Danicopan
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Identification
- Summary
Danicopan is a small molecule complement factor D inhibitor used to treat extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria.
- Brand Names
- Voydeya 200 Mg Dose Bottle
- Generic Name
- Danicopan
- DrugBank Accession Number
- DB15401
- Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematologic disease characterized by hemolysis, thrombophilia, and bone marrow dysfunction.1,7 Both hemolysis and thrombophilia are mediated primarily by the complement system.1 Standard therapy for PNH involves the use of complement C5 inhibitors (e.g. eculizumab, ravulizumab) which are effective in mitigating complement-mediated intravascular hemolysis and thromboembolism.1 Unfortunately, complement C5 inhibition does not address C3-mediated extravascular hemolysis, which occurs earlier in the complement cascade within the alternative pathway.1,5
Danicopan is a small molecule complement factor D inhibitor that selectively blocks the alternative pathway, thereby working to address extravascular hemolysis when used in conjunction with C5 inhibitors.3 It was first approved in January 2024 in Japan for patients with PNH,2,6 shortly after which the EMA adopted a positive opinion and recommended granting it marketing authorization.2 It was subsequently approved by the FDA in March 2024.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 580.418
Monoisotopic: 579.102979 - Chemical Formula
- C26H23BrFN7O3
- Synonyms
- (2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide
- (2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidine-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridine-2-yl)-4-fluoropyrrolidine-2-carboxamide
- ACH-0144471
- ACH-CFDIS
- Danicopan
- External IDs
- ACH 0144471
- ACH-4471
- ACH0144471
- ALXN 2040
- ALXN-2040
- ALXN2040
Pharmacology
- Indication
Danicopan is indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adult patients with paroxysmal nocturnal hemoglobinuria (PNH).3
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Extravascular haemolysis Regimen in combination with: Ravulizumab (DB11580) •••••••••••• ••••• •••••• Used in combination to treat Extravascular haemolysis Regimen in combination with: Eculizumab (DB01257) •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Danicopan exerts its pharmacologic effects by selectively inhibiting the alternative pathway (AP) of the complement system.3 In patients with PNH undergoing treatment with ravulizumab or eculizumab, co-administration of danicopan 150-200mg three times daily resulted in a >90% inhibition of AP activity. In addition, plasma levels of component Bb decreased by ~50% and the fraction of circulating PNH red blood cells with C3 fragment depostion decreased by >50%.3
- Mechanism of action
The complement system is an enzyme cascade that plays a role in innate immunity. It helps defend against infection by initiating a local inflammatory response and is the system responsible for producing the terminal membrane attack complex (MAC), which causes lysis of foreign cells.5 In addition, the components of the complement pathway have other immune functions, including the promotion of phagocytosis, the clearance of immune complexes, and the regulation of antibody production.5 There are three pathways to complement activation - Lectin, Classical, and Alternative - which converge at complement component C3.5,1
Danicopan reversibly binds to complement factor D, thereby selectively inhibiting the alternative complement pathway.3 It prevents the formation of complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway. In paroxysmal nocturnal hemoglobinuria, intravascular hemolysis is mediated by the MAC, while extravascular hemolysis is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control C3 fragment-mediated EVH, while co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH.3
Target Actions Organism AComplement factor D inhibitorHumans - Absorption
The median Tmax is 3.7 hours following oral administration of 150 mg danicopan in patients with PNH.3 When administered with a high-fat meal, the AUC and Cmax of danicopan increase approximately 25% and 93%, respectively, compared to the fasted state. Median Tmax remains comparable whether administered fed or fasted.3
- Volume of distribution
The apparent volume of distribution of danicopan for a 75 kg person was 395 liters.3
- Protein binding
Danicopan is extensively (91.5% - 94.3%) bound to plasma proteins.3
- Metabolism
Danicopan is extensively metabolized, primarily via oxidation, reduction, and hydrolysis pathways.3 The major pathway of elimination is amide hydrolysis. Although metabolism via CYP-mediated pathways is minimal, approximately 96% of danicopan is metabolized through the aforementioned non-CYP pathways.3 In vitro studies suggest that danicopan has a very low likelihood of being involved in CYP-based drug-drug interactions.3
- Route of elimination
Following the administration of a single radiolabeled dose of danicopan, 69% of total radioactivity was excreted in feces (3.57% as unchanged parent drug) and 25% was excreted in urine (0.48% as unchanged parent drug).3
- Half-life
The mean half-life of danicopan is 7.9 hours.3
- Clearance
The mean apparent clearance of danicopan is 63 L/h.3
- Adverse Effects
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- Toxicity
