Peringatan Keamanan

Animal studies have not revealed any mutagenic potential of avacopan and no impairment of fertility at doses up to 1000 mg/kg/day. Avacopan is not mutagenic based on the Ames test.L38919

Avacopan

DB15011

small molecule approved investigational

Deskripsi

Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is a rare (estimated incidence of 3 cases per 100,000 per year) form of "pauci-immune" systemic small-vessel vasculitis typified by the presence of ANCAs in the serum.A240249, A240254, A227003 The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN).A240249, A240254 Despite complex pathophysiology, studies over the past ~2 decades have identified a key role for the alternative complement pathway and, in particular, the interaction between the anaphylatoxin fragment C5a and its cognate C5aR receptor in AAV.A240254, A240259, A240264, A240269 Avacopan (formerly CCX168) is an allosteric C5aR antagonist indicated for use in AAV.A240269, A240329, L38919

Avacopan was granted FDA approval on October 8, 2021, and is currently marketed under the name TAVNEOS by ChemoCentryx, Inc.L38919 On January 19, 2022, the European Commission approved avacopan for the treatment of adult patients with severe, active granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA) - the two main forms of ANCA-associated vasculitis - in combination with rituximab or cyclophosphamide.L39850 Avacopan was approved by Health Canada on April 20, 2022.L41650

Struktur Molekul 2D

Berat 581.656
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) A single 30 mg dose of avacopan given with food to healthy subjects resulted in mean elimination half-lives of 97.6 and 55.6 hours for avacopan and its M1 metabolite, respectively.[L38919]
Volume Distribusi Avacopan has an apparent volume of distribution of 345 L.[L38919]
Klirens (Clearance) Avacopan has an estimated total apparent body clearance (CL/F) of 16.3 L/h.[L38919]

Absorpsi

In AAV patients receiving 30 mg avacopan twice daily, avacopan had a Cmax of 349 ± 169 ng/mL and an AUC0-12hr of 3466 ± 1921 ng\*h/mL. On this dosing scheme, steady-state plasma concentrations are reached by 13 weeks with a roughly 4-fold accumulation. Co-administration of 30 mg with a high-fat meal increased the Cmax by ~8%, the AUC by ~72%, and delayed the Tmax by four hours (from two hours).L38919

Metabolisme

Avacopan is metabolized primarily by CYP3A4. The major circulating M1 metabolite, a mono-hydroxylated form of avacopan, represents ~12% of drug plasma levels and acts as a C5aR antagonist with similar efficacy to avacopan itself.L38919

Rute Eliminasi

Avacopan is mainly eliminated in feces, with smaller amounts present in the urine. Following oral administration of the radiolabeled drug, roughly 77% (7% as unchanged avacopan) was recovered in feces while 10% (<0.1% unchanged) was recovered in urine.L38919

