Saquinavir

BRAND NAMES

The main brand names for saquinavir are Invirase and Fortovase. These are used to treat HIV/AIDS, often in combination with other medications like ritonavir to boost their effectiveness.

Invirase: A brand name for saquinavir, it is typically prescribed to be taken with ritonavir.

Fortovase: This was another brand name for saquinavir, but it is not bioequivalent to Invirase and cannot be used interchangeably.

Saquin: This is a generic version of saquinavir. 

MECHANISM OF ACTION

Saquinavir works by blocking the HIV protease enzyme, which is crucial for the virus to mature and become infectious. It binds to the enzyme’s active site, preventing the cleavage of viral polyproteins into the functional proteins needed for viral assembly. As a result, the virus produces immature, non-infectious particles that are unable to replicate, thereby halting the progression of HIV infection.

PHARMACOKINETICS

Absorption

Saquinavir is an HIV protease inhibitor with exceptionally poor oral absorption due to its low water solubility, extensive first-pass metabolism, and efflux by P-glycoprotein (P-gp). To achieve therapeutic blood levels, it must be taken in combination with ritonavir, another protease inhibitor that acts as a potent absorption booster.

Distribution

Saquinavir has a steady-state volume of distribution of approximately 700 liters, indicating extensive distribution into body tissues and significant tissue binding. This large volume of distribution contributes to its relatively long half-life of around 13 hours, allowing for sustained drug levels in the body.

Metabolism

Saquinavir is extensively metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. Due to significant first-pass metabolism, it has low oral bioavailability and is rapidly cleared from the system. Its metabolism can be influenced by drug interactions and certain foods; for example, grapefruit juice can inhibit CYP3A4 activity, potentially increasing saquinavir’s bioavailability and the risk of side effects.

Excretion

Saquinavir is primarily eliminated through hepatic metabolism via the CYP3A4 enzyme, with both the parent drug and its metabolites excreted mainly in the feces. Less than 2% of the unchanged drug is eliminated in the urine, indicating that renal excretion plays a minimal role in its clearance.

PHARMACODYNAMICS

Saquinavir is an HIV protease inhibitor that works by blocking the viral protease enzyme, which is essential for processing polyproteins into functional proteins needed to produce mature, infectious HIV particles. By inhibiting this enzyme, saquinavir causes the release of immature, non-infectious virus particles, thereby reducing viral replication. Although it does not cure HIV, it helps lower the viral load and slow disease progression. Saquinavir is most effective when used in combination with other antiretroviral drugs as part of a comprehensive HIV treatment regimen.

ADMINISTRATION

Saquinavir (brand name Invirase) is an HIV protease inhibitor that must be taken orally in combination with ritonavir and a meal. This combination, often called "boosting," is crucial because ritonavir significantly improves saquinavir's absorption into the body. 

DOSAGE AND STRENGTH

Saquinavir is typically available in 500 mg film-coated tablets (saquinavir mesylate). The usual recommended adult dosage is 1,000 mg twice daily (i.e., two 500 mg tablets), taken with ritonavir 100 mg twice daily as a pharmacokinetic enhancer. This combination should be administered with food to improve absorption.

FOOD INTERACTIONS

To ensure effective absorption, saquinavir should always be taken with food, preferably a meal high in fat and calories, as this significantly enhances its bioavailability. Taking saquinavir without food can greatly reduce its effectiveness. Additionally, certain foods and supplements can affect how the drug is processed in the body. For example, grapefruit can raise saquinavir levels to potentially dangerous amounts, while garlic supplements can lower its concentration, reducing its effectiveness. It's important to be aware of these interactions and consult a healthcare provider before making any changes to your diet or supplement routine while taking saquinavir.

DRUG INTERACTIONS

Saquinavir has significant drug interactions because it is often combined with ritonavir and is metabolized by the CYP3A4 enzyme. Life-threatening risks include severe liver toxicity when combined with rifampin, and dangerous heart rhythm problems with QT-prolonging drugs. It also has major interactions with statins like simvastatin and lovastatin, as well as erectile dysfunction medications like sildenafil, which require careful management or avoidance. Other important interactions involve certain anticonvulsants, some herbal supplements like St. John's wort, and even grapefruit juice, which can all alter saquinavir levels.

CONTRAINDICATIONS

Saquinavir, used with ritonavir, is contraindicated in patients with severe liver damage, significant heart rhythm problems (like long QT syndrome or AV block), and hypersensitivity to the drug. It is also forbidden with drugs causing serious interactions, including specific heart medications, sedatives, cholesterol-lowering statins like lovastatin, and the antibiotic rifampin, which can cause severe liver toxicity.

SIDE EFFECTS

Common side effects:

Gastrointestinal issues.

Fatigue.

Fat redistribution.

Headache.

Serious side effects:

Heart problems.

Liver damage.

Allergic reactions.

High blood sugar.

Increased bleeding in hemophiliacs.

Immune reconstitution inflammatory syndrome (IRIS).

OVERDOSE

Mild symptoms.

Heart-related issues.

Liver problems.

High blood sugar.

Allergic reaction.

TOXICITY

Saquinavir toxicity involves common gastrointestinal issues like nausea, diarrhea, and abdominal pain, especially when boosted with ritonavir. More serious risks include potential liver injury, heart rhythm problems (like QT prolongation), and metabolic changes such as high cholesterol and blood sugar. Long-term use can also cause body fat redistribution (lipodystrophy).