Details of the Drug Combination

General Information of Drug Combination (ID: DCKZC2D)

• Drug Combination Name: Aripiprazole + Modafinil
• Indication: Schizophrenia; Status: Phase 4 [1]
• Component Drugs:
  Aripiprazole (DM3NUMH): Small molecular drug
  Modafinil (DMYILBE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Aripiprazole

Disease Entry	ICD 11	Status	REF
Bipolar I disorder	N.A.	Approved	[2]
Erythropoietic porphyrias	5C58.12	Approved	[3]
Schizoaffective disorder	6A21	Approved	[2]
Schizophrenia	6A20	Approved	[4]
Major depressive disorder	6A70.3	Phase 3	[5]
Bipolar disorder	6A60	Application submitted	[6]
Autism	N.A.	Investigative	[2]

Aripiprazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[10]

Aripiprazole Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[12]

Aripiprazole Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Toll-like receptor 5 (TLR5)	OT8ZYKJ6	TLR5_HUMAN	Increases Expression	[13]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Expression	[14]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[13]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Decreases Expression	[13]
G antigen 1 (GAGE1)	OT53E50E	GAGE1_HUMAN	Increases Expression	[13]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Binding	[15]
Cancer/testis antigen 1 (CTAG1B)	OTIQGW6U	CTG1B_HUMAN	Increases Expression	[13]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[16]
Interferon-stimulated gene 20 kDa protein (ISG20)	OTCWRJJW	ISG20_HUMAN	Increases Expression	[13]
Fasciculation and elongation protein zeta-1 (FEZ1)	OTWCXPRE	FEZ1_HUMAN	Increases Expression	[13]
Synaptotagmin-17 (SYT17)	OTTW4MI3	SYT17_HUMAN	Decreases Expression	[13]
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2)	OTPGYWKC	NOD2_HUMAN	Increases Expression	[13]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Decreases Response To Substance	[17]

Indication(s) of Modafinil

Disease Entry	ICD 11	Status	REF
Malignant glioma	2A00.0	Approved	[7]
Methamphetamine dependence	6C46.2	Approved	[7]
Narcolepsy	7A20	Approved	[3]
Pain	MG30-MG3Z	Approved	[7]
Postpoliomyelitis syndrome	N.A.	Approved	[7]
Traumatic brain injury	NA07.Z	Approved	[7]
Bipolar disorder	6A60	Phase 4	[8]
Brain injury	NA07.Z	Investigative	[9]

Modafinil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine transporter (DAT)	TTVBI8W	SC6A3_HUMAN	Modulator	[18]

Modafinil Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]

Modafinil Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Affects Response To Substance	[20]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[21]

References

• [1] ClinicalTrials.gov (NCT01913327) Antipsychotic Effects on Brain Function in Schizophrenia
• [2] Aripiprazole 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: 34).
• [5] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034267)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Modafinil FDA Label
• [8] ClinicalTrials.gov (NCT01965925) Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil. U.S. National Institutes of Health.
• [9] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [10] Aripiprazole acts as a selective dopamine D2 receptor partial agonist. Expert Opin Investig Drugs. 2007 Jun;16(6):771-5.
• [11] Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs. 2004;64(15):1715-36.
• [12] Drug Interactions Flockhart Table
• [13] Small Molecule Antipsychotic Aripiprazole Potentiates Ozone-Induced Inflammation in Airway Epithelium. Chem Res Toxicol. 2019 Oct 21;32(10):1997-2005. doi: 10.1021/acs.chemrestox.9b00149. Epub 2019 Sep 11.
• [14] The efficacy, safety, and tolerability of aripiprazole for the treatment of schizoaffective disorder: results from a pooled analysis of a sub-population of subjects from two randomized, double-blind, placebo-controlled, pivotal trials. J Affect Disord. 2009 May;115(1-2):18-26. doi: 10.1016/j.jad.2008.12.017. Epub 2009 Feb 23.
• [15] Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter. J Med Chem. 2011 Sep 22;54(18):6305-18. doi: 10.1021/jm200682b. Epub 2011 Aug 23.
• [16] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [17] Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J. 2006 Jan-Feb;6(1):42-51. doi: 10.1038/sj.tpj.6500342.
• [18] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [19] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [20] Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT. Sleep. 2010 Aug;33(8):1027-35. doi: 10.1093/sleep/33.8.1027.
• [21] Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans. J Neurosci. 2014 Jan 8;34(2):566-73. doi: 10.1523/JNEUROSCI.4128-13.2014.