Details of the Drug

General Information of Drug (ID: DMOB58Q)

Drug Name
MK-8228
Synonyms Letermovir
Indication
Disease Entry ICD 11 Status REF
Cytomegalovirus Disease 1D82 Approved [1]
Cytomegalovirus infection 1D82 Phase 3 [2]
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 1 Molecular Weight (mw) 572.5
Topological Polar Surface Area (xlogp) 4.6
Rotatable Bond Count (rotbonds) 7
Hydrogen Bond Donor Count (hbonddonor) 1
Hydrogen Bond Acceptor Count (hbondacc) 10
ADMET Property
Absorption AUC
The area under the plot of plasma concentration (AUC) of drug is 27,438 mcgh/L [3]
Absorption Cmax
The maximum plasma concentration (Cmax) of drug is 1,291 mcg/L [3]
Bioavailability
The bioavailability of drug is 72% [3]
Clearance
The clearance of drug is 11.25 L/h in healthy subjects [4]
Elimination
93% of drug is excreted in the feces with 70% as the parent drug, and less than 2% of drug is excreted in the urine [5]
Half-life
The concentration or amount of drug in body reduced by one-half in 12 hours [6]
Metabolism
The drug is metabolized via UGT1A1/1A3 [6]
Vd
The volume of distribution (Vd) of drug is 45.5 L [5]
Chemical Identifiers
Formula
C29H28F4N4O4
IUPAC Name
2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
Canonical SMILES
COC1=C(C=C(C=C1)C(F)(F)F)N2[C@H](C3=C(C(=CC=C3)F)N=C2N4CCN(CC4)C5=CC(=CC=C5)OC)CC(=O)O
InChI
InChI=1S/C29H28F4N4O4/c1-40-20-6-3-5-19(16-20)35-11-13-36(14-12-35)28-34-27-21(7-4-8-22(27)30)23(17-26(38)39)37(28)24-15-18(29(31,32)33)9-10-25(24)41-2/h3-10,15-16,23H,11-14,17H2,1-2H3,(H,38,39)/t23-/m0/s1
InChIKey
FWYSMLBETOMXAG-QHCPKHFHSA-N
Cross-matching ID
PubChem CID
45138674
CAS Number
917389-32-3
TTD ID
D0G8PA
VARIDT ID
DR00621
INTEDE ID
DR0928
ACDINA ID
D00355

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Cytomegalovirus Terminase (CMV TRM) TTZHSBO NOUNIPROTAC Inhibitor [1]
Cytomegalovirus Terminase UL56 (CMV TRM1) TTOGPL1 TRM1_HCMVA Inhibitor [2], [7]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)
Main DME 		DEYGVN4 UD11_HUMAN Substrate [8]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from MK-8228 (Comorbidity)
DDI Drug Name DDI Drug ID Severity Mechanism Comorbidity REF
Ivosidenib DM8S6T7 Major Increased metabolism of MK-8228 caused by Ivosidenib mediated induction of CYP450 enzyme. Acute myeloid leukaemia [2A60] [20]
Oliceridine DM6MDCF Major Decreased metabolism of MK-8228 caused by Oliceridine mediated inhibition of CYP450 enzyme. Acute pain [MG31] [21]
Pexidartinib DMS2J0Z Major Decreased metabolism of MK-8228 caused by Pexidartinib mediated inhibition of CYP450 enzyme. Bone/articular cartilage neoplasm [2F7B] [22]
Polatuzumab vedotin DMF6Y0L Moderate Decreased metabolism of MK-8228 caused by Polatuzumab vedotin mediated inhibition of CYP450 enzyme. Diffuse large B-cell lymphoma [2A81] [23]
Bay 80-6946 DMLOS5R Moderate Decreased clearance of MK-8228 due to the transporter inhibition by Bay 80-6946. Follicular lymphoma [2A80] [24]
Tazemetostat DMWP1BH Major Decreased metabolism of MK-8228 caused by Tazemetostat mediated inhibition of CYP450 enzyme. Follicular lymphoma [2A80] [25]
Ripretinib DM958QB Moderate Decreased metabolism of MK-8228 caused by Ripretinib mediated inhibition of CYP450 enzyme. Gastrointestinal stromal tumour [2B5B] [26]
