Saquinavir

Last updated

Saquinavir
Saquinavir structure.svg
Saquinavir ball-and-stick.png
Clinical data
Trade names Invirase, Fortovase
Other namesSQV
AHFS/Drugs.com Monograph
MedlinePlus a696001
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~4% (without ritonavir boosting) [3]
Protein binding 98%
Metabolism Liver, mainly by CYP3A4
Elimination half-life 9–15 hours
Excretion feces (81%) and urine (3%)
Identifiers
  • (2S)-N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C38H50N6O5
Molar mass 670.855 g·mol−1
3D model (JSmol)
  • 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
  • InChI=1S/C38H50N6O5/c1-38(2,3)43-37(49)32-20-26-14-7-8-15-27(26)22-44(32)23-33(45)30(19-24-11-5-4-6-12-24)41-36(48)31(21-34(39)46)42-35(47)29-18-17-25-13-9-10-16-28(25)40-29/h4-6,9-13,16-18,26-27,30-33,45H,7-8,14-15,19-23H2,1-3H3,(H2,39,46)(H,41,48)(H,42,47)(H,43,49)/t26-,27+,30-,31-,32-,33+/m0/s1 Yes check.svgY
  • Key:QWAXKHKRTORLEM-UGJKXSETSA-N Yes check.svgY
   (verify)

Saquinavir, sold under the brand name Invirase among others, is an antiretroviral medication used together with other medications to treat or prevent HIV/AIDS. [4] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. [4] It is taken by mouth. [4]

Contents

Common side effects include nausea, vomiting, diarrhea, and feeling tired. [4] More serious side effects include problems with QT prolongation, heart block, high blood lipids, and liver problems. [4] It appears to be safe in pregnancy. [4] It is in the protease inhibitor class and works by blocking the HIV protease. [4]

Saquinavir was patented in 1988 and first sold in 1995. [5] [6]

Medical uses

Saquinavir is used together with other medications to treat or prevent HIV/AIDS. [4] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. [4]

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.[ medical citation needed ]

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. [7]

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.[ medical citation needed ]

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 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.[ medical citation needed ]

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole. [8]

Mechanism of action

Saquinavir is a protease inhibitor. Proteases 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 HIV-1 and HIV-2 proteases. [9]

History

New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy", of which saquinavir, ritonavir and indinavir were key as the first three protease inhibitors. .mw-parser-output cite.citation{font-style:inherit;word-wrap:break-word}.mw-parser-output .citation q{quotes:"\"""\"""'""'"}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)}.mw-parser-output .id-lock-free a,.mw-parser-output .citation .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-limited a,.mw-parser-output .id-lock-registration a,.mw-parser-output .citation .cs1-lock-limited a,.mw-parser-output .citation .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/d/d6/Lock-gray-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-subscription a,.mw-parser-output .citation .cs1-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/a/aa/Lock-red-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg")right 0.1em center/12px no-repeat}.mw-parser-output .cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;color:#d33}.mw-parser-output .cs1-visible-error{color:#d33}.mw-parser-output .cs1-maint{display:none;color:#3a3;margin-left:0.3em}.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit} Cully M (28 November 2018). "Protease inhibitors give wings to combination therapy". Nature Research. Open Publishing. Retrieved 28 October 2020. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years. HIV new infections and deaths 1981-2008.jpg
New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy", of which saquinavir, ritonavir and indinavir were key as the first three protease inhibitors.Cully M (28 November 2018). "Protease inhibitors give wings to combination therapy". Nature Research. Open Publishing. Retrieved 28 October 2020. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.

Saquinavir was developed by the pharmaceutical company Roche. [11] 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. [12] 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. [10] [13]

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. [14] [ better source needed ] It was approved again on November 7, 1997, as Fortovase, [15] 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, [16] owing to the ability of the latter co-formulated drug to inhibit the enzyme that metabolizes the AIDS drugs.[ citation needed ]

Society and culture

Economics

As of 2015, it is not available as a generic medication. [17]

Formulations

Two formulations have been marketed:

Related Research Articles

Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

<span class="mw-page-title-main">Didanosine</span> Chemical compound

Didanosine, sold under the brand name Videx, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor class.

<span class="mw-page-title-main">Abacavir</span> Chemical compound

Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

<span class="mw-page-title-main">Atazanavir</span> Chemical compound

Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth.

<span class="mw-page-title-main">Ritonavir</span> Antiretroviral medication

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor and is used with other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth. Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<span class="mw-page-title-main">Nelfinavir</span> Antiretroviral drug

Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is almost always used in combination with other antiretroviral drugs.

<span class="mw-page-title-main">Efavirenz</span> Antiretroviral medication

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. It is taken by mouth.

