Details of the Drug

General Information of Drug (ID: DMP6G8T)

Drug Name

Topotecan

Synonyms

Hycamptamine; Hycamptin; Hycamtamine; Topotecane; Topotecanum; Topotecan lactone; SKF 104864; SKF-S 104864; TOPOTECAN, HYCAMTIN; Topotecan (BAN); Topotecan [INN:BAN]; Topotecane [INN-French]; Topotecanum [INN-Latin]; Topotecan Monohydrochloride, (S)-Isomer; (4S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; (S)-10-((Dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione; (S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-DIHYDROXY-1H-PYRANO[3',4':6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE; (S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]-quinoline-3,14(4H,12H)-dione; (S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 9-Dimethylaminomethyl-10-hydroxycamptothecin

Indication

Disease Entry	ICD 11	Status	REF
Central nervous system neoplasm	N.A.	Approved	[1]
Cervical cancer	2C77.0	Approved	[1]
Epithelial ovarian cancer	2B5D	Approved	[1]
Lung cancer	2C25.0	Approved	[1]
Ovarian cancer	2C73	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Approved	[3]
Small-cell lung cancer	2C25.Y	Phase 1	[4]
Neuroblastoma	2D11.2	Investigative	[1]


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Therapeutic Class

Anticancer Agents

Affected Organisms

Humans and other mammals

ATC Code

L01CE01: Topotecan

L01CE: Topoisomerase 1 (TOP1) inhibitors

L01C: PLANT ALKALOIDS AND OTHER NATURAL PRODUCTS

L01: ANTINEOPLASTIC AGENTS

L: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

421.4

Logarithm of the Partition Coefficient (xlogp)

0.5

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [5]
Clearance: The drug present in the plasma can be removed from the body at the rate of 13 mL/min/kg [6]
Elimination: 40% of drug is excreted from urine in the unchanged form [5]
Half-life: The concentration or amount of drug in body reduced by one-half in 2 - 3 hours [6]
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 6.1572 micromolar/kg/day [7]
Unbound Fraction: The unbound fraction of drug in plasma is 0.65% [6]
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 1.8 L/kg [6]
Water Solubility: The ability of drug to dissolve in water is measured as 1 mg/mL [5]

Chemical Identifiers

Formula: C23H23N3O5
IUPAC Name: (19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
Canonical SMILES: CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=CC5=C(C=CC(=C5CN(C)C)O)N=C4C3=C2)O
InChI: InChI=1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
InChIKey: UCFGDBYHRUNTLO-QHCPKHFHSA-N

Cross-matching ID

PubChem CID: 60700
ChEBI ID: CHEMBL63632
CAS Number: 123948-87-8
UNII: 7M7YKX2N15
DrugBank ID: DB01030
TTD ID: D02PMO
VARIDT ID: DR00044
ACDINA ID: D00690

Drug-Molecule Activity Atlas (DMA)^NEW

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Drug Pharmacogenomic Perturbation (DPP)^NEW

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Drug ADMET Endpoint Profile (DAE)^NEW

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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 I (TOP1)	TTGTQHC	TOP1_HUMAN	Modulator	[8]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[9]
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[10]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[11]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial (BCKDHA)	OT0LHOZB	ODBA_HUMAN	Drug Response	[14]
A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1)	OTTLJH8W	ATS1_HUMAN	Drug Response	[14]
Acetyl-CoA acetyltransferase, cytosolic (ACAT2)	OTZ092ZJ	THIC_HUMAN	Drug Response	[14]
Acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A)	OTRHPFO2	AN32A_HUMAN	Drug Response	[14]
Actin, gamma-enteric smooth muscle (ACTG2)	OTRDWUO0	ACTH_HUMAN	Drug Response	[14]
Ankycorbin (RAI14)	OT6USGBK	RAI14_HUMAN	Drug Response	[14]
Ankyrin repeat domain-containing protein 10 (ANKRD10)	OTIZ2VK8	ANR10_HUMAN	Drug Response	[14]
AP-5 complex subunit mu-1 (AP5M1)	OTDLWEBL	AP5M1_HUMAN	Drug Response	[14]
Arginine and glutamate-rich protein 1 (ARGLU1)	OTRVRZ4Z	ARGL1_HUMAN	Drug Response	[14]
Argininosuccinate synthase (ASS1)	OT4ZMG0Q	ASSY_HUMAN	Drug Response	[14]

Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Central nervous system neoplasm

ICD Disease Classification

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
DNA topoisomerase I (TOP1)	DTT	TOP1	1.05E-01	0.17	0.27
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTP	MATE1	4.58E-22	-5.44E-01	-9.06E-01
P-glycoprotein 1 (ABCB1)	DTP	P-GP	3.61E-73	-1.15E+00	-1.66E+00
Multidrug resistance-associated protein 1 (ABCC1)	DTP	MRP1	1.33E-51	5.67E-01	1.25E+00
Breast cancer resistance protein (ABCG2)	DTP	BCRP	1.46E-65	-1.41E+00	-1.41E+00
Multidrug resistance-associated protein 4 (ABCC4)	DTP	MRP4	6.84E-05	8.79E-02	1.77E-01
Multidrug and toxin extrusion protein 2 (SLC47A2)	DTP	MATE2	6.25E-01	-5.97E-03	-1.97E-02

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Moderate	Accelerated clearance of Topotecan due to the transporter induction by Arn-509.	Acute myeloid leukaemia [2A60]	[15]
Gilteritinib	DMTI0ZO	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Gilteritinib.	Acute myeloid leukaemia [2A60]	[16]
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Topotecan and Roflumilast.	Asthma [CA23]	[15]
Ofloxacin	DM0VQN3	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by Ofloxacin.	Bacterial infection [1A00-1C4Z]	[17]
Sparfloxacin	DMB4HCT	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by Sparfloxacin.	Bacterial infection [1A00-1C4Z]	[17]
Gemifloxacin	DMHT34O	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by Gemifloxacin.	Bacterial infection [1A00-1C4Z]	[17]
Norfloxacin	DMIZ6W2	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by Norfloxacin.	Bacterial infection [1A00-1C4Z]	[17]
ABT-492	DMJFD2I	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by ABT-492.	Bacterial infection [1A00-1C4Z]	[17]
Levofloxacin	DMS60RB	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by Levofloxacin.	Bacterial infection [1A00-1C4Z]	[17]
Ag-221	DMS0ZBI	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Ag-221.	BCR-ABL1-negative chronic myeloid leukaemia [2A41]	[16]
Erdafitinib	DMI782S	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Erdafitinib.	Bladder cancer [2C94]	[18]
Tucatinib	DMBESUA	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Tucatinib.	Breast cancer [2C60-2C6Y]	[19]
PF-04449913	DMSB068	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by PF-04449913.	Chronic myelomonocytic leukaemia [2A40]	[15]
Fostemsavir	DM50ILT	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Fostemsavir.	Human immunodeficiency virus disease [1C60-1C62]	[20]
Teriflunomide	DMQ2FKJ	Major	Additive myelosuppressive effects by the combination of Topotecan and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[21]
BMS-201038	DMQTAGO	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by BMS-201038.	Hyper-lipoproteinaemia [5C80]	[22]
Tolvaptan	DMIWFRL	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Tolvaptan.	Hypo-osmolality/hyponatraemia [5C72]	[16]
Denosumab	DMNI0KO	Moderate	Additive myelosuppressive effects by the combination of Topotecan and Denosumab.	Low bone mass disorder [FB83]	[23]
Capmatinib	DMYCXKL	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Capmatinib.	Lung cancer [2C25]	[24]
Lasmiditan	DMXLVDT	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Lasmiditan.	Migraine [8A80]	[25]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Topotecan and Thalidomide.	Multiple myeloma [2A83]	[26]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Topotecan and Tecfidera.	Multiple sclerosis [8A40]	[27]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Topotecan and Siponimod.	Multiple sclerosis [8A40]	[16]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Topotecan and Fingolimod.	Multiple sclerosis [8A40]	[28]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Topotecan and Ozanimod.	Multiple sclerosis [8A40]	[15]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive immunosuppressive effects by the combination of Topotecan and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[29]
Rolapitant	DM8XP26	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Rolapitant.	Nausea/vomiting [MD90]	[30]
Lonafarnib	DMGM2Z6	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Lonafarnib.	Premature ageing appearance [LD2B]	[31]
Enzalutamide	DMGL19D	Moderate	Accelerated clearance of Topotecan due to the transporter induction by Enzalutamide.	Prostate cancer [2C82]	[32]
Darolutamide	DMV7YFT	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Darolutamide.	Prostate cancer [2C82]	[33]
Gatifloxacin	DMSL679	Minor	Decreased absorption of Topotecan due to intestinal mucosa variation caused by Gatifloxacin.	Respiratory infection [CA07-CA4Z]	[17]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Topotecan and Canakinumab.	Rheumatoid arthritis [FA20]	[34]
Rilonacept	DMGLUQS	Moderate	Additive immunosuppressive effects by the combination of Topotecan and Rilonacept.	Rheumatoid arthritis [FA20]	[34]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Topotecan and Golimumab.	Rheumatoid arthritis [FA20]	[35]
Leflunomide	DMR8ONJ	Major	Additive immunosuppressive effects by the combination of Topotecan and Leflunomide.	Rheumatoid arthritis [FA20]	[21]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Topotecan when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[36]
Tedizolid	DMG2SKR	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Tedizolid.	Skin and skin-structure infection [1F28-1G0Z]	[15]
Fostamatinib	DM6AUHV	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Fostamatinib.	Thrombocytopenia [3B64]	[37]
Eltrombopag	DMOGFIX	Moderate	Decreased clearance of Topotecan due to the transporter inhibition by Eltrombopag.	Thrombocytopenia [3B64]	[38]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Topotecan and Valganciclovir.	Virus infection [1A24-1D9Z]	[16]


