RIFAPENTINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C47H64N4O12
Molecular Weight	877.0307
Optical Activity	UNSPECIFIED
Defined Stereocenters	9 / 9
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CO[C@H]1\C=C\O[C@@]2(C)OC3=C(C2=O)C4=C(O)C(\C=N\N5CCN(CC5)C6CCCC6)=C(NC(=O)C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C(O)=C4C(O)=C3C

InChI

InChIKey=WDZCUPBHRAEYDL-GZAUEHORSA-N

InChI=1S/C47H64N4O12/c1-24-13-12-14-25(2)46(59)49-37-32(23-48-51-20-18-50(19-21-51)31-15-10-11-16-31)41(56)34-35(42(37)57)40(55)29(6)44-36(34)45(58)47(8,63-44)61-22-17-33(60-9)26(3)43(62-30(7)52)28(5)39(54)27(4)38(24)53/h12-14,17,22-24,26-28,31,33,38-39,43,53-57H,10-11,15-16,18-21H2,1-9H3,(H,49,59)/b13-12+,22-17+,25-14-,48-23+/t24-,26+,27+,28+,33-,38-,39+,43+,47-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f768e337-a948-420a-9fbe-9be359c7a170
Curator's Comment: description was created based on several sources, including: http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/21024lbl.pdf http://www.drugbank.ca/drugs/DB01201

PRIFTIN® (rifapentine) is indicated in adults and children 12 years and older for the treatment of active pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis. PRIFTIN must always be used in combination with one or more antituberculosis (anti-TB) drugs to which the isolate is susceptible. Rifapentine is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. And it acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. Because of rapid emergence of resistant bacteria, use is restricted to treatment of mycobacterial infections and a few other indications. Rifampin is well absorbed when taken orally and is distributed widely in body tissues and fluids, including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine, but dose adjustments are unnecessary with renal insufficiency. Rifapentine has shown higher bacteriostatic and bactericidal activities especially against intracellular bacteria growing in human monocyte-derived macrophages.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Bacterial DNA-directed RNA polymerase 11 Target ID: CHEMBL2364672 Sources: http://www.drugbank.ca/drugs/DB01201	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary tuberculosis 17 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f768e337-a948-420a-9fbe-9be359c7a170	Curative		Approved 8429	PRIFTIN Approved Use is indicated in adults and children 12 years and older for the treatment of active pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis. PRIFTIN must always be used in combination with one or more antituberculosis (anti-TB) drugs to which the isolate is susceptible Launch Date 9.3934079E11

C_max

Value	Dose	Co-administered	Analyte	Population
25.8 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered: ISONIAZID	ISONIAZID	RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FED
15.05 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	600 mg 1 times / 3 days steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
817 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered: ISONIAZID	ISONIAZID	RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FED
319.54 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	600 mg 1 times / 3 days steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
16.6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered: ISONIAZID	ISONIAZID	RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FED
13.19 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	600 mg 1 times / 3 days steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.3% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf	600 mg 1 times / 3 days steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RIFAPENTINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
20 mg/kg 1 times / day multiple, oral MTD Dose: 20 mg/kg, 1 times / day Route: oral Route: multiple Dose: 20 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22472995 Page: p.2, p.4	healthy n = 6 Health Status: healthy Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22472995 Page: p.2, p.4	Sources: https://pubmed.ncbi.nlm.nih.gov/22472995 Page: p.2, p.4
600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1	Disc. AE: Hepatotoxicity... Other AEs: Hyperbilirubinemia, Discoloration urine... AEs leading to discontinuation/dose reduction: Hepatotoxicity Other AEs: Hyperbilirubinemia Discoloration urine Clostridium difficile colitis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1
600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Co-administed with:: isoniazid, po(q.d.) pyrazinamide, po(q.d.) ethambutol, po(q.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	unhealthy n = 361 Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Population Size: 361 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	Disc. AE: Hepatitis, ALT increased... AEs leading to discontinuation/dose reduction: Hepatitis (0.28%) ALT increased (0.28%) AST increased (0.28%) LDH increased (0.28%) Bilirubin increased (0.28%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6

AEs

AE	Significance	Dose	Population
Clostridium difficile colitis		600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1
Discoloration urine		600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1
Hyperbilirubinemia		600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1
Hepatotoxicity	Disc. AE	600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.1
ALT increased	0.28% Disc. AE	600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Co-administed with:: isoniazid, po(q.d.) pyrazinamide, po(q.d.) ethambutol, po(q.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	unhealthy n = 361 Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Population Size: 361 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6
AST increased	0.28% Disc. AE	600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Co-administed with:: isoniazid, po(q.d.) pyrazinamide, po(q.d.) ethambutol, po(q.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	unhealthy n = 361 Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Population Size: 361 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6
Bilirubin increased	0.28% Disc. AE	600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Co-administed with:: isoniazid, po(q.d.) pyrazinamide, po(q.d.) ethambutol, po(q.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	unhealthy n = 361 Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Population Size: 361 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6
Hepatitis	0.28% Disc. AE	600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Co-administed with:: isoniazid, po(q.d.) pyrazinamide, po(q.d.) ethambutol, po(q.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	unhealthy n = 361 Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Population Size: 361 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6
LDH increased	0.28% Disc. AE	600 mg 2 times / week multiple, oral Recommended Dose: 600 mg, 2 times / week Route: oral Route: multiple Dose: 600 mg, 2 times / week Co-administed with:: isoniazid, po(q.d.) pyrazinamide, po(q.d.) ethambutol, po(q.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6	unhealthy n = 361 Health Status: unhealthy Condition: Pulmonary tuberculosis caused by Mycobacterium tuberculosis Population Size: 361 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021024s009lbl.pdf Page: p.6

