Details of the Drug Combination

General Information of Drug Combination (ID: DCMFNTG)

• Drug Combination Name: Vonoprazan + Amoxicillin
• Indication: Helicobacter Pylori Infection; Status: Phase 3 [1]
• Component Drugs:
  Vonoprazan (DMO6315): Small molecular drug
  Amoxicillin (DMUYNEI): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vonoprazan

Disease Entry	ICD 11	Status	REF
Helicobacter infection	DA42-DA63	Approved	[2]
Gastroesophageal reflux disease	DA22.Z	Phase 3	[3]

Vonoprazan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gastric H(+)/K(+) ATPase (Proton pump)	TTLOKXP	ATP4A_HUMAN; ATP4B_HUMAN	Modulator	[2]

Vonoprazan Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[6]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[6]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[6]
Sulfotransferase 2A1 (SULT2A1)	DE0P6LK	ST2A1_HUMAN	Metabolism	[6]

Indication(s) of Amoxicillin

Disease Entry	ICD 11	Status	REF
Acute otitis media	AB00	Approved	[4]
Bacterial infection	1A00-1C4Z	Approved	[5]
Staphylococcus aureus infection	N.A.	Approved	[4]
Streptococcal pneumonia	N.A.	Approved	[4]
Urinary tract infection	GC08	Approved	[4]
Pneumonia due to Klebsiella pneumoniae	CA40.03	Investigative	[4]
Sinusitis	CA0A.Z	Investigative	[4]

Amoxicillin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Cell membrane (Bact CM)	TTXT4D5	NOUNIPROTAC	Modulator	[7]

Amoxicillin Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[9]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[9]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[10]

