Details of the Drug Combination

General Information of Drug Combination (ID: DCBJPXX)

• Drug Combination Name: Dolutegravir + Lamivudine
• Indication: HIV-1-infection; Status: Phase 4 [1]
• Component Drugs:
  Dolutegravir (DMCZGRE): Small molecular drug
  Lamivudine (DMI347A): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dolutegravir

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[2]

Dolutegravir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Integrase (HIV IN)	TT5FH9Y	POL_HV1B1	Modulator	[6]

Dolutegravir Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Dolutegravir Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]

Dolutegravir Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 26A1 (CYP26A1)	OTL1DFWV	CP26A_HUMAN	Decreases Expression	[9]
T-box transcription factor TBX6 (TBX6)	OTW1Q8RM	TBX6_HUMAN	Increases Expression	[9]
Homeobox protein Hox-B1 (HOXB1)	OTGC0EKI	HXB1_HUMAN	Increases Expression	[9]
Fibroblast growth factor 8 (FGF8)	OTFU0IUW	FGF8_HUMAN	Increases Expression	[9]
Homeobox protein MIXL1 (MIXL1)	OT584VOQ	MIXL1_HUMAN	Increases Expression	[9]

Indication(s) of Lamivudine

Disease Entry	ICD 11	Status	REF
Chronic HBV infection	1E51.0Z	Approved	[3]
Chronic hepatitis B virus infection	N.A.	Approved	[4]
Human immunodeficiency virus infection	1C62	Approved	[3]
Human immunodeficiency virus-1 infection	1C62	Approved	[5]
Diarrhea	ME05.1	Investigative	[4]

Lamivudine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[10]

Lamivudine Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[12]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[13]

Lamivudine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Deoxy-5'-nucleotidase 1 (NT5C)	DE4E31Z	NT5C_HUMAN	Metabolism	[14]
Phosphorylcholine transferase A (PCYT1A)	DEQYXD4	PCY1A_HUMAN	Metabolism	[15]
Phosphorylethanolamine transferase (PCYT2)	DEIX1PO	PCY2_HUMAN	Metabolism	[15]

Lamivudine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Increases Uptake	[16]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Increases Uptake	[16]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[17]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[18]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[19]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[19]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[20]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[21]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[22]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[19]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Increases Secretion	[17]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[18]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Decreases Phosphorylation	[17]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[18]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Expression	[23]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[18]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[18]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[21]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Infection, Human Immunodeficiency Virus	DC7UAKK	N. A.	Phase 3	[24]
HIV-1 Infection	DCK6V4R	N. A.	Phase 2	[25]
HIV-1 Infection	DCAF4N7	N. A.	Phase 2	[26]
HIV	DC6FEJE	N. A.	Phase 1	[27]
HIV Infections	DC7HBSZ	N. A.	Phase 1	[28]
Human immunodeficiency virus infection	DCUEQ7V	N. A.	Phase 1	[29]
Human immunodeficiency virus infection	DCA7NHZ	N. A.	Phase 1	[30]

References

• [1] ClinicalTrials.gov (NCT03360682) Clinical Trial to Evaluate the Efficacy, Pharmacokinetics (PK) Interactions and Safety of Dolutegravir Plus 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in HIV-1-Infected Solid Organ Transplant Patients
• [2] 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: 7365).
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Lamivudine FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [7] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [8] Mechanisms of action, pharmacology and interactions of dolutegravir. Enferm Infecc Microbiol Clin. 2015 Mar;33 Suppl 1:2-8.
• [9] Dolutegravir Impairs Stem Cell-Based 3D Morphogenesis Models in a Manner Dependent on Dose and Timing of Exposure: An Implication for Its Developmental Toxicity. Toxicol Sci. 2021 Nov 24;184(2):191-203. doi: 10.1093/toxsci/kfab112.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol. 2007 Nov;64(5):645-54.
• [12] Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos. 2012 Apr;33(3):170-8.
• [13] Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos. 2008 Aug;36(8):1616-23.
• [14] Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2010 Jan;85(1):39-58.
• [15] Model for intracellular Lamivudine metabolism in peripheral blood mononuclear cells ex vivo and in human immunodeficiency virus type 1-infected adolescents. Antimicrob Agents Chemother. 2006 Aug;50(8):2686-94.
• [16] Transport of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J Pharmacol Exp Ther. 2009 Apr;329(1):252-61. doi: 10.1124/jpet.108.146225. Epub 2009 Jan 13.
• [17] Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment. Toxicol Sci. 2013 Aug;134(2):323-34. doi: 10.1093/toxsci/kft105. Epub 2013 May 2.
• [18] Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells. Mutagenesis. 2005 Mar;20(2):139-46. doi: 10.1093/mutage/gei019. Epub 2005 Mar 22.
• [19] Effect of lamivudine treatment on plasma levels of transforming growth factor beta1, tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B. World J Gastroenterol. 2004 Sep 15;10(18):2661-5. doi: 10.3748/wjg.v10.i18.2661.
• [20] Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology. 2005 Nov;42(5):1028-36. doi: 10.1002/hep.20888.
• [21] Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol. 2001 Dec;35(6):749-55. doi: 10.1016/s0168-8278(01)00218-5.
• [22] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [23] Serotonin transporter mRNA expression is decreased by lamivudine and ribavirin and increased by interferon in immune cells. Scand J Immunol. 2006 Feb;63(2):106-15. doi: 10.1111/j.1365-3083.2005.01715.x.
• [24] ClinicalTrials.gov (NCT02831673) An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment nave HIV Infected Subjects (Gemini 1)
• [25] ClinicalTrials.gov (NCT02566707) Pharmacokinetics of Atazanavir /Dolutegravir/Lamivudine Regimen as Maintenance Regimen
• [26] ClinicalTrials.gov (NCT02582684) Dolutegravir Plus Lamivudine Dual Therapy in Treatment Nave HIV-1 Patients
• [27] ClinicalTrials.gov (NCT02384395) Safety and Efficacy of Fixed Dose Combination Dolutegravir/Abacavir/Lamivudine FDC Initiated During Acute HIV Infection
• [28] ClinicalTrials.gov (NCT04019873) 'COMBINE-2': Real-world Evidence for Effectiveness of Two Drug Regimen, Antiretroviral Therapy With Integrase Inhibitors Plus a Reverse Transcriptase Inhibitor
• [29] Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection. Drugs. 2015 Apr;75(5):503-14.
• [30] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)