Avapritinib DMK2GZX Major Decreased metabolism of MK-8228 caused by Avapritinib mediated inhibition of CYP450 enzyme. Gastrointestinal stromal tumour [2B5B] [27]
MK-1439 DM215WE Minor Decreased metabolism of MK-8228 caused by MK-1439 mediated inhibition of CYP450 enzyme. Human immunodeficiency virus disease [1C60-1C62] [28]
Pemigatinib DM819JF Major Decreased metabolism of MK-8228 caused by Pemigatinib mediated inhibition of CYP450 enzyme. Liver cancer [2C12] [27]
Brigatinib DM7W94S Major Decreased metabolism of MK-8228 caused by Brigatinib mediated inhibition of CYP450 enzyme. Lung cancer [2C25] [26]
Lurbinectedin DMEFRTZ Major Decreased metabolism of MK-8228 caused by Lurbinectedin mediated inhibition of CYP450 enzyme. Lung cancer [2C25] [29]
PF-06463922 DMKM7EW Moderate Accelerated clearance of MK-8228 due to the transporter induction by PF-06463922. Lung cancer [2C25] [30]
Pralsetinib DMWU0I2 Moderate Decreased metabolism of MK-8228 caused by Pralsetinib mediated inhibition of CYP450 enzyme. Lung cancer [2C25] [31]
Selpercatinib DMZR15V Major Decreased metabolism of MK-8228 caused by Selpercatinib mediated inhibition of CYP450 enzyme. Lung cancer [2C25] [27]
Ubrogepant DM749I3 Moderate Decreased metabolism of MK-8228 caused by Ubrogepant mediated inhibition of CYP450 enzyme. Migraine [8A80] [32]
Rimegepant DMHOAUG Moderate Decreased metabolism of MK-8228 caused by Rimegepant mediated inhibition of CYP450 enzyme. Migraine [8A80] [33]
Siponimod DM2R86O Major Decreased metabolism of MK-8228 caused by Siponimod mediated inhibition of CYP450 enzyme. Multiple sclerosis [8A40] [26]
Fedratinib DM4ZBK6 Minor Decreased metabolism of MK-8228 caused by Fedratinib mediated inhibition of CYP450 enzyme. Myeloproliferative neoplasm [2A20] [27]
Lefamulin DME6G97 Moderate Decreased clearance of MK-8228 due to the transporter inhibition by Lefamulin. Pneumonia [CA40] [34]
Darolutamide DMV7YFT Minor Decreased metabolism of MK-8228 caused by Darolutamide mediated inhibition of CYP450 enzyme. Prostate cancer [2C82] [35]
Upadacitinib DM32B5U Moderate Decreased metabolism of MK-8228 caused by Upadacitinib mediated inhibition of CYP450 enzyme. Rheumatoid arthritis [FA20] [36]
Voxelotor DMCS6M5 Moderate Decreased metabolism of MK-8228 caused by Voxelotor mediated inhibition of CYP450 enzyme. Sickle-cell disorder [3A51] [37]
Larotrectinib DM26CQR Moderate Decreased metabolism of MK-8228 caused by Larotrectinib mediated inhibition of CYP450 enzyme. Solid tumour/cancer [2A00-2F9Z] [26]
Fluticasone DMGCSVF Moderate Decreased metabolism of MK-8228 caused by Fluticasone mediated inhibition of CYP450 enzyme. Vasomotor/allergic rhinitis [CA08] [26]
Betrixaban DM2C4RF Moderate Accelerated clearance of MK-8228 due to the transporter induction by Betrixaban. Venous thromboembolism [BD72] [38]
⏷ Show the Full List of 26 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG
DIG Name DIG ID PubChem CID Functional Classification
Carmellose sodium E00625 Not Available Disintegrant
Eisenoxyd E00585 56841934 Colorant
Ferric hydroxide oxide yellow E00539 23320441 Colorant
Lactose monohydrate E00393 104938 Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate E00208 11177 lubricant
Silicon dioxide E00670 Not Available Anticaking agent; Opacifying agent; Viscosity-controlling agent
