Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Saquinavir: Difference between pages

{{Short description|Chemical compound}}

{{Use dmy dates|date=January 2020}}

| verifiedrevid = 464387150

| drug_name =

| INN =

| type = <!-- empty -->

| image = Saquinavir structure.svg

| width = 250

| alt =

| image2 = Saquinavir ball-and-stick.png

| width2 =

| alt2 =

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Invirase, Fortovase

| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->

| licence_EU = yes

| DailyMedID = Saquinavir

| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->

| pregnancy_AU = B1

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Saquinavir Use During Pregnancy | website=Drugs.com | date=20 March 2018 | url=https://www.drugs.com/pregnancy/saquinavir.html | access-date=28 January 2020}}</ref>

| pregnancy_category=

| routes_of_administration = [[By mouth]]

| class =

| ATCvet =

| ATC_prefix = J05

| ATC_suffix = AE01

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref name="Invirase PI">{{cite web | title = Invirase® (Saquinavir mesilate) | author = Roche Products Pty Limited | work = Australian Product Information | date = 6 November 2018 | via = MedAdvisor International Pty Ltd | url = https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropinvir10814 }}</ref>

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->

| bioavailability = ~4% (without ritonavir [[Ritonavir#Mechanism of action|boosting]])<ref name="Invirase label">{{cite web | title=Invirase- saquinavir mesylate capsule INVIRASE- saquinavir mesylate tablet, film coated | website=DailyMed | date=26 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c00d1607-ac36-457b-a34b-75ad74f9cf0a | access-date=28 January 2020}}</ref>

| metabolism = Liver, mainly by [[CYP3A4]]

| metabolites =

| onset =

| elimination_half-life = 9–15 hours

| duration_of_action =

| excretion = feces (81%) and urine (3%)

<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 4813

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref =

| ChEBI =

| NIAID_ChemDB = 000640

| PDB_ligand = ROC

| synonyms = SQV

<!-- Chemical and physical data -->

| IUPAC_name = (2''S'')-''N''-[(2''S'',3''R'')-4-[(3''S'')-3-(''tert''-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide

| C=38 | H=50 | N=6 | O=5

| SMILES = O=C(N)C[C@H](NC(=O)c1nc2c(cc1)cccc2)C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN5[C@H](C(=O)NC(C)(C)C)C[C@@H]4CCCC[C@@H]4C5

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Saquinavir''', sold under the brand name '''Invirase''' among others, is an [[antiretroviral medication]] used together with other medications to treat or prevent [[HIV/AIDS]].<ref name=AHFS2015>{{cite web|title=Saquinavir|url=https://www.drugs.com/monograph/saquinavir.html|publisher=The American Society of Health-System Pharmacists|access-date= 5 September 2015 |url-status=live|archive-url=https://web.archive.org/web/20150908033239/http://www.drugs.com/monograph/saquinavir.html|archive-date= 8 September 2015 }}</ref> Typically it is used with [[ritonavir]] or [[lopinavir/ritonavir]] to increase its effect.<ref name=AHFS2015/> It is taken [[by mouth]].<ref name=AHFS2015/>

<!-- Side effects and mechanism -->

Common side effects include nausea, vomiting, diarrhea, and feeling tired.<ref name=AHFS2015/> More serious side effects include problems with [[QT prolongation]], [[heart block]], [[hyperlipidemia|high blood lipids]], and liver problems.<ref name=AHFS2015/> It appears to be safe in pregnancy.<ref name=AHFS2015/> It is in the [[protease inhibitor (pharmacology)|protease inhibitor]] class and works by blocking the [[HIV protease]].<ref name=AHFS2015/>

<!-- Society and culture -->

Saquinavir was patented in 1988 and first sold in 1995.<ref name=Min2006>{{cite book| vauthors = Minor LK |title=Handbook of Assay Development in Drug Discovery.|date=2006|publisher=CRC Press|location=Hoboken|isbn=9781420015706|page=117|url=https://books.google.com/books?id=RmrLBQAAQBAJ&pg=PA117|url-status=live|archive-url=https://web.archive.org/web/20160331125835/https://books.google.com/books?id=RmrLBQAAQBAJ&pg=PA117|archive-date= 31 March 2016}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=509 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA509 |language=en}}</ref>

