Velpatasvir

Velpatasvir
Clinical data
Trade names	Epclusa, Sofosvel, Velpanat (all in combination with sofosbuvir)
Routes of; administration	Oral (tablets)
ATC code	J05AP55 (WHO) (combination with sofosbuvir); J05AP56 (WHO) (combination with sofosbuvir and voxilaprevir);
Legal status
Legal status	US: ℞-only;
Pharmacokinetic data
Protein binding	>99.5%
Metabolism	Liver (CYP2B6, 2C8, 3A4)
Elimination half-life	15 hours
Excretion	Feces (94%), urine (0.4%)
Identifiers
	IUPAC name Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methyl-1-pyrrolidinyl]-3-methyl-1-oxo-2-butanyl}carbamate;
CAS Number	1377049-84-7;
PubChem CID	67683363;
DrugBank	DB11613;
ChemSpider	34501056;
UNII	KCU0C7RS7Z;
KEGG	D10806;
ChEBI	CHEBI:133009 ;
CompTox Dashboard (EPA)	DTXSID70722565 ;
Chemical and physical data
Formula	C49H54N8O8
Molar mass	883.019 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6[nH]c([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)nc65)cc3-4)[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1;
	InChI InChI=1S/C49H54N8O8/c1-26(2)41(54-48(60)63-5)47(59)57-27(3)12-17-38(57)45-51-36-16-14-30-20-35-33-15-13-31(19-32(33)25-65-40(35)21-34(30)43(36)53-45)37-22-50-44(52-37)39-18-28(24-62-4)23-56(39)46(58)42(55-49(61)64-6)29-10-8-7-9-11-29/h7-11,13-16,19-22,26-28,38-39,41-42H,12,17-18,23-25H2,1-6H3,(H,50,52)(H,51,53)(H,54,60)(H,55,61)/t27-,28-,38-,39-,41-,42+/m0/s1; Key:FHCUMDQMBHQXKK-CDIODLITSA-N;

Velpatasvir is an NS5A inhibitor (by Gilead) which is used together with sofosbuvir in the treatment of hepatitis C infection of all six major genotypes.^[2]^[3]

Side effects

Side effects in studies occurred with similar frequencies as in people treated with placebo.^[4]

Interactions

Velpatasvir is both an inhibitor and a substrate of the transporter proteins P-glycoprotein (Pgp), ABCG2, OATP1B1 and OATP1B3. It is partly degraded by the liver enzymes CYP2B6, CYP2C8 and CYP3A4. Substances that are transported or inactivated by these proteins, or interfere with them, can interact with velpatasvir. In studies, this has been found for the HIV combination efavirenz/emtricitabine/tenofovir, which reduces the area under the curve (AUC) of velpatasvir by about 50%, and the CYP3A4 and Pgp inducer rifampicin, which reduces its AUC by about 80%, rendering it likely ineffective. Digoxin is eliminated by Pgp; its AUC is increased by about 30% in combination with velpatasvir and sofosbuvir (although it is not clear which of the two is responsible for this effect).^[4]

Substances that reduce gastric acid, such as antacids, H₂ blockers, and proton pump inhibitors, reduce velpatasvir AUC by 20–40%.^[4]

Pharmacology

Mechanism of action

The substance blocks NS5A, a protein necessary for hepatitis C virus replication and assembly.^[4]

Pharmacokinetics

Velpatasvir reaches highest blood plasma levels three hours after oral intake together with sofosbuvir. Plasma protein binding is over 99.5%. It is slowly metabolised by the liver enzymes CYP2B6, CYP2C8 and CYP3A4. While monohydroxylated and demethylated metabolites have been identified in human blood plasma and faeces, over 98% of the circulating substance is velpatasvir itself.^[4] 94% are excreted via the faeces, and only 0.4% via the urine.^[1] Biological half-life is about 15 hours.^[4]

References

^ ^a ^b "Epclusa (sofosbuvir and velpatasvir) Tablets, for Oral Use. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Foster City, CA 94404. Retrieved 1 August 2016.
^ "FDA Approves Epclusa". Drugs.com.
^ Heo YA, Deeks ED (April 2018). "Sofosbuvir/Velpatasvir/Voxilaprevir: A Review in Chronic Hepatitis C". Drugs. 78 (5): 577–587. doi:10.1007/s40265-018-0895-5. PMID 29546556.
^ ^a ^b ^c ^d ^e ^f Haberfeld H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Epclusa 400 mg/100 mg Filmtabletten.

[PrescribingInfo-1] "Epclusa (sofosbuvir and velpatasvir) Tablets, for Oral Use. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Foster City, CA 94404. Retrieved 1 August 2016.

[2] "FDA Approves Epclusa". Drugs.com.

[pmid29546556-3] Heo YA, Deeks ED (April 2018). "Sofosbuvir/Velpatasvir/Voxilaprevir: A Review in Chronic Hepatitis C". Drugs. 78 (5): 577–587. doi:10.1007/s40265-018-0895-5. PMID 29546556.

[AC-4] ^ ^a ^b ^c ^d ^e ^f Haberfeld H, ed. (2016). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Epclusa 400 mg/100 mg Filmtabletten.

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