Saquinavir

Uses

Saquinavir is an HIV-1 protease inhibitor used for the treatment of HIV1 infection in combination with ritonavir and other antiretroviral agents in adults (over the age of 16 years)

Saquinavir is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Saquinavir works

The HIV lifecycle is comprised of 3 distinct stages: assembly, involving creation and packaging of essential viral components; budding, wherein the viral particle crosses the host cell plasma membrane and forms a lipid envelope; and maturation, wherein the viral particle alters its structure and becomes infectious. At the center of this lifecycle is the Gag polyprotein which, along with the products of its proteolysis, coordinate these stages and function as the major structural proteins of the virus. The HIV-1 protease enzyme, a dimeric aspartic protease, is the enzyme responsible for cleaving the Gag polyprotein and thus plays a critical role in many aspects of the HIV viral lifecycle.

Saquinavir is an inhibitor of the HIV-1 protease enzyme. Its design is based on the "peptidomimetic" principle, wherein the molecule contains a hydroxyethylene scaffold that mimics the normal peptide linkage (cleaved by HIV protease) but which itself cannot be cleaved. By preventing HIV-1 protease activity, and thus the proteolysis of the Gag polyprotein, saquinavir results in the production of immature, non-infectious viral particles.

Dosage

Saquinavir dosage

Saquinavir must be administered in combination with ritonavir.

Adults (over the age of 16 years): Saquinavir 1000 mg twice daily (5x200 mg capsules or 2x500 mg tablets) in combination with ritonavir 100 mg twice daily.

Saquinavir and ritonavir should be taken within 2 hours after a meal.

Side Effects

The most common adverse reactions are nausea, vomiting, diarrhea, fatigue, pneumonia, lipodystrophy and abdominal pain

Toxicity

The oral LD₅₀ of saquinavir in both rats and mice is >5 g/kg. Data regarding overdose with saquinavir are limited. No acute toxicities or sequelae were noted in a patient ingesting 8 grams of saquinavir as a single dose, and a second subject ingesting 2.4 grams as a single dose experienced throat pain that lasted for 6 hours and subsequently resolved. Treatment of overdose should consist of symptomatic and supportive measures. Dialysis is unlikely to be of benefit given saquinavir's extensive protein-binding.

Interaction

Saquinavir/ritonavir is a potent inhibitor of CYP3A, significantly increasing the exposure of drugs primarily metabolized by CYP3A.

Coadministration of Saquinavir/ritonavir with drugs that induce CYP3A may result in decreased plasma concentrations of saquinavir and reduced efficacy.

Certain drugs or drug classes should not be coadministered with Saquinavir/ritonavir based on drug interaction studies or predicted drug interactions

Food Interaction

• Avoid grapefruit products. Co-administration with grapefruit-containing products inhibits the metabolism of saquinavir.
• Take after a meal.

[Moderate] ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir.

The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant.

A high degree of intersubject variability in the grapefruit juice effect was also observed.

The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown.

However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability.

Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

Saquinavir Cholesterol interaction

[Moderate] Hyperlipidemia has been observed in 10% of patients receiving ritonavir during clinical trials.

Increases of 30% to 40% from baseline have been reported for total cholesterol and 200% to 300% or more for triglycerides.

These effects have also been reported during postmarketing experience with other protease inhibitors (PIs) but may be the most dramatic with ritonavir.

The clinical significance of these elevations is unclear.

Severe hyperlipidemia is known to sometimes cause pancreatitis.

In addition, some patients have reportedly developed symptomatic atherosclerosis and coronary artery disease after initiating PI treatment.

Patients with preexisting hyperlipidemia may require closer monitoring during PI therapy, and adjustments made accordingly in their lipid-lowering regimen.

PI therapy should be administered cautiously in patients with coronary artery disease or a history of ischemic heart disease.

Saquinavir Drug Interaction

Major: sotalolModerate: indinavir, dexamethasone, glycerinUnknown: aspirin, barium sulfate, dextran, low molecular weight, epoetin alfa, heparin, sodium iodide, arginine, acetaminophen, vitamin a topical, bioflavonoids, valproic acid, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione

Saquinavir Disease Interaction

Major: hemophilia, QT prolongationModerate: hyperglycemia, hyperlipidemia, liver disease, renal impairment

Volume of Distribution

The steady-state volume of distribution of saquinavir is approximately 700 L, suggesting extensive distribution into tissues.

Elimination Route

The absolute bioavailability of orally administered saquinavir is only ~4%, thought to be a consequence of incomplete absorption and extensive first-pass metabolism. It is co-administered with ritonavir, another protease inhibitor and a potent inhibitor of the enzymes responsible for saquinavir's first-pass metabolism, in order to dramatically boost its serum concentrations and, by extension, its therapeutic efficacy. Following administration of saquinavir 1000mg twice daily with ritonavir 100mg twice daily the AUC_24h at steady-state was 39026 ng.h/mL.

Clearance

The systemic clearance of saquinavir is approximately 1.14 L/h/kg following intravenous administration.

Elimination Route

The primary means of elimination of saquinavir appears to be extensive hepatic metabolism followed by fecal excretion of both the parent drug and metabolic products. Following the administration of radiolabeled saquinavir (both orally and intravenously), approximately 81-88% of radioactivity is recovered in the feces within 5 days of dosing while only 1-3% is recovered in the urine. Mass balance studies indicate that only 13% of orally-administered plasma radioactivity is attributed to unchanged parent drug, with the remainder comprising metabolic products of saquinavir's hepatic metabolism. In contrast, intravenous administration resulted in approximately 66% of the circulating plasma radioactivity being attributed to unchanged parent drug, suggesting a high degree of first-pass metabolism with oral administration.

Pregnancy & Breastfeeding use

Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Do not breastfeed if HIV-1-infected mothers are receiving Saquinavir therapy.

Contraindication

Patients with congenital or documented acquired QT prolongation, patients with refractory hypokalemia or hypomagnesemia, or those on concomitant therapy with other drugs that prolong the QT interval.

Saquinavir is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block.

Saquinavir is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients

Saquinavir when administered with ritonavir is contraindicated in patients with severe hepatic impairment.

Coadministration of Saquinavir/ritonavir with CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions.

Coadministration of Saquinavir/ritonavir with rifampin due to the risk of severe hepatotoxicity.

Special Warning

Pediatric Use: Pediatric dose recommendations that are both reliably effective and below thresholds of concern with respect to QT and PR prolongation could not be determined

Geriatric Use: Caution should be exercised due to greater frequency of decreased hepatic, renal or cardiac function in elderly population.

Impaired Renal Function: No initial dose adjustment is necessary for patients with renal impairment.

Impaired Hepatic Function: No dose adjustment is necessary for patients with mild or moderate hepatic impairment.

Storage Condition

The capsules and tablets should be stored at 25 degree C

Innovators Monograph

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