Details of the Drug Combination

General Information of Drug Combination (ID: DCSAHE5)

• Drug Combination Name: Clarithromycin + Pomalidomide
• Indication: Multiple Myeloma; Status: Phase 1 [1]
• Component Drugs:
  Clarithromycin (DM4M1SG): Small molecular drug
  Pomalidomide (DMTGBAX): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clarithromycin

Disease Entry	ICD 11	Status	REF
Acute maxillary sinusitis	N.A.	Approved	[2]
Acute otitis media	AB00	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Streptococcal pneumonia	N.A.	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Pneumonia caused by chlamydia	N.A.	Investigative	[2]

Clarithromycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 50S ribosomal RNA (Bact 50S rRNA)	TTUWYEA	NOUNIPROTAC	Binder	[7]

Clarithromycin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Clarithromycin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Clarithromycin Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[12]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[13]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Decreases Expression	[14]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Decreases Expression	[14]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[14]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[16]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[17]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[18]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Integrin beta-4 (ITGB4)	OT28UK84	ITB4_HUMAN	Decreases Expression	[20]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[21]
Translation initiation factor IF-2, mitochondrial (MTIF2)	OTAIOZ0J	IF2M_HUMAN	Decreases Response To Substance	[16]
Misshapen-like kinase 1 (MINK1)	OTKB0RA8	MINK1_HUMAN	Increases ADR	[21]

Indication(s) of Pomalidomide

Disease Entry	ICD 11	Status	REF
Plasma cell myeloma	2A83.1	Approved	[5]
Systemic sclerosis	4A42	Approved	[6]

Pomalidomide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiogenesis/myeloma cell growth (AMCG)	TTDIBYJ	NOUNIPROTAC	Modulator	[22]

Pomalidomide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]

Pomalidomide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[24]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[25]

Pomalidomide Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Oxidation	[26]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[27]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Secretion	[27]
Granulocyte colony-stimulating factor (CSF3)	OT9GC6TP	CSF3_HUMAN	Increases Secretion	[27]
Fibroblast growth factor receptor 1 (FGFR1)	OT4GLCXW	FGFR1_HUMAN	Decreases Expression	[28]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[27]
Erythroid transcription factor (GATA1)	OTX1R7O1	GATA1_HUMAN	Decreases Expression	[27]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Decreases Expression	[27]
Transcription factor PU.1 (SPI1)	OTVCA1D0	SPI1_HUMAN	Increases Expression	[27]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[27]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Affects Expression	[28]
Endothelial transcription factor GATA-2 (GATA2)	OTBP2QQ2	GATA2_HUMAN	Decreases Expression	[27]
Rhombotin-2 (LMO2)	OTCC370G	RBTN2_HUMAN	Decreases Expression	[27]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Decreases Secretion	[27]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[27]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[27]
CCAAT/enhancer-binding protein delta (CEBPD)	OTNBIPMY	CEBPD_HUMAN	Increases Expression	[27]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[27]
Krueppel-like factor 1 (KLF1)	OT1FK08U	KLF1_HUMAN	Decreases Expression	[27]
CCAAT/enhancer-binding protein epsilon (CEBPE)	OTKZA25M	CEBPE_HUMAN	Increases Expression	[27]
Transcription factor NF-E2 45 kDa subunit (NFE2)	OTLM94BI	NFE2_HUMAN	Decreases Expression	[27]
Zinc finger protein Gfi-1b (GFI1B)	OTRDW8YO	GFI1B_HUMAN	Decreases Expression	[27]
Zinc finger protein Gfi-1 (GFI1)	OT9HB9H8	GFI1_HUMAN	Increases Expression	[27]
Sal-like protein 4 (SALL4)	OTC08PR5	SALL4_HUMAN	Affects Binding	[29]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Oxidation	[26]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Increases Oxidation	[26]
Protein cereblon (CRBN)	OTXH9MDC	CRBN_HUMAN	Increases Response To Substance	[30]

References

• [1] ClinicalTrials.gov (NCT01745588) Autologous Stem Cell Transplant With Pomalidomide (CC-4047) Maintenance Versus Continuous Clarithromycin/ Pomalidomide / Dexamethasone Salvage Therapy in Relapsed or Refractory Multiple Myeloma
• [2] Clarithromycin FDA Label
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early (ACHIEVE)
• [5] Pomalidomide FDA Label
• [6] 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: 7348).
• [7] Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001 Oct 25;413(6858):814-21.
• [8] 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.
• [9] Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis. J Cyst Fibros. 2014 Mar;13(2):179-85.
• [10] Drug Interactions Flockhart Table
• [11] Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection. Clin Gastroenterol Hepatol. 2005 Jun;3(6):564-73.
• [12] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [13] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [14] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [15] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [16] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.
• [17] Liver toxicity of macrolide antibiotics in zebrafish. Toxicology. 2020 Aug;441:152501. doi: 10.1016/j.tox.2020.152501. Epub 2020 May 23.
• [18] Differential effects of three antibiotics on T helper cell cytokine expression. J Antimicrob Chemother. 2005 Sep;56(3):502-6. doi: 10.1093/jac/dki251. Epub 2005 Jul 8.
• [19] T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest. 2001 Jun;107(11):1433-41. doi: 10.1172/JCI12118.
• [20] Effects of eight antibacterial agents on cell survival and expression of epithelial-cell- or cell-adhesion-related genes in human gingival epithelial cells. J Periodontal Res. 2004 Feb;39(1):50-8. doi: 10.1111/j.1600-0765.2004.00704.x.
• [21] 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.
• [22] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [23] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB08910)
• [24] Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects. J Clin Pharmacol. 2015 Feb;55(2):168-78.
• [25] Population pharmacokinetics of pomalidomide. J Clin Pharmacol. 2015 May;55(5):563-72.
• [26] Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide. Chem Res Toxicol. 2014 Jan 21;27(1):147-56. doi: 10.1021/tx4004215. Epub 2013 Dec 24.
• [27] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [28] Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity. Chem Res Toxicol. 2019 Apr 15;32(4):589-602. doi: 10.1021/acs.chemrestox.8b00286. Epub 2019 Mar 15.
• [29] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [30] A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple Myeloma Patient Samples. Appl Immunohistochem Mol Morphol. 2016 Nov/Dec;24(10):695-702. doi: 10.1097/PAI.0000000000000246.