Saquinavir
Encyclopedia
Saquinavir is an antiretroviral drug
used in HIV
therapy. It falls in the protease inhibitor
class. Two formulations have been marketed:
Both formulations are generally used as a component of highly active antiretroviral therapy
(HAART).
(FDA). It was approved on December 6, 1995, as Invirase, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients. The manufacturer, Roche
, and the FDA rushed Invirase to market in light of the dire conditions of the HIV/AIDS epidemic that prevailed at the time and there was a lot of pressure to produce products quickly.
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
.
. 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 inhibits both HIV-1 and HIV-2 proteases.
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
.
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
used in HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
therapy. It falls in the protease inhibitor
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
class. Two formulations have been marketed:
- a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavirRitonavirRitonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
to increase the saquinavir bioavailabilityBioavailabilityIn pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
;
- a soft-gel capsule formulation of saquinavir, with trade name Fortovase.
Both formulations are generally used as a component of highly active antiretroviral therapy
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
(HAART).
History
Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA). It was approved on December 6, 1995, as Invirase, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients. The manufacturer, Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
, and the FDA rushed Invirase to market in light of the dire conditions of the HIV/AIDS epidemic that prevailed at the time and there was a lot of pressure to produce products quickly.
It was approved again on Nov 7, 1997 as Fortovase, a soft gel capsule reformulated for improved bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
. 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
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
.
Mode of action
Saquinavir is a protease inhibitorProtease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
. Protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
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 inhibits both HIV-1 and HIV-2 proteases.
Adverse reactions
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.In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
. 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
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
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
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
.
Further reading
- Cohen Stuart JW, Schuurman R, Burger DM, et al. (1999) Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study). AIDS 13:F53-58
- Dragsted UB, Gerstoft J, Pedersen C, et al. (2003) Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin 1 Trial. J Infect Dis 188:635-642
- Actual photo of saquinavir and more saquinavir information.