Details of the Drug

General Information of Drug (ID: DMDYA31)

Drug Name

Pretomanid

Synonyms

PA-824; 187235-37-6; Pretomanid; PA 824; PA824; UNII-2XOI31YC4N; (S)-PA 824; (S)-2-Nitro-6-((4-(trifluoromethoxy)benzyl)oxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; 2XOI31YC4N; CHEMBL227875; MMV688755; AK161427; (6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; (6S)-6,7-Dihydro-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-5H-imidazo[2,1-b][1,3]oxazine; Pretomanid [USAN:INN]; C14H12F3N3O5; PA-824(Pretomanid); AC1L9UFX; Pretomanid (USAN/INN); MLS006011141; SCHEMBL2983011

Indication

Disease Entry	ICD 11	Status	REF
Tuberculosis	1B10-1B14	Approved	[1]
Mycobacterium infection	1B10-1B21	Phase 3	[2]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

359.26

Topological Polar Surface Area (xlogp)

2.8

Rotatable Bond Count (rotbonds)

4

Hydrogen Bond Donor Count (hbonddonor)

0

Hydrogen Bond Acceptor Count (hbondacc)

9

ADMET Property

Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 28.1 mgh/L [3]
Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1.7 mg/L [3]
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4-5 h [3]
Clearance: The clearance of drug is 4.8 +/- 0.2 L/h [4]
Elimination: An average of about 53% of the radioactive dose was found to be excreted in the urine [3]
Half-life: The concentration or amount of drug in body reduced by one-half in 16.9 - 17.4 hours [3]
Vd: The volume of distribution (Vd) of drug is 130 +/- 5 L [4]

Chemical Identifiers

Formula: C14H12F3N3O5
IUPAC Name: (6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
Canonical SMILES: C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F
InChI: InChI=1S/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1
InChIKey: ZLHZLMOSPGACSZ-NSHDSACASA-N

Cross-matching ID

PubChem CID: 456199
CAS Number: 187235-37-6
DrugBank ID: DB05154
TTD ID: D02AYL
INTEDE ID: DR1338
ACDINA ID: D01360

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Mycobacterium Mycolic acid synthase (MycB cma)	TT08ESN	CMAS1_MYCTU; CMAS2_MYCTU; CMAS3_MYCTU	Inhibitor	[1]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[5]

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Molecular Interaction Atlas (MIA)

MIA Detail

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 Pretomanid (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Major	Increased metabolism of Pretomanid caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[15]
Pexidartinib	DMS2J0Z	Major	Increased metabolism of Pretomanid caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[15]
Lumacaftor	DMCLWDJ	Major	Increased metabolism of Pretomanid caused by Lumacaftor mediated induction of CYP450 enzyme.	Cystic fibrosis [CA25]	[16]
Cenobamate	DMGOVHA	Major	Increased metabolism of Pretomanid caused by Cenobamate mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[15]
Eslicarbazepine	DMZREFQ	Major	Increased metabolism of Pretomanid caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[15]
Etravirine	DMGV8QU	Major	Increased metabolism of Pretomanid caused by Etravirine mediated induction of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[15]
PF-06463922	DMKM7EW	Major	Increased metabolism of Pretomanid caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[15]
Dabrafenib	DMX6OE3	Major	Increased metabolism of Pretomanid caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[15]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Pretomanid caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[17]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Pretomanid caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[18]
Enzalutamide	DMGL19D	Major	Increased metabolism of Pretomanid caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[15]
Telotristat ethyl	DMDIYFZ	Major	Increased metabolism of Pretomanid caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[16]
Pitolisant	DM8RFNJ	Major	Increased metabolism of Pretomanid caused by Pitolisant mediated induction of CYP450 enzyme.	Somnolence [MG42]	[15]
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⏷ Show the Full List of 13 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
Sodium lauryl sulfate	E00464	3423265	Emulsifying agent; Modified-release agent; Penetration agent; Solubilizing agent; Surfactant; lubricant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Povidone	E00667	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Hydrophobic colloidal silica	E00285	24261	Anticaking agent; Emulsion stabilizing agent; Glidant; Suspending agent; Viscosity-controlling agent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
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⏷ Show the Full List of 6 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Pretomanid 200 mg tablet	200 mg	Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
2	ClinicalTrials.gov (NCT02342886) Shortening Treatment by Advancing Novel Drugs. U.S. National Institutes of Health.
3	Pretomanid FDA label, August 2019
4	Lyons MA: Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: AAC.02359-17. doi: 10.1128/AAC.02359-17. Print 2018 Jul.
5	FDA briefing document - pretomanid tablet, 200 mg meeting of the antimicrobial drugs advisory committee (AMDAC).
6	Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
7	Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
8	Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
9	Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
10	Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
11	Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
12	Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
13	The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
14	Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
15	Product Information. Pretomanid (pretomanid). The Global Alliance for TB Drug Development, New York, NY.
16	Patel S, Robinson R, Burk M "Hypertensive crisis associated with St. John's Wort." Am J Med 112 (2002): 507-8. [PMID: 11959071]
17	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
18	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.