Details of the Drug

General Information of Drug (ID: DMM39BF)

Drug Name

Mitoxantrone

Synonyms

DHAD; DHAQ; Dihydroxyanthraquinone; MIX; Misostol; Mitoxanthrone; Mitoxantron; Mitoxantrona; Mitoxantronum; Mitozantrone; DHAQ HCl; Mitoxantrone [INN]; Mitozantrone hydrochloride; Mitoxantrone 2HCl; Liposome Encapsulated Mitoxantrone (LEM); Misostol (TN); Mitoxantrona [INN-Spanish]; Mitoxantrone (INN); Mitoxantrone (free base); Mitoxantronum [INN-Latin]; Novantrone (TN); AN-584/42007670; Novantrone(R) (mitoxantrone for injection concentrate); DHAQ (*Diacetate salt*); MITOXANTRONE, Mitoxantrone Hydrochloride, Mitoxantrone dihydrochloride, MITOXANTHRONE HYDROCHLORIDE; MITOXANTRONE, 1,4-DIHYDROXY-5,8-BIS({2-[(2-HYDROXYETHYL)AMINO]ETHYL}AMINO)ANTHRA-9,10-QUINONE; 1,4-Bis(2-(2-hydroxyethylamino)ethyl)amino)-5,8-dihydroxyanthraquinone; 1,4-DIHYDROXY-5,8-BIS({2-[(2-HYDROXYETHYL)AMINO]ETHYL}AMINO)-9,10-ANTHRACENEDIONE; 1,4-Dihydroxy-5,8-bis(2-((2-hydroxyethyl)amino)ethylamino)-9,10-anthracenedione; 1,4-Dihydroxy-5,8-bis(5-hydroxy-3-azapentylamino)anthrachinon; 1,4-Dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione; 1,4-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione; 1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthra-9,10-quinone; 1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthracene-9,10-dione; 5,8-Bis((2-((2-hydroxyethyl)amino)ethyl)amino)-1,4-dihydroxyanthraquinone; 9,10-Anthracenedione, 1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-(9CI)

Indication

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[1]
Adult acute monocytic leukemia	N.A.	Approved	[1]
Leukemia	N.A.	Approved	[1]
Solid tumour/cancer	2A00-2F9Z	Approved	[2]
Non-hodgkin lymphoma	2B33.5	Phase 1/2	[3]
Metastatic prostate carcinoma	N.A.	Investigative	[1]
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Therapeutic Class

Analgesics

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 2

Molecular Weight (mw)

444.5

Logarithm of the Partition Coefficient (xlogp)

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption: The drug is poorly absorbed following oral administration []
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [4]
Clearance: The drug present in the plasma can be removed from the body at the rate of 7.9 mL/min/kg [5]
Elimination: 7% of drug is excreted from urine in the unchanged form [4]
Half-life: The concentration or amount of drug in body reduced by one-half in 75 hours [5]
Metabolism: The drug is metabolized via the hepatic []
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.7784 micromolar/kg/day [6]
Unbound Fraction: The unbound fraction of drug in plasma is 0.25% [5]
Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 12 L/kg [5]
Water Solubility: The ability of drug to dissolve in water is measured as 7.5 mg/mL [4]

Adverse Drug Reaction (ADR)

ADR Term	Variation	Related DOT	DOT ID	REF
Apoptosis	Not Available	CCND1	OT8HPTKJ	[7]
Apoptosis	Not Available	MYB	OTJH64IV	[7]
Cytogenetic investigations	Not Available	TOP1	OT51O0CF	[7]
Drug toxicity	Not Available	EPHX1	OTBKWQER	[7]
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Chemical Identifiers

Formula: C22H28N4O6
IUPAC Name: 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione
Canonical SMILES: C1=CC(=C2C(=C1NCCNCCO)C(=O)C3=C(C=CC(=C3C2=O)O)O)NCCNCCO
InChI: InChI=1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2
InChIKey: KKZJGLLVHKMTCM-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 4212
ChEBI ID: CHEBI:50729
CAS Number: 65271-80-9
DrugBank ID: DB01204
TTD ID: D0R3JB
VARIDT ID: DR00269
INTEDE ID: DR1102

