabolism of (R)-warfarin can be decreased when combined with Pirtobrutinib.
Ethyl biscoumacetate The risk or severity of bleeding can be increased when Ethyl biscoumacetate is combined with Pirtobrutinib.
Nadroparin The risk or severity of bleeding can be increased when Nadroparin is combined with Pirtobrutinib.
Ditazole The risk or severity of bleeding can be increased when Ditazole is combined with Pirtobrutinib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Pirtobrutinib.
Sodium citrate The risk or severity of bleeding can be increased when Sodium citrate is combined with Pirtobrutinib.
Dextran The risk or severity of bleeding can be increased when Dextran is combined with Pirtobrutinib.
Bemiparin The risk or severity of bleeding can be increased when Bemiparin is combined with Pirtobrutinib.

Target Protein

Tyrosine-protein kinase BTK BTK

Referensi & Sumber

Synthesis reference: Guisot, N. (2017). Compounds useful as kinase inhibitors (WO 2017/103611 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/d7/16/21/9300e49071a21a/WO2017103611A1.pdf
Artikel (PubMed)
  • PMID: 35747462
    Jensen JL, Mato AR, Pena C, Roeker LE, Coombs CC: The potential of pirtobrutinib in multiple B-cell malignancies. Ther Adv Hematol. 2022 Jun 16;13:20406207221101697. doi: 10.1177/20406207221101697. eCollection 2022.
  • PMID: 35595730
    Aslan B, Kismali G, Iles LR, Manyam GC, Ayres ML, Chen LS, Gagea M, Bertilaccio MTS, Wierda WG, Gandhi V: Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022 May 20;12(5):80. doi: 10.1038/s41408-022-00675-9.
  • PMID: 36183125
    Alu A, Lei H, Han X, Wei Y, Wei X: BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J Hematol Oncol. 2022 Oct 1;15(1):138. doi: 10.1186/s13045-022-01353-w.
  • PMID: 33676628
    Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M: Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5.
  • PMID: 35196427
    Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, Durham BH, Penson A, Witkowski MT, Lu SX, Bourcier J, Hogg SJ, Erickson C, Cui D, Cho H, Singer M, Totiger TM, Chaudhry S, Geyer M, Alencar A, Linley AJ, Palomba ML, Coombs CC, Park JH, Zelenetz A, Roeker L, Rosendahl M, Tsai DE, Ebata K, Brandhuber B, Hyman DM, Aifantis I, Mato A, Taylor J, Abdel-Wahab O: Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors. N Engl J Med. 2022 Feb 24;386(8):735-743. doi: 10.1056/NEJMoa2114110.

Contoh Produk & Brand

Produk: 11 • International brands: 1
Produk
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Menampilkan 8 dari 11 produk.
International Brands
  • Jaypirca — Eli Lilly

Sekuens Gen/Protein (FASTA)

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