SIMEPREVIR SODIUM

US Previously Marketed

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C38H46N5O7S2.Na
Molecular Weight	771.921
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].[H][C@@]12C[C@]1(NC(=O)[C@]3([H])C[C@H](C[C@@]3([H])C(=O)N(C)CCCCC=C2)OC4=CC(=NC5=C4C=CC(OC)=C5C)C6=NC(=CS6)C(C)C)C(=O)[N-]S(=O)(=O)C7CC7

InChI

InChIKey=LLXQGDWGCCKOQP-MVZLLIIPSA-M

InChI=1S/C38H47N5O7S2.Na/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25;/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H2,41,42,44,46);/q;+1/p-1/b10-8-;/t23-,24-,27-,28-,38-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	Na
Molecular Weight	22.9898
Charge	1
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C38H46N5O7S2
Molecular Weight	748.931
Charge	-1
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/205123s000lbledt.pdf

Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor approved for the treatment of Chronic Hepatitis C (genotype 1 and 4). Inhibiting NS3/4A, simeprevir blocks viral replication. In in vitro assays simeprevir was potent against HCV genotype 1a and 1b. Simeprevir must not be administered as monotherapy and should only be prescribed with both peginterferon alfa and ribavirin.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Target ID: Q91RS4_9HEPC Sources: http://www.ncbi.nlm.nih.gov/pubmed/18678486	Inhibitor 8146		0.36 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic hepatitis C 42 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/205123s000lbledt.pdf	Primary		Approved 8307	OLYSIO Approved Use Indicated for the treatment of chronic hepatitis C (CHC) genotype 1 or 4 infection as a component of a combination antiviral treatment regimen. OLYSIO monotherapy is not recommended. Launch Date 1.38507846E12

C_max

Value	Dose	Analyte	Population
11470 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2304 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4067 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6172 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
206000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
24630 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
56430 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
79710 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	SIMEPREVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
41.32 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		SIMEPREVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
16.04 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19852962/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		SIMEPREVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg 1 times / day multiple, oral Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22326470	unhealthy, 18–70 years n = 37 Health Status: unhealthy Condition: HCV genotypes 2–6 infection Age Group: 18–70 years Sex: M+F Population Size: 37 Sources: https://pubmed.ncbi.nlm.nih.gov/22326470	Other AEs: Headache, Diarrhoea... Other AEs: Headache (13.5%) Diarrhoea (10.8%) Fatigue (10.8%) Pruritus (10.8%) Anorexia (8.1%) Back pain (8.1%) Myalgia (8.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/22326470
400 mg 1 times / day multiple, oral Highest studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19852962	healthy, 24.0 years(range: 20-44 years) n = 9 Health Status: healthy Age Group: 24.0 years(range: 20-44 years) Sex: M+F Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/19852962	Sources: https://pubmed.ncbi.nlm.nih.gov/19852962
600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19852962	healthy, 38.0 years (range: 23-55 years) n = 9 Health Status: healthy Age Group: 38.0 years (range: 23-55 years) Sex: M Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/19852962	Sources: https://pubmed.ncbi.nlm.nih.gov/19852962
200 mg 2 times / day multiple, oral Highest studied dose Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19852962	healthy, 38.0 years (range: 25-54 years) n = 9 Health Status: healthy Age Group: 38.0 years (range: 25-54 years) Sex: M+F Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/19852962	Other AEs: Photosensitivity reaction, Diarrhea... Other AEs: Photosensitivity reaction (3 patients) Diarrhea (2 patients) Abdominal pain upper (2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/19852962
150 mg 1 times / day steady, oral Recommended Dose: 150 mg, 1 times / day Route: oral Route: steady Dose: 150 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000MedR.pdf Page: p. 57	unhealthy, 49 years (range: 18-73 years) n = 781 Health Status: unhealthy Age Group: 49 years (range: 18-73 years) Sex: M+F Population Size: 781 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000MedR.pdf Page: p. 57	Disc. AE: Pruritus, Psoriasis... AEs leading to discontinuation/dose reduction: Pruritus (<1%) Psoriasis (<1%) Rash (1%) Rash erythematous (<1%) Skin burning sensation (<1%) Aggression (<1%) Blood bilirubin increased (<1%) Major depression (<1%) Stomatitis (<1%) Headache (<1%) Pain (<1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000MedR.pdf Page: p. 57

