Details of the Drug Combination

General Information of Drug Combination (ID: DCFD368)

• Drug Combination Name: Rivoceranib + Digoxin
• Indication: Advanced Solid Tumor; Status: Phase 1 [1]
• Component Drugs:
  Rivoceranib (DM13V0P): Small molecular drug
  Digoxin (DMQCTIH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Rivoceranib

Disease Entry	ICD 11	Status	REF
Gastric adenocarcinoma	2B72	Phase 3	[2]
Sarcoma	2A60-2C35	Phase 2	[3]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

Rivoceranib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Antagonist	[2]

Indication(s) of Digoxin

Disease Entry	ICD 11	Status	REF
Arrhythmia	BC9Z	Approved	[4]
Atrial fibrillation	BC81.3	Approved	[5]
Chronic heart failure	BD1Z	Approved	[5]
Congestive cardiac insufficiency	BD1Z	Approved	[4]
Heart failure	BD10-BD13	Approved	[4]

Digoxin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium/potassium-transporting ATPase (SPT ATPase)	TTQ38E9	AT1A1_HUMAN; AT1A2_HUMAN; AT1A3_HUMAN; AT1B1_HUMAN; AT1B2_HUMAN; AT1B3_HUMAN	Inhibitor	[7]
Organic anion transporter M1 (SLCO4C1)	TTACFNR	SO4C1_HUMAN	Modulator	[8]

Digoxin Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Multidrug resistance protein 3 (ABCB4)	DTZRMK5	MDR3_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[12]
Organic solute transporter subunit alpha (SLC51A)	DTMEQ32	OSTA_HUMAN	Substrate	[13]
Organic solute transporter subunit beta (SLC51B)	DT1V9AJ	OSTB_HUMAN	Substrate	[13]
Organic anion transporting polypeptide 4C1 (SLCO4C1)	DTY0QMU	SO4C1_HUMAN	Substrate	[14]

Digoxin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cardiac glycoside reductase 1 (cgr1)	DE84PFW	CGR1_EGGLE	Metabolism	[16]
Cardiac glycoside reductase 2 (cgr2)	DE9VSLW	CGR2_EGGLE	Metabolism	[16]

Digoxin Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[17]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases ADR	[18]
Interleukin-6 receptor subunit alpha (IL6R)	OTCQL07Z	IL6RA_HUMAN	Decreases Expression	[6]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Decreases Expression	[6]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[6]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[6]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[20]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[21]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Activity	[17]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[22]
Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1)	OTCJ458Q	AT1A1_HUMAN	Increases ADR	[18]
p21 protein (HRAS)	OTFYE6AJ	P78460_HUMAN	Increases ADR	[18]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases ADR	[18]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Response To Substance	[23]

References

• [1] ClinicalTrials.gov (NCT04322552) A Pharmacokinetic Interaction Study Between Apatinib Mesylate and Transporter Pgp Substrate Digoxin in Advanced Solid Tumor Subjects
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] ClinicalTrials.gov (NCT04072042) BIOmarker Driven Trial of VEGFR2 Inhibitor in Advanced Sarcoma (BIOVAS). U.S. National Institutes of Health.
• [4] 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: 4726).
• [5] Digoxin FDA Label
• [6] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [7] Fab antibody fragments: some applications in clinical toxicology. Drug Saf. 2004;27(14):1115-33.
• [8] 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. (Target id: 1227).
• [9] MDR1 function is sensitive to the phosphorylation state of myosin regulatory light chain. Biochem Biophys Res Commun. 2010 Jul 16;398(1):7-12.
• [10] MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem. 2000 Aug 4;275(31):23530-9.
• [11] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [12] Drug Interactions in Infectious Diseases.
• [13] Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003 Jul 25;278(30):27473-82.
• [14] Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74.
• [15] Omeprazole-associated digoxin toxicity. South Med J. 2007 Apr;100(4):400-2.
• [16] Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. Gut Microbes. 2014 Mar-Apr;5(2):233-8.
• [17] Digoxin and ouabain induce P-glycoprotein by activating calmodulin kinase II and hypoxia-inducible factor-1alpha in human colon cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):385-92. doi: 10.1016/j.taap.2009.07.026. Epub 2009 Jul 30.
• [18] 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.
• [19] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
• [20] Chronic digoxin toxicity and significantly elevated BNP levels in the presence of mild heart failure. Am J Emerg Med. 2005 Jul;23(4):561-2. doi: 10.1016/j.ajem.2004.10.009.
• [21] Intracellular potassium stabilizes human ether--go-go-related gene channels for export from endoplasmic reticulum. Mol Pharmacol. 2009 Apr;75(4):927-37. doi: 10.1124/mol.108.053793. Epub 2009 Jan 12.
• [22] Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 2005 Jan;312(1):144-52. doi: 10.1124/jpet.104.073916. Epub 2004 Sep 13.
• [23] Insulin interacts directly with Na?/K?ATPase and protects from digoxin toxicity. Toxicology. 2012 Sep 4;299(1):1-9. doi: 10.1016/j.tox.2012.04.013. Epub 2012 May 4.