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inhibitor 1767 inducer 389	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478 CYP2E1 882 UGT1A1 204 UGT1A4 77 UGT1A6 108 UGT1A9 116 UGT2B7 146 UGT2B15 64 CYP3A 214 CYP2B6 810 CYP2C8 911 CYP1A2 1524		CYP2C8 168 OATP1B1 26 OATP1B3 6 MRP1 48 MRP2 111

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP2C8 965	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP2E1 970	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
CYP3A 298	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
UGT1A6 141	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
UGT1A9 121	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
UGT2B15 64	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	no
UGT1A4 80	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	yes [IC50 230 uM]
UGT2B7 157	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	yes [IC50 357 uM]
UGT1A1 254	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/ Page: -	yes [IC50 70 uM]
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf#page=1 Page: 1.0	yes
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf#page=1 Page: 1.0	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021024s017s018lbl.pdf#page=1 Page: 1.0	yes
MRP1 172	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/ Page: -	yes
MRP2 475	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/ Page: -	yes
OATP1B1 803	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/ Page: -	yes
OATP1B3 715	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/ Page: -	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45304	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45304
ChemicalBook	CB7482119	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7482119
MolPort	MolPort-006-132-325	https://www.molport.com/shop/molecule-link/MolPort-006-132-325
MolPort	MolPort-035-395-832	https://www.molport.com/shop/molecule-link/MolPort-035-395-832
Selleck Chemicals	Rifapentine(Priftin)	http://www.selleckchem.com/products/Rifapentine(Priftin).html
ZINC	ZINC000169621228	http://zinc15.docking.org/substances/ZINC000169621228
eMolecules	30100394	https://www.emolecules.com/cgi-bin/more?vid=30100394

PubMed

Title	Date	PubMed
Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative.	1981 Aug	7319918
Comparative in vitro activities of MDL 473, rifampin, and ansamycin against Mycobacterium intracellulare.	1985 Sep	4073865
[In-vitro antimycobacterial activity of rifapentine (comparison with rifampicin)].	1986 Dec	3573500
Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobacterium avium complex within human macrophages.	1991 Jul	1656860
Activity of rifapentine against Mycobacterium avium infection in beige mice.	1992 May	1624393
Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine.	1993 Mar	8384809
Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis.	1994 Oct	7840568
Mutation position and type of substitution in the beta-subunit of the RNA polymerase influence in-vitro activity of rifamycins in rifampicin-resistant Mycobacterium tuberculosis.	1995 Feb	7759399
New drugs for tuberculosis.	1995 Sep	8590571
Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages.	1995 Sep	8540718
Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.	1996 Dec	9124846
Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium.	1997 May	9145860
Contribution of rpoB mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis.	1998 Jul	9661035
Development of rifapentine susceptibility tests for Mycobacterium tuberculosis.	1999 Jan	9869560
Evaluation of rifapentine in long-term treatment regimens for tuberculosis in mice.	1999 Oct	10508006
In vitro susceptibilities of rapidly growing mycobacteria to telithromycin (HMR 3647) and seven other antimicrobials.	2000 Jan	10602744
Antituberculosis activity of once-weekly rifapentine-containing regimens in mice. Long-term effectiveness with 6- and 8-month treatment regimens.	2000 May	10806157
Comparison of the in vitro activities of rifapentine and rifampicin against Mycobacterium tuberculosis complex.	2000 Oct	11020254
Activity of rifapentine and its metabolite 25-O-desacetylrifapentine compared with rifampicin and rifabutin against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M. bovis BCG.	2000 Oct	11020253
Potent in vitro antifungal activities of naturally occurring acetylenic acids.	2008 Jul	18458131
Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine.	2011 Dec 1	21856291
Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs.	2015 Jun	25752796

Patents

Sample Use Guides

In Vivo Use Guide

600 mg twice weekly for two months

Route of Administration: Oral

In Vitro Use Guide

In a comparison of in vitro properties of rifapentine (RIF), the minimal inhibitory concentration of RIF against Mycobacterium tuberculosis in Tween-albumin liquid medium was usually 0.02 micrograms/ml; the bactericidal activity against a log phase culture was slightly less than that of RMP and the recovery after pulsed exposures to 1 microgram/ml of RIF lasting 6, 24 and 96 h was identical for the two rifamycins.

Name

Type

Language

RIFAPENTINE

Official Name

English

KTC-1

Code

English

RIFAPENTINE [VANDF]

Common Name

English

R-773

Code

English

DL-473

Code

English

R-77-3

Code

English

rifapentine [INN]

Common Name

English

Rifapentine [WHO-DD]

Common Name

English

RIFAPENTINE [MART.]

Common Name

English

RIFAMYCIN AF/ACPP

Common Name

English

MDL 473

Code

English

RIFAPENTINE [MI]

Common Name

English

3-((4-CYCLOPENTYL-1-PIPERAZINYL)IMINO)METHYL)RIFAMYCIN

Common Name

English

RIFAMYCIN, 3-(((4-CYCLOPENTYL-1-PIPERAZINYL)IMINO)METHYL)-

Common Name

English

3-(((4-CYCLOPENTYL-1-PIPERAZINYL)IMINO)METHYL)RIFAMYCIN

Common Name

English

RIFAPENTIN

Common Name

English

RIFAPENTINE [ORANGE BOOK]

Common Name

English

PRIFITIN

Brand Name

English

PRIFTIN

Brand Name

English

ANTIBIOTIC DL-473IT

Code

English

RIFAPENTINE [USAN]

Common Name

English

MDL-473

Code

English

3-[N-(4-Cyclopentyl-1-piperazinyl)formimidoyl]rifamycin

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C280