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN ; TOP2B_HUMAN	Modulator	[8]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
ATP-binding cassette sub-family A member 3 (ABCA3)	DT2T6VQ	ABCA3_HUMAN	Substrate	[9]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2E1 (CYP2E1)_{Main DME}	DEVDYN7	CP2E1_HUMAN	Substrate	[13]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon (AGPAT5)	OTNY3VMD	PLCE_HUMAN	Drug Response	[14]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 (PLCB4)	OTPA0QHW	PLCB4_HUMAN	Drug Response	[14]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Drug Response	[14]
3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D)	OT1RWFV0	PDE4D_HUMAN	Drug Response	[14]
3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1)	OTQRET2B	S5A1_HUMAN	Drug Response	[14]
Actin, alpha skeletal muscle (ACTA1)	OTOVGLPG	ACTS_HUMAN	Gene/Protein Processing	[15]
Actin, gamma-enteric smooth muscle (ACTG2)	OTRDWUO0	ACTH_HUMAN	Drug Response	[14]
ADP-ribose glycohydrolase MACROD1 (MACROD1)	OTWFEVRW	MACD1_HUMAN	Drug Response	[14]
Aldehyde dehydrogenase, mitochondrial (ALDH2)	OTKJ9I3N	ALDH2_HUMAN	Drug Response	[14]
AN1-type zinc finger protein 1	OTGZ9X6J	ZFAN1_HUMAN	Drug Response	[14]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Mitoxantrone (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Moderate	Accelerated clearance of Mitoxantrone due to the transporter induction by Arn-509.	Acute myeloid leukaemia [2A60]	[16]
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Mitoxantrone and Roflumilast.	Asthma [CA23]	[16]
Sparfloxacin	DMB4HCT	Minor	Decreased absorption of Mitoxantrone due to intestinal mucosa variation caused by Sparfloxacin.	Bacterial infection [1A00-1C4Z]	[17]
ABT-492	DMJFD2I	Minor	Decreased absorption of Mitoxantrone due to intestinal mucosa variation caused by ABT-492.	Bacterial infection [1A00-1C4Z]	[17]
Fostemsavir	DM50ILT	Moderate	Decreased clearance of Mitoxantrone due to the transporter inhibition by Fostemsavir.	Human immunodeficiency virus disease [1C60-1C62]	[18]
Teriflunomide	DMQ2FKJ	Major	Additive immunosuppressive effects by the combination of Mitoxantrone and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[19]
Denosumab	DMNI0KO	Moderate	Additive myelosuppressive effects by the combination of Mitoxantrone and Denosumab.	Low bone mass disorder [FB83]	[20]
Lasmiditan	DMXLVDT	Moderate	Decreased clearance of Mitoxantrone due to the transporter inhibition by Lasmiditan.	Migraine [8A80]	[21]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Mitoxantrone and Tecfidera.	Multiple sclerosis [8A40]	[22]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Mitoxantrone and Siponimod.	Multiple sclerosis [8A40]	[23]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Mitoxantrone and Fingolimod.	Multiple sclerosis [8A40]	[24]
Ocrelizumab	DMEZ2KH	Moderate	Additive immunosuppressive effects by the combination of Mitoxantrone and Ocrelizumab.	Multiple sclerosis [8A40]	[25]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Mitoxantrone and Ozanimod.	Multiple sclerosis [8A40]	[16]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Mitoxantrone and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[26]
Enzalutamide	DMGL19D	Moderate	Accelerated clearance of Mitoxantrone due to the transporter induction by Enzalutamide.	Prostate cancer [2C82]	[27]
Darolutamide	DMV7YFT	Moderate	Decreased clearance of Mitoxantrone due to the transporter inhibition by Darolutamide.	Prostate cancer [2C82]	[28]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Mitoxantrone and Canakinumab.	Rheumatoid arthritis [FA20]	[29]
Rilonacept	DMGLUQS	Moderate	Additive immunosuppressive effects by the combination of Mitoxantrone and Rilonacept.	Rheumatoid arthritis [FA20]	[29]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Mitoxantrone and Golimumab.	Rheumatoid arthritis [FA20]	[30]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Mitoxantrone when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[31]
Eltrombopag	DMOGFIX	Moderate	Decreased clearance of Mitoxantrone due to the transporter inhibition by Eltrombopag.	Thrombocytopenia [3B64]	[32]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Mitoxantrone and Valganciclovir.	Virus infection [1A24-1D9Z]	[23]
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References

1	Mitoxantrone FDA Label
2	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7242).
3	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
4	BDDCS applied to over 900 drugs
5	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
6	Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
7	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
8	Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 1998 Jan;100(1):142-6.
9	A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14228-33.
10	Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
11	Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol Pharmacol. 2006 Apr;69(4):1499-505.
12	Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun. 2001 Jul 6;285(1):111-7.
13	FDA label of Mitoxantrone. The 2020 official website of the U.S. Food and Drug Administration.
14	Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
15	Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
16	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
17	Johnson EJ, MacGowan AP, Potter MN, et al "Reduced absorption of oral ciprofloxacin after chemotherapy for haematological malignancy." J Antimicrob Chemother 25 (1990): 837-42. [PMID: 2373666]
18	Product Information. Rukobia (fostemsavir). ViiV Healthcare, Research Triangle Park, NC.
19	Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
20	Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
21	Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
22	Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
23	Cerner Multum, Inc. "Australian Product Information.".
24	Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
25	Product Information. Ocrevus (ocrelizumab). Genentech, South San Francisco, CA.
26	Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
27	Benoist G, van Oort I, et al "Drug-drug interaction potential in men treated with enzalutamide: Mind the gap." Br J Clin Pharmacol 0 (2017): epub. [PMID: 28881501]
28	Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
29	Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
30	Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
31	CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]
32	Allred AJ, Bowen CJ, Park JW, et al. "Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers." Br J Clin Pharmacol 72 (2011): 321-9. [PMID: 21434975]