Saquinavir

Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. 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, with trade name Fortovase®.

    • Both formulations are generally used as a component of highly active antiretroviral therapy (HAART).

    History

    Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (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, is alleged to have rushed Invirase® to market, but the conditions that prevailed at the time were very bad 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.

    Mode of action

    Saquinavir is a protease inhibitor. The protease is an enzyme which cleaves viral protein molecules into smaller fragments, and it is vital for both the replication of the virus within the cell and also the release of mature viral particles from an infected cell. Saquinavir inhibits both HIV-1 & HIV-2 proteases.

    Toxicity

    The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhoea, 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. 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.

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