HIV Protease Inhibitor – Antiretroviral Agent
Action And Clinical Pharmacology: Saquinavir is a selective inhibitor of the viral pol-encoded aspartic protease which cleaves precursor molecules into the structural proteins of the mature virion core and activates reverse transcriptase during the HIV growth cycle. Because of these functions, this protease is essential for the release of infectious virus (as proved by active site mutagenesis).
Saquinavir is a potent (KiÂ£0.12 nM) inhibitor of HIV proteases. No inhibition of human aspartyl or other proteases has been seen even at a concentration of 10 ÂµM, indicating high selectivity (at least 50 000-fold). Experiments in cell culture indicate that saquinavir produces an additive to synergistic effect against HIV in double and triple combination with various reverse transcriptase inhibitors (including zidovudine, didanosine and zalcitabine), without enhanced cytotoxicity.
Two mutations have been identified in the protease gene which contribute to genotypic saquinavir resistance (G48V and L90M). After 1 year of therapy, at least 1 of these mutations has occurred in 31% of patients taking saquinavir in combination with zidovudine [ZDV] or zalcitabine [ddC]), and in 45% of patients taking saquinavir monotherapy (600 mg t.i.d.). Genotypic evidence suggests that patients with these mutations will not develop broad cross-resistance to other protease inhibitors. Evidence also suggests that combination therapy with ZDV or ddC decreases the emergence of reduced sensitivity to saquinavir in culture (=phenotypic resistance): after 1 year of therapy, reduced sensitivity to saquinavir has been seen in 38% of patients treated with saquinavir plus ZDV or ddC, vs 45% of patients treated with saquinavir monotherapy (600 mg t.i.d.). Additionally, dual therapy with saquinavir and ZDV appears to restrict the emergence of ZDV resistance.
Saquinavir must be taken anytime within 2 hours following a meal. The extent of absorption (as reflected by AUC) after a 600 mg oral dose in fasting healthy volunteers was substantially increased when given following food, from 24 to 161 ng.h/mL. The presence of food also increased the time taken to achieve maximum concentration from 2.4 to 3.8 hours, and substantially increased the mean maximum plasma concentrations (Cmax) from 3.0 to 35.5 ng/mL. The effect of food has been shown to be present for up to 2 hours after food intake. Additionally, exposure to saquinavir was doubled (AUC(0-12) increased from 183.2 ng.h/mL to 374.4 ng.h/mL) when saquinavir was coadministered with “double-strength” grapefruit juice; and increased by 40% (AUC(0-12) from 183.2 ng.h/mL to 238.1 ng.h/mL) when taken with normal strength grapefruit juice in a single dose study.
Following administration of a 600 mg oral dose to healthy volunteers in the presence of food, the mean absolute bioavailability is 4%. This low bioavailability is thought to be due to a combination of incomplete absorption (approximately 30%) and extensive first pass metabolism.
The mean steady-state volume of distribution following i.v. administration of a 12 mg dose of saquinavir is 700 L, indicating extensive partitioning into tissues. Saquinavir shows a high degree of protein binding (approximately 98%), which is independent of concentration over the range 15 to 700 ng/mL. Greater than 96% of a radiolabelled i.v. dose appears in the feces within 48 hours, indicating extensive hepatic clearance. Hepatic metabolism is P450-mediated, of which >90% is the work of one isozyme (CYP3A4). Renal excretion is a very minor route of elimination for saquinavir (
After single and multiple oral doses as capsules (25 to 600 mg) in the presence of food, the increase in exposure (50-fold) was greater than directly proportional to the increase in dose (24-fold). Accumulation following multiple dosing (25 to 600 mg t.i.d.) in HIV-infected patients is modest: AUC was increased 150% at steady state compared to single doses.
Indications And Clinical Uses: In combination with reverse transcriptase inhibitor (RTI) nucleoside analogues for the treatment of advanced HIV infection. This indication is based on changes in surrogate markers in patients who initiated saquinavir concomitantly with zalcitabine or zalcitabine and zidovudine. Results available from limited uncontrolled open-label studies suggest that saquinavir in combination with other RTI nucleoside analogues also produces improvement in surrogate markers.
Patients in these studies had prolonged prior antiretroviral therapy and CD4 cell counts less than 300/mm RTI nucleoside analogues used in open-label clinical trials include lamivudine, stavudine, didanosine, zalcitabine and zidovudine. There are no results available from clinical trials confirming the clinical benefit of combination therapy with saquinavir on HIV disease progression or survival.
Contra-Indications: Patients with clinically significant hypersensitivity to saquinavir or to any components contained in the capsule.
Manufacturers’ Warnings In Clinical States: The indication for saquinavir for the treatment of HIV infection is based on changes in surrogate markers. At present there are no results from controlled clinical trials evaluating the effect of regimens containing saquinavir on survival or the clinical progression of HIV infection, such as the occurrence of opportunistic infections or malignancies.
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose-adjustment of insulin or oral hypoglycemic agents for the treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Precautions: General: When saquinavir is prescribed in combination with other antiretroviral therapies, physicians should refer to the appropriate Product Monographs for safety and prescribing information.