In the event of an overdose of danicopan, increases in liver enzymes may occur. If an overdose is suspected, employ general supportive measures as clinically indicated.3
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Danicopan. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Danicopan. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Danicopan. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Danicopan. Afatinib The serum concentration of Afatinib can be increased when it is combined with Danicopan. - Food Interactions
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Voydeya Tablet, film coated 100 mg Oral Alexion Europe Sas 2024-07-10 Not applicable EU Voydeya Tablet, film coated 100 mg/1 Oral Alexion Pharma Gmbh 2024-03-29 Not applicable US Voydeya Tablet 200 mg / dose Oral Alexion Pharma Gmbh Not applicable Not applicable Canada Voydeya Tablet, film coated 100 mg Oral Alexion Europe Sas 2024-07-10 Not applicable EU Voydeya Tablet 150 mg / dose Oral Alexion Pharma Gmbh Not applicable Not applicable Canada - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Voydeya Danicopan (50 mg/1) + Danicopan (100 mg/1) Kit; Tablet, film coated Oral Alexion Pharma Gmbh 2024-03-29 Not applicable US Voydeya Danicopan (50 mg/1) + Danicopan (100 mg/1) Kit; Tablet, film coated Oral Alexion Pharma Gmbh 2024-03-29 Not applicable US Voydeya Danicopan (50 mg/1) + Danicopan (100 mg/1) Kit; Tablet, film coated Oral Alexion Pharma Gmbh 2024-03-29 Not applicable US Voydeya Danicopan (50 mg/1) + Danicopan (100 mg/1) Kit; Tablet, film coated Oral Alexion Pharma Gmbh 2024-03-29 Not applicable US
Categories
- ATC Codes
- L04AJ09 — Danicopan
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- JM8C1SFX0U
- CAS number
- 1903768-17-1
- InChI Key
- PIBARDGJJAGJAJ-NQIIRXRSSA-N
- InChI
- InChI=1S/C26H23BrFN7O3/c1-14(36)25-19-8-16(17-10-29-15(2)30-11-17)6-7-20(19)35(33-25)13-24(37)34-12-18(28)9-21(34)26(38)32-23-5-3-4-22(27)31-23/h3-8,10-11,18,21H,9,12-13H2,1-2H3,(H,31,32,38)/t18-,21+/m1/s1
- IUPAC Name
- (2S,4R)-1-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl]acetyl}-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide
- SMILES
- CC(=O)C1=NN(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NC2=CC=CC(Br)=N2)C2=C1C=C(C=C2)C1=CN=C(C)N=C1
References
- Synthesis Reference
Wiles, JA et. al.; Achillion Pharmaceuticals Inc. "Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders." US Patent US20180179186A1. June 28, 2018.
- General References
- Risitano AM, Kulasekararaj AG, Lee JW, Maciejewski JP, Notaro R, Brodsky R, Huang M, Geffner M, Browett P: Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021 Dec 1;106(12):3188-3197. doi: 10.3324/haematol.2020.261826. [Article]
- Kang C: Danicopan: First Approval. Drugs. 2024 Mar 26. doi: 10.1007/s40265-024-02023-6. [Article]
- FDA Approved Drug Products: Voydeya (danicopan) tablets for oral use [Link]
- AstraZeneca Press Release: Voydeya approved in the US as add-on therapy to ravulizumab or eculizumab for treatment of extravascular haemolysis in adults with the rare disease PNH [Link]
- MSD Manual: Complement System [Link]
- AstraZeneca Press Release: Voydeya (danicopan) granted first-ever regulatory approval in Japan for adults with PNH to be used in combination with C5 inhibitor therapy [Link]
- National Organization for Rare Disorders (NORD): Paroxysmal Nocturnal Hemoglobinuria [Link]
- External Links
- ChemSpider
- 75531295
- BindingDB
- 354268
- 2678952
- ChEMBL
- CHEMBL4250860
- Wikipedia
- Danicopan
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Available Not Available Extravascular haemolysis / Paroxysmal Nocturnal Hemoglobinuria (PNH) / PNH 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Paroxysmal Nocturnal Hemoglobinuria (PNH) 1 somestatus stop reason just information to hide 3 Completed Treatment Paroxysmal Nocturnal Hemoglobinuria (PNH) 1 somestatus stop reason just information to hide 3 Not Yet Recruiting Treatment Extravascular haemolysis / Paroxysmal Nocturnal Hemoglobinuria (PNH) / PNH 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Dry Macular Degeneration 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Kit; tablet, film coated Oral Tablet Oral 150 mg / dose Tablet Oral 200 mg / dose Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 100 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9796741 No 2015-02-25 2035-02-25 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Slightly soluble (pH 1.2) to Insoluble (pH 4-7) FDA Label - Predicted Properties
Property Value Source Water Solubility 0.0163 mg/mL ALOGPS logP 3.05 ALOGPS logP 2.53 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 11.7 Chemaxon pKa (Strongest Basic) 2.23 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 122.97 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 153.34 m3·mol-1 Chemaxon Polarizability 54.71 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway
- Specific Function
- serine-type endopeptidase activity
- Gene Name
- CFD
- Uniprot ID
- P00746
- Uniprot Name
- Complement factor D
- Molecular Weight
- 27032.66 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Drug Products: Voydeya (danicopan) tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Voydeya (danicopan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Voydeya (danicopan) tablets for oral use [Link]
Drug created at May 20, 2019 15:25 / Updated at May 25, 2024 00:54