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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Glyceryl monostearate	E00310	24699	Emollient; Emulsifying agent; Emulsion stabilizing agent; Solubilizing agent; Surfactant; Viscosity-controlling agent
Hydrochloric acid	E00015	313	Acidulant
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Eisenoxyd	E00585	56841934	Colorant
Gelatin	E00630	Not Available	Other agent
Sodium hydroxide	E00234	14798	Alkalizing agent
Tartaric acid	E00029	875	Acidulant; Complexing agent; Flavoring agent
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Haematite red	E00236	14833	Colorant


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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Topotecan 0.25 mg capsule	0.25 mg	Oral Capsule	Oral
Topotecan 1 mg capsule	1 mg	Oral Capsule	Oral
Topotecan Hydrochloride eq 0.25mg base capsule	eq 0.25mg base	Capsule	Oral
Topotecan Hydrochloride eq 4mg base/vial injectable	eq 4mg base/vial	Injectable	Injection

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References

1	Topotecan 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: 7101).
3	Plant-derived compounds in clinical trials. Drug Discov Today. 2008 Feb;13(3-4):161-71.
4	ClinicalTrials.gov (NCT00765973) Topotecan Liposomes Injection for Small Cell Lung Cancer (SCLC), Ovarian Cancer and Other Advanced Solid Tumors. U.S. National Institutes of Health.
5	BDDCS applied to over 900 drugs
6	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
7	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
8	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
9	Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab. 2006 Jan;7(1):105-18.
10	Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
11	Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71.
12	Differential inhibition of murine Bcrp1/Abcg2 and human BCRP/ABCG2 by the mycotoxin fumitremorgin C. Eur J Pharmacol. 2010 Oct 10;644(1-3):41-8.
13	Involvement of P-glycoprotein, multidrug resistance protein 2 and breast cancer resistance protein in the transport of belotecan and topotecan in Caco-2 and MDCKII cells. Pharm Res. 2008 Nov;25(11):2601-12.
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	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
16	Cerner Multum, Inc. "Australian Product Information.".
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. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.
19	Product Information. Tukysa (tucatinib). Seattle Genetics Inc, Bothell, WA.
20	Product Information. Rukobia (fostemsavir). ViiV Healthcare, Research Triangle Park, NC.
21	Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
22	Product Information. Juxtapid (lomitapide). Aegerion Pharmaceuticals Inc, Cambridge, MA.
23	Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
24	Product Information. Tabrecta (capmatinib). Novartis Pharmaceuticals, East Hanover, NJ.
25	Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
26	Bennett CL, Nebeker JR, Samore MH, et al "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA 293 (2005): 2131-40. [PMID: 15870417]
27	Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
28	Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
29	Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
30	Product Information. Varubi (rolapitant). Tesaro Inc., Waltham, MA.
31	Product Information. Zokinvy (lonafarnib). Eiger BioPharmaceuticals, Palo Alto, CA.
32	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]
33	Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
34	Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
35	Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
36	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]
37	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.
38	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]