Saquinavir mesylate is a different formulation, designed to be combined with another protease inhibitor that increases the bioavailability of the saquinavir.

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.

It was approved again on Nov 7, 1997 as Fortovase®, a soft gel capsule reformulated for improved bioavailability. 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.

Method of activity

When given alone, the HIV Protease Inhibitor (HPI) saquinavir has a very low oral bioavailability. In the clinic, it was found that the oral bioavailability of saquinavir significantly increases when patients also receive the HPI 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 enzyme Cytochrome P450 3A4. 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.

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SAQUINAVIR - Fortovase or Invirase
From Research Initiative/Treatment Action!, 3/1/00

The 200 mg saquinavir soft-gel capsules are beige, opaque, soft gelatin capsules imprinted with "ROCHE" and "0246". Other formulations of saquinavir are available. Dosing may vary.

"Participants who drank one glass of grapefruit juice with the saquinavir, and then another glass an hour later saw their AUCs (areas under the curve, a measure of the total exposure of the drug) increase 50 percent to 150 percent. The AUC of saquinavir was increased to 220 percent when double-strength grapefruit juice was given. Despite such results, there could be some uncertainties or drawbacks in taking grapefruit juice [with] saquinavir to increase the efficacy of a low dose. First, the effects of the juice--which can vary from batch to batch--can also vary from person to person.... for these and other reasons, Hoffmann-La Roche will not pursue the grapefruit juice method, and is instead designing a new formulation of saquinavir which raises bioavailability by about 300 percent."

--AIDS Treatment News 235, p. 5, 1995

Also known as: Ro 31-8959, saquinavir mesylate, SQV, SQV-HGC, SQV-SGC

Background and description. Saquinavir is a protease inhibitor manufactured by F. Hoffmann-La Roche Ltd. and distributed by Roche Laboratories Inc. The US Food & Drug Administration (FDA) approved it in its first formulation (saquinavir hard-gel, saquinavir mesylate or Invirase) for use in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in December 1995. Saquinavir hard-gel was the first FDA-approved protease inhibitor. Subsequently, the FDA approved a new formulation (saquinavir soft-gel or Fortovase) in November 1997.

Guidelines classification. The Panel on Clinical Practices for the Treatment of HIV Infection recommends saquinavir soft-gel as an "alternative" protease inhibitor when used alone. Both formulations are "strongly recommended" when given in combination with ritonavir (Norvir). Saquinavir hard-gel is "not recommended" except when used in combination with ritonavir.

Dose. Saquinavir soft-gel (Fortovase) is dosed at 1200 mg (six 200 mg capsules) 3 times a day. Saquinavir hard-gel (Invirase) is only recommended when combined with ritonavir. Dosing with ritonavir is generally 400 mg of Saquinavir (hard-gel or soft-gel) with 400 mg of ritonavir twice a day.

Food restrictions. Saquinavir soft-gel should be taken with a meal or up to 2 hours after a meal. Combining saquinavir soft-gel or saquinavir hard-gel with ritonavir eliminates the food effect.

Storage. Saquinavir soft-gel capsules should be refrigerated at 36 [degrees] to 46 [degrees] F in tightly closed bottles until dispensed. Refrigerated capsules remain stable until the expiration date printed on the label. Once brought to room temperature capsules should be used within 3 months. Saquinavir hard-gel capsules may be stored at room temperature.

Side effects. The most common side effects seen with saquinavir are gastrointestinal disturbances including nausea, bloating and diarrhea. Elevated liver function has been noted with saquinavir. Metabolic (lipid and glucose) and morphologic (fat accumulation and fat atrophy) abnormalities have been associated with protease inhibitors in general.

Resistance and cross-resistance. Resistance to saquinavir hard-gel has been generally associated with mutations at positions 48 and 90. Resistance to saquinavir soft-gel has been generally associated with mutations at positions 48, 54 and 82. In addition, a mutation at position 90 can occur with saquinavir soft-gel. Resistance to saquinavir hard-gel or soft-gel results in potential cross-resistance to other protease inhibitors.

Drug interactions. Saquinavir should not be taken with the following: cisapride (Propulsid), triazolam (Halcion), midazolam (Versed), ergot derivatives (Wigraine and Cafergot), simvastatin (Zocor), lovastatin (Mevacor), rifampin (Rifadin, Rimactane), rifabutin (Mycobutin), efavirenz (Sustiva) and indinavir (Crixivan), which is antagonistic in vivo.

Lipid-lowering drugs such as atorvastatin (Lipitor), pravastatin (Pravachol) or fluvastatin (Lescol) should be used with caution when combined with saquinavir. A dose reduction of sildenafil (Viagra) to 25 mg within a 48-hour period is recommended when taken with saquinavir. When combining saquinavir soft-gel with nelfinavir (Viracept) consideration should be given to dosing 750 mg nelfinavir with 800 mg of saquinavir soft-gel 3 times a day. Delavirdine (Rescriptor) increases the levels of saquinavir soft-gel with a mild decrease in delavirdine levels. An increase in liver toxicities has been observed with this combination and patients with hepatitis B or C should be monitored carefully, especially during the first 6 weeks of administration. Ritonavir increases the levels of saquinavir soft-gel by 3 fold or higher.

Clinical data. Early trials studied saquinavir as monotherapy, in combination with zidovudine (Retrovir) and zalcitabine (Hivid) and in high doses. All of these trials produced small virologic benefits. Saquinavir hard-gel received approval on the basis of ACTG 229, a study comparing the combination of saquinavir hard-gel and zalcitabine versus monotherapy of either, in zidovudine experienced patients. FDA approval was based on surrogate marker data, but longer-term follow-up confirmed the clinical benefit of saquinavir hard-gel. Subsequent studies found saquinavir soft-gel to have an 8-fold greater increase in drug exposure than saquinavir hard-gel. In a study comparing saquinavir soft-gel/NRTIs versus saquinavir hard-gel/NRTIs, on-treatment analysis showed that at 16 weeks 67% of' patients on the soft-gel formulation compared to 37% of patients on the hard-gel formulation had viral loads below 400 copies/mL. The mean viral load decreases were 2.0 log in the saquinavir soft-gel as compared to 1.6 log in the saquinavir hard-gel formulation.

Patient assistance. Roche offers a patient assistance program for those who qualify. For more information call 800.282.7780.

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