Amoxicillin Interacts with 46 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]
Beta-lactamase (blaB)	DED0TBR	A0A414M273_9BACE	Metabolism	[12]
Beta-lactamase (blaB)	DEX8KJO	A6NX15_9FIRM	Metabolism	[13]
Beta-lactamase (blaB)	DEAYSTX	C0W968_9FIRM	Metabolism	[14]
Beta-lactamase (blaB)	DERGEVU	C3WC84_FUSMR	Metabolism	[15]
Beta-lactamase (blaB)	DEV0KWQ	Q8KT52_9BACT	Metabolism	[16]
Beta-lactamase (blaB)	DEQMISO	F9Z530_ODOSD	Metabolism	[15]
Beta-lactamase (blaB)	DEHFJ4G	Q8KT51_9BACT	Metabolism	[15]
Beta-lactamase (blaB)	DEHPJRC	Q8KT60_9BACT	Metabolism	[15]
Beta-lactamase (blaB)	DEITMS0	Q9XBM2_ACIFE	Metabolism	[17]
N-acylhomoserine lactone acylase (lacA)	DEIU0XN	A0A0A1VBK6_9BURK	Metabolism	[18]
Beta-lactamase (blaB)	DET9I1W	BLAC_BACUN	Metabolism	[19]
Beta-lactamase (blaB)	DE7IH52	AMPC_CITFR	Metabolism	[16]
Beta-lactamase (blaB)	DENJ2SQ	BLAB_BACFG	Metabolism	[19]
Beta-lactamase (blaB)	DE5HV8P	A0A4Q5I6I2_9BACE	Metabolism	[19]
Beta-lactamase (blaB)	DE47ARF	B5WXV2_9BACT	Metabolism	[20]
Beta-lactamase (blaB)	DEG2PK9	B5WXV3_BACOV	Metabolism	[19]
Beta-lactamase (blaB)	DEWHJ7A	B5WXV7_BACT4	Metabolism	[19]
Beta-lactamase (blaB)	DEU1RXB	BLAC_BACVU	Metabolism	[19]
Beta-lactamase (blaB)	DETDS7E	A0A2S0LB67_9FLAO	Metabolism	[16]
Beta-lactamase (blaB)	DE37FJH	C6JIU1_FUSVA	Metabolism	[15]
Beta-lactamase (blaB)	DEC7JEF	A0A1S1G219_9NEIS	Metabolism	[16]
Beta-lactamase (blaB)	DEP7MN1	Q9X4S7_PREIN	Metabolism	[21]
Beta-lactamase (blaB)	DEAILCM	A0A246EJV2_9BACT	Metabolism	[21]
Beta-lactamase (blaB)	DET4XFN	Q8KT59_9BACT	Metabolism	[16]
Metallo-beta-lactamase (blaM)	DEPCQ12	Q68K11_ALCXX	Metabolism	[22]
Beta-lactamase (blaB)	DEACNTL	Q2F4C6_SHISO	Metabolism	[23]
Beta-lactamase (blaB)	DEE8742	O32372_CAPOC	Metabolism	[24]
Beta-lactamase (blaB)	DEY09SU	C9MN73_9BACT	Metabolism	[16]
Beta-lactamase (blaB)	DEQLVCA	C9LD75_9BACT	Metabolism	[21]
Beta-lactamase (blaB)	DE2IL34	C2M7J0_CAPGI	Metabolism	[24]
Beta-lactamase (blaB)	DE1NJIW	B6VMJ3_PHOAA	Metabolism	[25]
Beta-lactamase (blaB)	DEDIMN9	A0A413GBG0_9BACE	Metabolism	[19]
Beta-lactamase (blaB)	DEJ8X2W	A0A412YFL9_9BACE	Metabolism	[19]
Beta-lactamase (blaB)	DEFEVNH	A0A381DV31_9FLAO	Metabolism	[24]
Beta-lactamase (blaB)	DEAPGXV	A0A347B2J2_9BACT	Metabolism	[16]
Beta-lactamase (blaB)	DE0PDVC	A0A2A3N1K0_CAPSP	Metabolism	[24]
Beta-lactamase (blaB)	DEQL32N	A0A250F962_9FLAO	Metabolism	[24]
Beta-lactamase (blaB)	DE9HF0I	A0A120A1C6_BACSE	Metabolism	[19]
Beta-lactamase (blaB)	DESHI6O	A0A108T9G3_9BACE	Metabolism	[19]
Beta-lactamase (blaB)	DEZS3N4	A0A069QS91_PRELO	Metabolism	[16]
Beta-lactamase (blaB)	DE5NSUX	A0A095XPV0_9FIRM	Metabolism	[16]
New delhi metallo-beta-lactamase NDM-1 (blaNDM)	DEBGCYQ	A0A345N7K5_SALET	Metabolism	[26]
Beta-lactamase (blaB)	DEW193R	BLA1_KLEPN	Metabolism	[22]
Metallo-beta-lactamase (blaM)	DEK9VG2	BLAN1_KLEPN	Metabolism	[22]
Beta-lactamase (blaB)	DEQ1CTE	A0A2T4TNV5_9BACT	Metabolism	[27]

Amoxicillin Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[28]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[28]
C-C chemokine receptor type 9 (CCR9)	OT5FSOD8	CCR9_HUMAN	Increases ADR	[29]
C-C chemokine receptor type 4 (CCR4)	OT68KZ9B	CCR4_HUMAN	Increases ADR	[29]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Increases ADR	[30]
C-X-C chemokine receptor type 3 (CXCR3)	OTIGS220	CXCR3_HUMAN	Increases ADR	[29]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Increases Expression	[31]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Increases Expression	[31]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[32]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[33]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[33]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[33]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Decreases Expression	[34]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[34]
Organic solute transporter subunit alpha (SLC51A)	OTDJRZ0P	OSTA_HUMAN	Increases Expression	[35]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Helicobacter Pylori Infection	DCI69N4	N. A.	Phase 4	[36]
Helicobacter Pylori Infection	DCHMOXE	N. A.	Phase 1	[37]