Interaksi Makanan

1 Data
  • 1. Take with food.

Interaksi Obat

535 Data
Phenytoin The metabolism of Avacopan can be increased when combined with Phenytoin.
Pentobarbital The metabolism of Avacopan can be increased when combined with Pentobarbital.
Carbamazepine The serum concentration of Carbamazepine can be increased when it is combined with Avacopan.
Mitotane The metabolism of Avacopan can be increased when combined with Mitotane.
Primidone The metabolism of Avacopan can be increased when combined with Primidone.
Rifampin The metabolism of Avacopan can be increased when combined with Rifampicin.
Phenobarbital The metabolism of Avacopan can be increased when combined with Phenobarbital.
Rifapentine The metabolism of Avacopan can be increased when combined with Rifapentine.
Dexamethasone The risk or severity of adverse effects can be increased when Dexamethasone is combined with Avacopan.
Fosphenytoin The serum concentration of Fosphenytoin can be increased when it is combined with Avacopan.
St. John's Wort The metabolism of Avacopan can be increased when combined with St. John's Wort.
Midostaurin The metabolism of Avacopan can be decreased when combined with Midostaurin.
Enzalutamide The serum concentration of Avacopan can be decreased when it is combined with Enzalutamide.
Lumacaftor The metabolism of Avacopan can be increased when combined with Lumacaftor.
Apalutamide The serum concentration of Avacopan can be decreased when it is combined with Apalutamide.
Cyclosporine Avacopan may increase the immunosuppressive activities of Cyclosporine.
Fluvoxamine The metabolism of Avacopan can be decreased when combined with Fluvoxamine.
Fluconazole The metabolism of Avacopan can be decreased when combined with Fluconazole.
Erythromycin The serum concentration of Avacopan can be increased when it is combined with Erythromycin.
Ziprasidone The metabolism of Avacopan can be decreased when combined with Ziprasidone.
Isradipine The metabolism of Avacopan can be decreased when combined with Isradipine.
Diltiazem The metabolism of Avacopan can be decreased when combined with Diltiazem.
Clozapine The metabolism of Avacopan can be decreased when combined with Clozapine.
Haloperidol The serum concentration of Haloperidol can be increased when it is combined with Avacopan.
Ciprofloxacin The metabolism of Avacopan can be decreased when combined with Ciprofloxacin.
Voriconazole The metabolism of Avacopan can be decreased when combined with Voriconazole.
Nicardipine The metabolism of Avacopan can be decreased when combined with Nicardipine.
Verapamil The metabolism of Avacopan can be decreased when combined with Verapamil.
Aprepitant The metabolism of Avacopan can be decreased when combined with Aprepitant.
Isoniazid The metabolism of Avacopan can be decreased when combined with Isoniazid.
Primaquine The metabolism of Avacopan can be decreased when combined with Primaquine.
Miconazole The metabolism of Avacopan can be decreased when combined with Miconazole.
Danazol The metabolism of Avacopan can be decreased when combined with Danazol.
Fusidic acid The metabolism of Avacopan can be decreased when combined with Fusidic acid.
Zimelidine The metabolism of Avacopan can be decreased when combined with Zimelidine.
Dronedarone The serum concentration of Dronedarone can be increased when it is combined with Avacopan.
Milnacipran The metabolism of Avacopan can be decreased when combined with Milnacipran.
Simeprevir The metabolism of Avacopan can be decreased when combined with Simeprevir.
Isavuconazonium The metabolism of Avacopan can be decreased when combined with Isavuconazonium.
Desvenlafaxine The metabolism of Avacopan can be decreased when combined with Desvenlafaxine.
Nilvadipine The metabolism of Avacopan can be decreased when combined with Nilvadipine.
Seproxetine The metabolism of Avacopan can be decreased when combined with Seproxetine.
Crizotinib The serum concentration of Crizotinib can be increased when it is combined with Avacopan.
Linagliptin The metabolism of Avacopan can be decreased when combined with Linagliptin.
Indalpine The metabolism of Avacopan can be decreased when combined with Indalpine.
Netupitant The metabolism of Avacopan can be decreased when combined with Netupitant.
Barnidipine The metabolism of Avacopan can be decreased when combined with Barnidipine.
Benidipine The metabolism of Avacopan can be decreased when combined with Benidipine.
Venetoclax The serum concentration of Venetoclax can be increased when it is combined with Avacopan.
Isavuconazole The metabolism of Avacopan can be decreased when combined with Isavuconazole.
Fosnetupitant The metabolism of Avacopan can be decreased when combined with Fosnetupitant.
Berotralstat The metabolism of Avacopan can be decreased when combined with Berotralstat.
Nelfinavir The metabolism of Avacopan can be decreased when combined with Nelfinavir.
Indinavir The metabolism of Avacopan can be decreased when combined with Indinavir.
Terfenadine The metabolism of Avacopan can be decreased when combined with Terfenadine.
Ritonavir The serum concentration of Avacopan can be increased when it is combined with Ritonavir.
Efavirenz The metabolism of Avacopan can be decreased when combined with Efavirenz.
Ergotamine The metabolism of Avacopan can be decreased when combined with Ergotamine.
Amprenavir The metabolism of Avacopan can be decreased when combined with Amprenavir.
Delavirdine The metabolism of Avacopan can be decreased when combined with Delavirdine.
Methimazole The metabolism of Avacopan can be decreased when combined with Methimazole.
Conivaptan The metabolism of Avacopan can be decreased when combined with Conivaptan.
Tipranavir The metabolism of Avacopan can be decreased when combined with Tipranavir.
Telithromycin The metabolism of Avacopan can be decreased when combined with Telithromycin.
Ketoconazole The metabolism of Avacopan can be decreased when combined with Ketoconazole.
Atazanavir The metabolism of Avacopan can be decreased when combined with Atazanavir.
Amiodarone The metabolism of Avacopan can be decreased when combined with Amiodarone.
Nefazodone The metabolism of Avacopan can be decreased when combined with Nefazodone.
Itraconazole The metabolism of Avacopan can be decreased when combined with Itraconazole.
Clarithromycin The metabolism of Avacopan can be decreased when combined with Clarithromycin.
Saquinavir The metabolism of Avacopan can be decreased when combined with Saquinavir.
Posaconazole The metabolism of Avacopan can be decreased when combined with Posaconazole.
Darunavir The metabolism of Avacopan can be decreased when combined with Darunavir.
Lopinavir The serum concentration of Avacopan can be increased when it is combined with Lopinavir.
Ditiocarb The metabolism of Avacopan can be decreased when combined with Ditiocarb.
Nilotinib The metabolism of Avacopan can be decreased when combined with Nilotinib.
Telaprevir The metabolism of Avacopan can be decreased when combined with Telaprevir.
Lonafarnib The metabolism of Avacopan can be decreased when combined with Lonafarnib.
Boceprevir The metabolism of Avacopan can be decreased when combined with Boceprevir.
Elvitegravir The metabolism of Avacopan can be decreased when combined with Elvitegravir.
Stiripentol The metabolism of Avacopan can be decreased when combined with Stiripentol.
Curcumin The metabolism of Avacopan can be decreased when combined with Curcumin.
Ribociclib The metabolism of Avacopan can be decreased when combined with Ribociclib.
Danoprevir The metabolism of Avacopan can be decreased when combined with Danoprevir.
Troleandomycin The metabolism of Avacopan can be decreased when combined with Troleandomycin.
Pitolisant The serum concentration of Avacopan can be decreased when it is combined with Pitolisant.
Metreleptin The metabolism of Avacopan can be increased when combined with Metreleptin.
Azithromycin The metabolism of Azithromycin can be decreased when combined with Avacopan.
Methysergide The metabolism of Methysergide can be decreased when combined with Avacopan.
Meperidine The metabolism of Meperidine can be decreased when combined with Avacopan.
Chlorpromazine The metabolism of Chlorpromazine can be decreased when combined with Avacopan.
Albendazole The metabolism of Albendazole can be decreased when combined with Avacopan.
Cephalexin The metabolism of Cephalexin can be decreased when combined with Avacopan.
Doxazosin The metabolism of Doxazosin can be decreased when combined with Avacopan.
Cisapride The metabolism of Cisapride can be decreased when combined with Avacopan.
Astemizole The serum concentration of Astemizole can be increased when it is combined with Avacopan.
Norethisterone The metabolism of Norethisterone can be decreased when combined with Avacopan.
Fenofibrate The metabolism of Fenofibrate can be decreased when combined with Avacopan.
Rosuvastatin The metabolism of Rosuvastatin can be decreased when combined with Avacopan.
Pimozide The serum concentration of Pimozide can be increased when it is combined with Avacopan.

