Details of the Drug Combination

General Information of Drug Combination (ID: DCBA29L)

• Drug Combination Name: Alfacalcidol + Mefloquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  Alfacalcidol (DM1237M): N.A.
  Mefloquine (DMWT905): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 3.179
  Bliss Independence Score: 3.247
  Loewe Additivity Score: 1.865
  LHighest Single Agent (HSA) Score: 3.932

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Alfacalcidol

Disease Entry	ICD 11	Status	REF
Hyperparathyroidism	5A51	Approved	[2]
Hypoparathyroidism	5A50	Approved	[3]
Renal osteodystrophy	N.A.	Approved	[4]

Alfacalcidol Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Vitamin D(3) 25-hydroxylase (CYP27A1)	DEBS639	CP27A_HUMAN	Metabolism	[10]
Cytochrome P450 2J2 (CYP2J2)	DERSX5P	CP2J2_HUMAN	Metabolism	[11]

Alfacalcidol Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Increases Expression	[12]
Toll-like receptor 2 (TLR2)	OTGO5P4R	TLR2_HUMAN	Decreases Expression	[13]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Increases Expression	[14]
Monocyte differentiation antigen CD14 (CD14)	OT83GJ47	CD14_HUMAN	Increases Expression	[13]
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Affects Binding	[15]
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B)	OTDS2EAR	TNR1B_HUMAN	Decreases Expression	[14]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Hydroxylation	[16]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Affects Response To Substance	[17]

Indication(s) of Mefloquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[6]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[7]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[7]
Progressive multifocal leukoencephalopathy	8A45.02	Investigative	[8]

Mefloquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium 80S ribosome (Malaria 80S)	TTT28H3	NOUNIPROTAC	Binder	[18]

Mefloquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]

Mefloquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] X-Linked Hypophosphatemia. 2012 Feb 9 [updated 2023 Dec 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Auditing the Efficacy and Safety of Alfacalcidol and Calcium Therapy in Idiopathic Hypoparathyroidism. J Clin Endocrinol Metab. 2019 Apr 1;104(4):1325-1335.
• [4] Cross-linked C-terminal telopeptide of type I collagen in serum before and after treatment with alfacalcidol and calcium carbonate in early and moderate chronic renal failure. Nephron. 2002 Oct;92(2):304-8.
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 019578
• [6] ClinicalTrials.gov (NCT04347031) An Open Randomized Study of the Effectiveness of Mefloquine for the Treatment of Patients With COVID19. U.S. National Institutes of Health.
• [7] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [8] Mefloquine FDA Label
• [9] Functional evolution of the vitamin D and pregnane X receptors. BMC Evol Biol. 2007 Nov 12;7:222. doi: 10.1186/1471-2148-7-222.
• [10] Kidney microsomal 25- and 1alpha-hydroxylase in vitamin D metabolism: catalytic properties, molecular cloning, cellular localization and expression during development. Biochim Biophys Acta. 2002 Feb 28;1580(2-3):133-44.
• [11] Characterization of rat and human CYP2J enzymes as Vitamin D 25-hydroxylases. Steroids. 2006 Oct;71(10):849-56.
• [12] Dermal fibroblasts pretreated with a sterol Delta7-reductase inhibitor produce 25-hydroxyvitamin D3 upon UVB irradiation. J Photochem Photobiol B. 2006 Oct 2;85(1):72-8.
• [13] 1-alpha-calcidol modulates major human monocyte antigens and toll-like receptors TLR 2 and TLR4 in vitro. Eur J Med Res. 2005 Apr 20;10(4):179-82.
• [14] Supplementation with Alfacalcidol increases protein intake and serum albumin concentration in patients undergoing hemodialysis with hpoalbumineamia. Blood Purif. 2004;22(2):210-5. doi: 10.1159/000076855.
• [15] Hydrogen/deuterium exchange reveals distinct agonist/partial agonist receptor dynamics within vitamin D receptor/retinoid X receptor heterodimer. Structure. 2010 Oct 13;18(10):1332-41. doi: 10.1016/j.str.2010.07.007.
• [16] CYP3A4 is a human microsomal vitamin D 25-hydroxylase. J Bone Miner Res. 2004 Apr;19(4):680-8.
• [17] Association of transforming growth factor beta1 genotype with therapeutic response to active vitamin D for postmenopausal osteoporosis. J Bone Miner Res. 2000 Mar;15(3):415-20. doi: 10.1359/jbmr.2000.15.3.415.
• [18] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [19] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [20] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.