==Medical uses==

Saquinavir is used together with other medications to treat or prevent [[HIV/AIDS]].<ref name=AHFS2015/> Typically it is used with [[ritonavir]] or [[lopinavir/ritonavir]] to increase its effect.<ref name=AHFS2015/>

==Side effects==

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including [[diarrhoea]], [[nausea]], loose stools and abdominal discomfort. Invirase is better tolerated than Fortovase.{{medcn|date=January 2020}}

==Bioavailability and drug interactions==

Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.<ref>{{cite web | title=Fortovase | website=Drugs.com | date=22 March 2019 | url=https://www.drugs.com/pro/fortovase.html | access-date=28 January 2020 | archive-date=28 April 2020 | archive-url=https://web.archive.org/web/20200428232636/https://www.drugs.com/pro/fortovase.html | url-status=dead }}</ref>

In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI [[ritonavir]]. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.{{medcn|date=January 2020}}

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the [[Cytochrome P450 oxidase|cytochrome P450]] [[CYP3A4|3A4]] isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.{{medcn|date=January 2020}}

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by [[omeprazole]].<ref>{{cite journal | vauthors = Winston A, Back D, Fletcher C, Robinson L, Unsworth J, Tolowinska I, Schutz M, Pozniak AL, Gazzard B, Boffito M | display-authors = 6 | title = Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers | journal = AIDS | volume = 20 | issue = 10 | pages = 1401–1406 | date = June 2006 | pmid = 16791014 | doi = 10.1097/01.aids.0000233573.41597.8a | s2cid = 44506039 | doi-access = free }}</ref>

==Mechanism of action==

Saquinavir is a [[Protease inhibitor (pharmacology)|protease inhibitor]]. [[Protease]]s are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both [[Subtypes of HIV|HIV-1]] and HIV-2 proteases.<ref>{{cite book | veditors = Dolin R, Masur H, Saag MS | url = https://books.google.com/books?id=oeJrAAAAMAAJ&q=Saquinavir+inhibits+both+HIV-1+HIV-2+proteases | title = AIDS Therapy | publisher = Churchill Livingstone | date = 1999 | page = 129 | isbn=9780443075926 }}</ref>

==History==

[[File:HIV new infections and deaths 1981-2008.jpg|thumb|alt=|New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy",<ref name=MMWR0621/> of which saquinavir, ritonavir and indinavir were key as the first three protease inhibitors.{{cite journal |url=https://www.nature.com/articles/d42859-018-00015-7#:~:text=The%20first%20protease%20inhibitor%20to,and%20indinavir%2C%20were%20also%20approved. |title=Protease inhibitors give wings to combination therapy | vauthors = Cully M |publisher=Open Publishing |date=November 28, 2018 |journal=Nature Research |access-date=October 28, 2020}} As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.<ref name=MMWR0621/>]]

Saquinavir was developed by the pharmaceutical company [[Hoffmann-La Roche|Roche]].<ref>{{cite web |url=https://www.nytimes.com/1995/12/08/us/fda-backs-a-new-drug-to-fight-aids.html |title= F.D.A. Backs A New Drug To Fight AIDS | vauthors = Hilts PJ |date=December 8, 1995 |website=New York Times |access-date=October 28, 2020}}</ref> Saquinavir was the sixth antiretroviral and the first protease inhibitor approved by the US [[Food and Drug Administration]] (FDA), leading [[ritonavir]] and [[indinavir]] by a few months.<ref>{{cite web |url=https://www.niaid.nih.gov/diseases-conditions/antiretroviral-drug-development |title=Antiretroviral Drug Discovery and Development |date=November 26, 2018 |website=NIH |access-date=October 29, 2020}}</ref> This new class of antiretrovirals played a critical role in the development of highly active antiretroviral therapy (HAART), which helped significantly lower the risk of death from AIDS-related causes, as seen by a reduction of the annual U.S. HIV-associated death rate, from over 50,000 to about 18,000 over a period of two years.<ref name = MMWR0621>{{cite journal | title = HIV Surveillance—United States, 1981-2008 | journal = Morbidity and Mortality Weekly Report (MMWR) | date = 3 June 2011 | volume = 60 | issue = 21 | pages = 689–693 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6021a2.htm | access-date = 8 November 2013 | url-status = live | archive-url = https://web.archive.org/web/20131109001606/http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6021a2.htm | archive-date = 9 November 2013 | pmid = 21637182 | author1 = Centers for Disease Control and Prevention (CDC) }}</ref><ref>The CDC, in its ''Morbidity and Mortality Weekly Report,'' ascribes this to "highly active antiretroviral therapy", without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.</ref>