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1670 inducer 753	inhibitor 1695	inhibitor 1789	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2A6 670 CYP2C8 869 CYP2C19 1410 CYP3A 208 OATP1B1 770 NTCP 33 P-gp 1401 MRP2 363 BSEP 392 CYP1A 71 CYP2E1 846	CYP2C8 670 CYP2C19 955 P-gp 1491 MRP2 196 BCRP 545 OATP1B1/3 11 OATP2B1 103	CYP1A2 671

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2D6 1826	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	moderate [IC50 42.9 uM]
CYP2C8 923	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	moderate [IC50 49.1 uM]
CYP2A6 702	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	moderate [IC50 59.7 uM]
CYP1A 119	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
CYP1A2 1620	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
CYP2C9 1747	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
CYP2E1 929	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
CYP3A4 1857	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	no
CYP3A 291	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	weak [IC50 131 uM]	likely (co-administration study) Comment: Concomitant use of OLYSIO with these antiarrhythmics may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0
CYP2C19 1484	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	weak [IC50 86.1 uM]
BSEP 393	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 1.67 uM]
OATP1B1 785	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 25 uM]	yes (co-administration study) Comment: Concomitant use of OLYSIO with rosuvastatin resulted in increased plasma concentrations of rosuvastatin due to inhibition of OATP1B1 by simeprevir Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0
NTCP 34	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 3.47 uM]
MRP2 452	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 6.4 uM]
P-gp 1588	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0	yes [IC50 85.9 uM]	yes (co-administration study) Comment: Concomitant use of OLYSIO with digoxin resulted in increased concentrations of digoxin due to inhibition of P-gp by simeprevir Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=38 Page: 38.0

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 545	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
CYP2C19 955	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
CYP2C8 670	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
MRP2 196	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
OATP1B1/3 11	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
OATP2B1 103	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
P-gp 1491	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
CYP3A4 1670	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes	likely (co-administration study) Comment: Concomitant use of OLYSIO with carbamazepine, oxcarbazepine, phenobarbital or phenytoin may result in significantly decreased plasma concentrations of simeprevir due to strong CYP3A induction by these anticonvulsants; Concomitant use of OLYSIO with clarithromycin or telithromycin may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by these antibiotics Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf#page=37 Page: 37.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1603	inhibitor 1584 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205123Orig1s000PharmR.pdf#page=28

Sourcing

Vendor/Aggregator	ID	URL
AChemBlock	R16014
AK Scientific	4041AH
AstaTech	33532
Chem Scene	CS-0338
Hangzhou APIChem Technology	AC-27651
Innovapharm	VT-00687829
KeyOrganics	AS-56205
Lan Pharmatech	LQT-B48548
MedChem Express	HY-10241
MolPort	MolPort-039-139-798
MolPort	MolPort-046-416-844
MolPort	MolPort-046-795-603
MuseChem	I009489
TargetMol	T4686
ZINC	ZINC000253632968	http://zinc15.docking.org/substances/ZINC000253632968
eMolecules	313130810
mcule	MCULE-6850465396
mcule	MCULE-7634361057

PubMed

Title	Date	PubMed
In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.	2009 Apr	19171797
Advances in the development of macrocyclic inhibitors of hepatitis C virus NS3-4A protease.	2010	20536420
Changing the face of hepatitis C management - the design and development of sofosbuvir.	2015	25987834
Cost-effectiveness of sofosbuvir-based treatments for chronic hepatitis C in the US.	2015 Aug 5	26239358
Hepatitis C virus: Virology, diagnosis and treatment.	2015 Jun 8	26052383

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose is one 150 mg capsule taken once daily with food. OLYSIO should be administered with both peginterferon alfa and ribavirin. The recommended treatment duration of OLYSIO with peginterferon alfa and ribavirin is 12 weeks, followed by either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on prior response status.

Route of Administration: Oral

In Vitro Use Guide

The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM (7.05 ng/mL) and 19 nM (14.25 ng/mL), respectively.

Substance Class	Chemical Created by `admin` on `Sun Dec 18 02:15:43 UTC 2022` Edited by `admin` on `Sun Dec 18 02:15:43 UTC 2022`
Record UNII	16U7H60184
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SIMEPREVIR SODIUM

Common Name

English

TMC-435 SODIUM SALT

Code

English

OLYSIO

Brand Name

English

Simeprevir sodium [WHO-DD]

Common Name

English

SIMEPREVIR SODIUM [ORANGE BOOK]

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

OLYSIO (AUTHORIZED: HEPATITS C, CHRONIC)