Target Protein

C5a anaphylatoxin chemotactic receptor 1 C5AR1

Referensi & Sumber

Synthesis reference: Christopher Lange, Viengkham Malathong, Venkat Reddy Mali, Jeffrey McMahon, Darren J. McMurtrie, Sreenivas Punna, Howard S. Roth, Rajinder Singh, Yu Wang, Ju Yang, Penglie Zhang, "Immunomodulator compounds." U.S. Patent US10919852B2, issued May 9, 2019.
Artikel (PubMed)
  • PMID: 30542206
    Nakazawa D, Masuda S, Tomaru U, Ishizu A: Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol. 2019 Feb;15(2):91-101. doi: 10.1038/s41584-018-0145-y.
  • PMID: 31734405
    Brilland B, Garnier AS, Chevailler A, Jeannin P, Subra JF, Augusto JF: Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside. Autoimmun Rev. 2020 Jan;19(1):102424. doi: 10.1016/j.autrev.2019.102424. Epub 2019 Nov 15.
  • PMID: 17200182
    Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC: Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol. 2007 Jan;170(1):52-64. doi: 10.2353/ajpath.2007.060573.
  • PMID: 19073822
    Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R: C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol. 2009 Feb;20(2):289-98. doi: 10.1681/ASN.2008050497. Epub 2008 Dec 10.
  • PMID: 24179165
    Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, Seitz LC, Penfold ME, Gan L, Hu P, Lu B, Gerard NP, Gerard C, Schall TJ, Jaen JC, Falk RJ, Jennette JC: C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014 Feb;25(2):225-31. doi: 10.1681/ASN.2013020143. Epub 2013 Oct 31.
  • PMID: 27768695
    Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, Baumgart T, Shugarts S, Lohr L, Dang T, Miao S, Zeng Y, Fan P, Zhang P, Johnson D, Powers J, Jaen J, Charo I, Schall TJ: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. PLoS One. 2016 Oct 21;11(10):e0164646. doi: 10.1371/journal.pone.0164646. eCollection 2016.
  • PMID: 29867214
    Liu H, Kim HR, Deepak RNVK, Wang L, Chung KY, Fan H, Wei Z, Zhang C: Orthosteric and allosteric action of the C5a receptor antagonists. Nat Struct Mol Biol. 2018 Jun;25(6):472-481. doi: 10.1038/s41594-018-0067-z. Epub 2018 Jun 4.
  • PMID: 31631015
    Jayne D: Complement inhibition in ANCA vasculitis. Nephrol Ther. 2019 Nov;15(6):409-412. doi: 10.1016/j.nephro.2019.04.001. Epub 2019 Oct 17.

Contoh Produk & Brand

Produk: 5 • International brands: 0
Produk
  • Tavneos
    Capsule • 10 mg • Oral • EU • Approved
  • Tavneos
    Capsule • 10 mg/1 • Oral • US • Approved
  • Tavneos
    Capsule • 10 mg • Oral • EU • Approved
  • Tavneos
    Capsule • 10 mg • Oral • EU • Approved
  • Tavneos
    Capsule • 10 mg • Oral • Canada • Approved

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