Roche requested and received approval of Invirase via the FDA's "Accelerated Approval" program—a process designed to speed drugs to market for the treatment of serious diseases—a decision that was controversial, as AIDS activists disagreed over the benefits of thorough testing versus early access to new drugs.<ref>{{cite web|url=http://www.thebody.com/content/art14169.html|title=Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications|access-date=20 February 2013|publisher=The Body | author = AIDS Community Research Initiative of America |url-status=live|archive-url=https://web.archive.org/web/20131109001602/http://www.thebody.com/content/art14169.html|archive-date=9 November 2013}}</ref>{{better source|date=February 2020}} It was approved again on November 7, 1997, as Fortovase,<ref>{{cite web | title=Drug Approval Package: Fortovase/Saquinavir NDA 20828 | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020828_fortovase_toc.cfm | access-date=28 January 2020}}</ref> a soft gel capsule reformulated for improved [[bioavailability]]. Roche announced in May 2005 that, given reduced demand, Fortovase would cease being marketed early in 2006, in favor of Invirase boosted with [[ritonavir]],<ref>{{cite web | url = http://www.rocheusa.com/products/FTVDearDoctorFINAL.pdf | title = Withdrawal of Fortovase (PDF) | archive-url = https://web.archive.org/web/20060514173628/http://www.rocheusa.com/products/FTVDearDoctorFINAL.pdf | archive-date = 14 May 2006 }}</ref> owing to the ability of the latter co-formulated drug to inhibit the [[CYP3A4|enzyme that metabolizes the AIDS drugs]].{{citation needed|date=February 2020}}

==Society and culture==

===Economics===

{{As of|2015}}, it is not available as a [[generic medication]].<ref>{{cite web | title=Generic Invirase Availability | website=Drugs.com | url=https://www.drugs.com/availability/generic-invirase.html | access-date=9 July 2020}}</ref>

===Formulations===

Two formulations have been marketed:

* a hard-gel capsule formulation of the [[mesylate]], with trade name Invirase, which requires combination with [[ritonavir]] to increase the saquinavir [[bioavailability]];

* a soft-gel capsule formulation of saquinavir ([[microemulsion]],<ref>{{cite journal | vauthors = Gibaud S, Attivi D | title = Microemulsions for oral administration and their therapeutic applications | journal = Expert Opinion on Drug Delivery | volume = 9 | issue = 8 | pages = 937–951 | date = August 2012 | pmid = 22663249 | doi = 10.1517/17425247.2012.694865 | s2cid = 28468973 | url = https://hal.archives-ouvertes.fr/hal-00706176/file/Microemulsion%20oral%20delivery.pdf }}</ref> orally-administered formulation), with trade name Fortovase, which was discontinued worldwide in 2006.<ref>{{cite web | work = News-Medical.Net | url = http://www.news-medical.net/news/2005/05/18/10187.aspx | title = Roche to discontinue the sale and distribution of Fortovase (saquinavir) | archive-url = https://web.archive.org/web/20150222180953/http://www.news-medical.net/news/2005/05/18/10187.aspx | archive-date = 22 February 2015 | date = 18 May 2005 }}</ref>

== References ==

{{reflist}}

== External links ==

* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/saquinavir | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Saquinavir }}

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[[Category:Carboxamides]]

[[Category:CYP3A4 inhibitors]]

[[Category:Drugs developed by Hoffmann-La Roche]]

[[Category:Drugs developed by Genentech]]

[[Category:Hepatotoxins]]

[[Category:HIV protease inhibitors]]

[[Category:Decahydroisoquinolines]]

[[Category:Quinolines]]

[[Category:Wikipedia medicine articles ready to translate]]