Titanium dioxide E00322 26042 Coating agent; Colorant; Opacifying agent
Triacetin E00080 5541 Humectant; Plasticizing agent; Solvent
⏷ Show the Full List of 8 Pharmaceutical Excipients of This Drug
Pharmaceutical Formulation
Formulation Name Drug Dosage Dosage Form Route
Letermovir 480 mg tablet 480 mg Oral Tablet Oral
Letermovir 240 mg tablet 240 mg Oral Tablet Oral
Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
2 The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011 Oct;85(20):10884-93.
3 FDA Approved Drug Products: Tepmetko (tepotinib) tablets for oral use
4 Kropeit D, Scheuenpflug J, Erb-Zohar K, Halabi A, Stobernack HP, Hulskotte EGJ, van Schanke A, Zimmermann H, Rubsamen-Schaeff H: Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. Br J Clin Pharmacol. 2017 Sep;83(9):1944-1953. doi: 10.1111/bcp.13292. Epub 2017 May 5.
5 An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
6 FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
7 Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir.Antiviral Res. 2015 Apr;116:48-50.
8 Pharmacogenetic analysis of OATP1B1, UGT1A1, and BCRP variants in relation to the pharmacokinetics of letermovir in previously conducted clinical studies. J Clin Pharmacol. 2019 Sep;59(9):1236-1243.
9 Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009 Mar 1;69(5):1892-900.
10 Functional characterization of human and cynomolgus monkey UDP-glucuronosyltransferase 1A1 enzymes. Life Sci. 2010 Aug 14;87(7-8):261-8.
11 Effect of UDP-glucuronosyltransferase (UGT) 1A polymorphism (rs8330 and rs10929303) on glucuronidation status of acetaminophen. Dose Response. 2017 Sep 11;15(3):1559325817723731.
12 UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos. 2007 Mar;35(3):371-80.
13 Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation. J Clin Pharmacol. 2009 Sep;49(9):1079-90.
14 Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Drug Metab Dispos. 2009 Jan;37(1):229-36.
15 Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9.
16 Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
17 Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):211-4.
18 Identification and preliminary characterization of UDP-glucuronosyltransferases catalyzing formation of ethyl glucuronide. Anal Bioanal Chem. 2014 Apr;406(9-10):2325-32.
19 Progress in Drug Research, 2012. Page(106).
20 Product Information. Tibsovo (ivosidenib). Agios Pharmaceuticals, Cambridge, MA.
21 Product Information. Olinvyk (oliceridine). Trevena Inc, Chesterbrook, PA.
22 Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
23 Product Information. Polivy (polatuzumab vedotin). Genentech, South San Francisco, CA.
24 Product Information. Aliqopa (copanlisib). Bayer Pharmaceutical Inc, West Haven, CT.
25 Product Information. Tazverik (tazemetostat). Epizyme, Inc, Cambridge, MA.
26 Cerner Multum, Inc. "Australian Product Information.".
27 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
28 Product Information. Pifeltro (doravirine). Merck & Company Inc, Whitehouse Station, NJ.
29 Product Information. Zepzelca (lurbinectedin). Jazz Pharmaceuticals, Palo Alto, CA.
30 Product Information. Lorbrena (lorlatinib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
31 Product Information. Gavreto (pralsetinib). Blueprint Medicines Corporation, Cambridge, MA.
32 Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
33 Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
34 Product Information. Xenleta (lefamulin). Nabriva Therapeutics US, Inc., King of Prussia, PA.
35 Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
36 Product Information. Rinvoq (upadacitinib). AbbVie US LLC, North Chicago, IL.
37 Product Information. Oxbryta (voxelotor). Global Blood Therapeutics, Inc., South San Francisco, CA.
38 Gelosa P, Castiglioni L, Tenconi M, et.al "Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs)" Pharmacol Res 135 (2018): 60-79. [PMID: 30040996]