References

• [1] ClinicalTrials.gov (NCT04167670) Efficacy and Safety of Vonoprazan Compared to Lansoprazole in Participants With Helicobacter Pylori Infection
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2008
• [3] ClinicalTrials.gov (NCT02388724) Efficacy and Safety of Oral Once-Daily Vonoprazan (TAK-438) in Patients With Erosive Esophagitis. U.S. National Institutes of Health.
• [4] Amoxicillin FDA Label
• [5] Emerging therapies for the treatment and prevention of otitis media. Expert Opin Emerg Drugs. 2006 May;11(2):251-64.
• [6] In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker. Xenobiotica. 2017 Dec;47(12):1027-1034.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [8] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [9] Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dispos. 2006 Apr;34(4):547-55.
• [10] The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos. 2002 Jan;30(1):13-9.
• [11] High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
• [12] Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res. 2013 Mar;57(3):523-35.
• [13] The prevalence of beta-lactamase producing bacteria in subgingival plaque and their sensitivity to Augmentin. Br J Oral Maxillofac Surg. 1990 Jun;28(3):180-4.
• [14] ACI-1 beta-lactamase is widespread across human gut microbiomes in Negativicutes due to transposons harboured by tailed prophages. Environ Microbiol. 2018 Jun;20(6):2288-2300.
• [15] Beta-lactamase production and susceptibilities to amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis Bacteroides isolates and 129 fusobacteria from 28 U.S. centers. Antimicrob Agents Chemother. 1990 Aug;34(8):1546-50.
• [16] Detection and characterization of beta-lactamase genes in subgingival bacteria from patients with refractory periodontitis. FEMS Microbiol Lett. 2005 Jan 15;242(2):319-24.
• [17] ACI-1 from Acidaminococcus fermentans: characterization of the first beta-lactamase in Anaerobic cocci. Antimicrob Agents Chemother. 2000 Nov;44(11):3144-9.
• [18] A novel quorum-quenching N-acylhomoserine lactone acylase from Acidovorax sp. strain MR-S7 mediates antibiotic resistance. Appl Environ Microbiol. 2017 Jun 16;83(13). pii: e00080-17.
• [19] Prevalence of antimicrobial resistance genes in Bacteroides spp. and Prevotella spp. Dutch clinical isolates. Clin Microbiol Infect. 2019 Sep;25(9):1156.e9-1156.e13.
• [20] Presence of the cfxA gene in Bacteroides distasonis. Res Microbiol. 2003 Jun;154(5):369-74.
• [21] Prevotella strains and lactamic resistance gene distribution in different oral environments of children with pulp necrosis. Int Endod J. 2018 Nov;51(11):1196-1204.
• [22] Interspecies dissemination of a mobilizable plasmid harboring blaIMP-19 and the possibility of horizontal gene transfer in a single patient. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5412-9.
• [23] IncU plasmid harbouring bla CTX-M-8 in multidrug-resistant Shigella sonnei in Brazil. J Glob Antimicrob Resist. 2018 Sep;14:99-100.
• [24] High prevalence of beta-lactam and macrolide resistance genes in human oral Capnocytophaga species. J Antimicrob Chemother. 2014 Feb;69(2):381-4.
• [25] Yersinia enterocolitica and Photorhabdus asymbiotica beta-lactamases BlaA are exported by the twin-arginine translocation pathway. Int J Med Microbiol. 2013 Jan;303(1):16-24.
• [26] Genomic characterization of an extensively-drug resistance Salmonella enterica serotype Indiana strain harboring bla NDM-1 gene isolated from a chicken carcass in China. Microbiol Res. 2017 Nov;204:48-54.
• [27] High prevalence of cfxA beta-lactamase in aminopenicillin-resistant Prevotella strains isolated from periodontal pockets. Oral Microbiol Immunol. 2002 Apr;17(2):85-8.
• [28] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [29] 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.
• [30] HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity. PLoS One. 2013 Jul 9;8(7):e68111. doi: 10.1371/journal.pone.0068111. Print 2013.
• [31] Modulation of steroidogenic gene expression and hormone production of H295R cells by pharmaceuticals and other environmentally active compounds. Toxicol Appl Pharmacol. 2007 Dec 1;225(2):142-53.
• [32] Effect of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activities of human hepatic cytochromes P450. J Toxicol Sci. 2016 Feb;41(1):143-6.
• [33] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [34] Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol. 2015 Apr;35(4):398-406. doi: 10.1002/jat.3033. Epub 2014 Aug 4.
• [35] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [36] ClinicalTrials.gov (NCT05419674) Efficacy and Safety of Dual Therapy as First-line Treatment for Hp Infection
• [37] ClinicalTrials.gov (NCT05189444) The Evaluation of Triple Therapy With Vonoprazan, Amoxicillin and Bismuth for Eradication of Helicobacter Pylori