Saquinavir

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Saquinavir
Saquinavir structure.svg
Saquinavir ball-and-stick.png
Systematic (IUPAC) name
(2S)-N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide
Clinical data
Trade names Invirase, Fortovase
AHFS/Drugs.com monograph
MedlinePlus a696001
Pregnancy
category
  • B1 (Australia)
Pharmacokinetic data
Bioavailability ~4% (without ritonavir boosting)[1]
Protein binding 98%
Metabolism Hepatic, mainly by CYP3A4
Biological half-life 9–15 hours
Excretion feces (81%) and urine (3%)
Identifiers
CAS Number 127779-20-8 YesY
ATC code J05AE01 (WHO)
PubChem CID: 441243
IUPHAR/BPS 4813
DrugBank DB01232 YesY
ChemSpider 390016 YesY
UNII L3JE09KZ2F YesY
KEGG D00429 YesY
ChEMBL CHEMBL114 YesY
NIAID ChemDB 000640
Chemical data
Formula C38H50N6O5
Molecular mass 670.841 g/mol
  • 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 YesY
  • Key:QWAXKHKRTORLEM-UGJKXSETSA-N YesY
  (verify)

Saquinavir, sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS.[2] Typically it is used with ritonavir or lopinavir/ritonavir. It is taken by mouth.[2]

Common side effects include nausea, vomiting, diarrhea, and feeling tired. More serious side effects include problems with QT prolongation, heart block, high blood lipids, and liver problems. It appears to be safe in pregnancy. It is in the protease inhibitor class and works by blocking the HIV protease.[2]

Saquinavir was first sold in 1995.[3] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[4] As of 2015 it is not available as a generic medication and is expensive.[5] The wholesale cost is about 4.50 USD per day.[6]

Medical uses

Saquinavir is used together with other medications to treat or prevent HIV/AIDS.[2] Typically it is used with ritonavir or lopinavir/ritonavir.[2]

Side effects

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhea, nausea, loose stools & abdominal discomfort. Invirase is better tolerated than Fortovase.

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.

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.

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.

History

United States HIV new infections and HIV deaths before and after the FDA approval of saquinavir.
HIV deaths in the United States fell from approximately 50,000 per year to 18,000 in the two years following the FDA approval of saquinavir[9]

Saquinavir was developed by the pharmaceutical company Roche. Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). Within 2 years of its approval, and that of ritonavir 4 months later, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000.[10] The manufacturer, 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. This decision was controversial, amid disagreement between AIDS activists over the benefits of thorough testing versus early access to new drugs.[11]

It was approved again on Nov 7, 1997 as Fortovase, a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, owing to reduction in demand, Fortovase would cease being marketed early in 2006 in favour of Invirase boosted with ritonavir.[12]

Society and culture

Cost

As of 2015 it is not available as a generic medication and is expensive.[5] The wholesale cost is about 4.50 USD per day.[6]

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,[13] orally-administered formulation), with trade name Fortovase, which was discontinued worldwide in 2006.[14]

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ FortovaseTM (saquinavir) soft gelatin capsules. Product information (November 1997)
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Withdrawal of Fortovase (PDF)
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ News-Medical.Net. May 18, 2005 Roche to discontinue the sale and distribution of Fortovase (saquinavir)

External links

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