<span class="mw-page-title-main">Tipranavir</span> Chemical compound

Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name AptivusAP-tiv-əs. It is administered with ritonavir in combination therapy to treat HIV infection.

<span class="mw-page-title-main">Indinavir</span> Chemical compound

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus.

<span class="mw-page-title-main">Lamivudine/zidovudine</span> Combination drug for HIV

Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.

<span class="mw-page-title-main">Fosamprenavir</span> Chemical compound

Fosamprenavir (FPV), sold under the brand names Lexiva and Telzir, is a medication used to treat HIV/AIDS. It is a prodrug of the protease inhibitor and antiretroviral drug amprenavir. It is marketed by ViiV Healthcare as the calcium salt.

<span class="mw-page-title-main">Lopinavir</span> Chemical compound

Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).

Synergistic enhancers of antiretrovirals usually do not possess any antiretroviral properties alone, but when they are taken concurrently with antiretroviral drugs they enhance the effect of that drug.

<span class="mw-page-title-main">Darunavir</span> Antiretroviral medication

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth once to twice a day.

<span class="mw-page-title-main">Raltegravir</span> Chemical compound

Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.

<span class="mw-page-title-main">Elvitegravir</span> Chemical compound

Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012, for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014, the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015, the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.

Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.

<span class="mw-page-title-main">Lopinavir/ritonavir</span> Combination medication for HIV/AIDS

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution.

<span class="mw-page-title-main">Charles Flexner</span> American physician and pharmaceutical scientist

Charles Williams Flexner is an American physician, clinical pharmaceutical scientist, academic, author and researcher. He is a Professor of Medicine at the Johns Hopkins University School of Medicine.

References

  1. ↑ "Saquinavir Use During Pregnancy". Drugs.com. 20 March 2018. Retrieved 28 January 2020.
  2. ↑ Roche Products Pty Limited (6 November 2018). "Invirase® (Saquinavir mesilate)". Australian Product Information– via MedAdvisor International Pty Ltd.
  3. ↑ "Invirase- saquinavir mesylate capsule INVIRASE- saquinavir mesylate tablet, film coated". DailyMed. 26 December 2019. Retrieved 28 January 2020.
  4. 1 2 3 4 5 6 7 8 9 "Saquinavir". The American Society of Health-System Pharmacists. Archived from the original on 8 September 2015. Retrieved 5 September 2015.
  5. ↑ Minor LK (2006). Handbook of Assay Development in Drug Discovery. Hoboken: CRC Press. p. 117. ISBN   9781420015706. Archived from the original on 31 March 2016.
  6. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN   9783527607495.
  7. ↑ "Fortovase". Drugs.com. 22 March 2019. Archived from the original on 28 April 2020. Retrieved 28 January 2020.
  8. ↑ Winston A, Back D, Fletcher C, Robinson L, Unsworth J, Tolowinska I, et al. (June 2006). "Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers". AIDS. 20 (10): 1401–1406. doi: 10.1097/01.aids.0000233573.41597.8a . PMID   16791014. S2CID   44506039.
  9. ↑ Dolin R, Masur H, Saag MS, eds. (1999). AIDS Therapy. Churchill Livingstone. p. 129. ISBN   9780443075926.
  10. 1 2 3 Centers for Disease Control and Prevention (CDC) (3 June 2011). "HIV Surveillance—United States, 1981-2008". Morbidity and Mortality Weekly Report (MMWR). 60 (21): 689–693. PMID   21637182. Archived from the original on 9 November 2013. Retrieved 8 November 2013.
  11. ↑ Hilts PJ (8 December 1995). "F.D.A. Backs A New Drug To Fight AIDS". New York Times. Retrieved 28 October 2020.
  12. ↑ "Antiretroviral Drug Discovery and Development". NIH. 26 November 2018. Retrieved 29 October 2020.
  13. ↑ 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.
  14. ↑ AIDS Community Research Initiative of America. "Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications". The Body. Archived from the original on 9 November 2013. Retrieved 20 February 2013.
  15. ↑ "Drug Approval Package: Fortovase/Saquinavir NDA 20828". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 28 January 2020.
  16. ↑ "Withdrawal of Fortovase (PDF)" (PDF). Archived from the original (PDF) on 14 May 2006.
  17. ↑ "Generic Invirase Availability". Drugs.com. Retrieved 9 July 2020.
  18. ↑ Gibaud S, Attivi D (August 2012). "Microemulsions for oral administration and their therapeutic applications" (PDF). Expert Opinion on Drug Delivery. 9 (8): 937–951. doi:10.1517/17425247.2012.694865. PMID   22663249. S2CID   28468973.
  19. ↑ "Roche to discontinue the sale and distribution of Fortovase (saquinavir)". News-Medical.Net. 18 May 2005. Archived from the original on 22 February 2015.
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