Details of the Drug Combination

General Information of Drug Combination (ID: DCS6I8C)

• Drug Combination Name: Everolimus + Itraconazole
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Everolimus (DM8X2EH): Small molecular drug
  Itraconazole (DMCR1MV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 13.55
  Bliss Independence Score: 13.55
  Loewe Additivity Score: 20.62
  LHighest Single Agent (HSA) Score: 20.68

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Advanced/metastatic breast cancer	2C60	Approved	[3]
Brainstem neoplasm	N.A.	Approved	[2]
Breast carcinoma	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Leukemia	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mucosal melanoma	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Renal cell carcinoma	2C90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Tuberous sclerosis	LD2D.2	Approved	[2]
Kidney cancer	2C90.0	Phase 3	[4]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Colon cancer	2B90.Z	Investigative	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[5]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[5]

Everolimus Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[8]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[5]

Everolimus Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Everolimus Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Indication(s) of Itraconazole

Disease Entry	ICD 11	Status	REF
Aspergillosis	1F20	Approved	[6]
Blastomycosis	1F22	Approved	[6]
Fungal infection	1F29-1F2F	Approved	[7]
Fusariosis	N.A.	Approved	[6]
Histoplasmosis	N.A.	Approved	[6]
Invasive candidiasis	1F23	Approved	[6]
Mycoses	1F2Z	Approved	[6]
Candidemia	1F23.3Y	Investigative	[6]
Esophageal candidiasis	N.A.	Investigative	[6]

Itraconazole Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Hedgehog signaling pathway (HS pathway)	TT4LXBC	NOUNIPROTAC	Inhibitor	[11]
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Modulator	[12]

Itraconazole Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

Itraconazole Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[15]

Itraconazole Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[17]
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Decreases Activity	[18]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[19]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Expression	[20]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[21]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[22]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[22]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[23]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[24]

References

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• [2] Everolimus FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 5889).
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] Itraconazole FDA Label
• [7] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076104.
• [8] Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
• [9] Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations. Ther Drug Monit. 2015 Oct;37(5):675-80.
• [10] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.
• [11] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [13] 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.
• [14] Effects of itraconazole and tandospirone on the pharmacokinetics of perospirone. Ther Drug Monit. 2006 Feb;28(1):73-5.
• [15] Investigation into UDP-glucuronosyltransferase (UGT) enzyme kinetics of imidazole- and triazole-containing antifungal drugs in human liver microsomes and recombinant UGT enzymes. Drug Metab Dispos. 2010 Jun;38(6):923-9.
• [16] Itraconazole cis-diastereoisomers activate aryl hydrocarbon receptor AhR and pregnane X receptor PXR and induce CYP1A1 in human cell lines and human hepatocytes. Toxicology. 2017 May 15;383:40-49.
• [17] Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. Ther Drug Monit. 2005 Jun;27(3):322-33. doi: 10.1097/01.ftd.0000150135.22645.ea.
• [18] The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
• [19] Induction of cytochrome P450 1A1 by ketoconazole and itraconazole but not fluconazole in murine and human hepatoma cell lines. Toxicol Sci. 2007 May;97(1):32-43.
• [20] Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression. Drug Metab Dispos. 2008 Feb;36(2):339-48.
• [21] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [22] Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis. J Invest Dermatol. 2001 Dec;117(6):1635-46. doi: 10.1046/j.0022-202x.2001.01566.x.
• [23] Inhibition of 11-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Biochem Pharmacol. 2017 Apr 15;130:93-103. doi: 10.1016/j.bcp.2017.01.010. Epub 2017 Jan 25.
• [24] Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homolo... Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603.