Hemophiliac Patients: There have been reports of increased bleeding including spontaneous skin hematomas and hemarthrosis in patients with Hemophilia Type A and Type B treated with protease inhibitors. In some patients, additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or re-introduced. There is no proven relationship between protease inhibitors and such bleeding, however, the frequency of bleeding episodes should be closely monitored in patients on saquinavir.
Children and Geriatrics: The safety and efficacy of saquinavir in HIV-infected children (younger than 13 years) has not been established. Only limited experience is available in elderly patients (older than 60 years).
Patients with Hepatic Impairment: Therapeutic studies with saquinavir included patients with a range of hepatic impairment from mild to moderate. In these patients, exposure to saquinavir was not correlated with laboratory markers of hepatic impairment. Increases in saquinavir plasma concentrations might be expected in patients with severe hepatic impairment; however, such patients have not been investigated and should therefore be treated with caution.
Patients with Renal Impairment: Therapeutic studies with saquinavir included patients with a range of renal impairment from mild to moderate. In these patients, exposure to saquinavir was not correlated with laboratory markers of renal impairment. Although renal clearance is only a minor elimination pathway for saquinavir, no data are available in patients with more severe renal impairment. Clinical judgment should be exercised when administering saquinavir to patients with renal insufficiency.
Drug Interactions: Combination therapy of saquinavir with zalcitabine (ddC) and/or zidovudine has been studied in adults with advanced HIV-disease, and been shown not to alter the rate or severity of known major toxicities previously associated with the use of zalcitabine and zidovudine. Data from pharmacokinetic studies also suggest that the absorption, metabolism and elimination of each drug is unchanged when they are administered together as triple combination therapy.
Concomitant use of ketoconazole (200 mg daily) and saquinavir (600 mg t.i.d.) caused a 1.5-fold increase in plasma concentrations of saquinavir, with no increase in the elimination half-life or any change in the absorption rate. This was due to inhibition of the P450 isozyme (CYP3A4) responsible for the metabolism of saquinavir. Ketoconazole pharmacokinetics were not affected by this coadministration. Dose adjustment should not be required for tolerability reasons when these compounds are coadministered. A similar interaction could occur with other compounds in this class, such as fluconazole, itraconazole and miconazole, or with other inhibitors of the CYP3A4 isozyme of P450.
Rifampicin (600 mg daily) was shown to decrease plasma concentrations of saquinavir by 80%, due to its induction of the CYP3A4 isozyme of cytochrome P450. The use of rifampicin in combination with saquinavir could therefore result in subtherapeutic concentrations of saquinavir. Rifabutin (300 mg daily) has also been shown to reduce saquinavir plasma concentration by 40% when these 2 compounds are coadministered. Considering the extensive hepatic metabolism of saquinavir, coadministration with other compounds known for their potential to induce hepatic enzymes (i.e., phenytoin, carbamazepine, alcohol or barbiturates) may result in decreased plasma concentrations of saquinavir. The potential reduction in effectiveness of saquinavir therapy should be considered when using such drugs concomitantly.
During the absorption phase of saquinavir, the high presystemic concentrations of saquinavir may decrease the activity of the CYP3A4 isozyme. Other compounds which are substrates of CYP3A4 (i.e., nifedipine and other calcium channel blockers, clindamycin, terfenadine) may compete with saquinavir for their metabolism, possibly resulting in increased plasma concentrations of the concomitant medications. Patients receiving saquinavir in combination with such drugs should be monitored for any toxicities associated with these medications.
Ritonavir is a potent inhibitor of the CYP3A4 isozyme of cytochrome P450, which is responsible for the metabolism of saquinavir. Because of this activity, combining these 2 protease inhibitors will likely result in substantially increased plasma levels of saquinavir. No data regarding potential interactions between saquinavir and other protease inhibitors are currently available.
Pregnancy and Lactation: Reproduction studies with saquinavir in rats have shown no embryotoxicity or teratogenicity at plasma exposures (AUC values) up to 5 times those achieved with human use (1 800 mg/day), or in rabbits at dose levels up to 24 times the recommended human dose. There are however, no adequate or well controlled studies of saquinavir in pregnant women. Because animal reproduction studies are not always predictive of human response, saquinavir should be used during pregnancy only if the potential benefits to the mother are considered to outweigh the potential risks to the fetus.
It is not known whether saquinavir is excreted in human milk. Because many drugs are excreted in human milk, it is advisable to caution mothers against breast-feeding while taking saquinavir. Animal studies indicate that administration of saquinavir to rats through the lactation period at plasma concentrations (AUC values) up to 5 times those achieved with the human dose (1 800 mg/day) had no effect on the survival, growth or development of offspring to weaning.
Adverse Reactions: The majority of adverse reactions observed in clinical trials were of mild intensity. The most frequently reported reactions concerned the gastrointestinal tract, with diarrhea, abdominal discomfort and nausea being the most common.
Saquinavir has been shown not to alter the rate or severity of known major toxicities previously associated with the use of zalcitabine (ddC) and/or zidovudine (ZDV), or to produce unexpected toxicities when used in combination with ddC and/or ZDV. For comprehensive dose adjustment recommendations and drug-associated adverse reactions for either ddC or ZDV, physicians should refer to the Product Monograph for each of these drugs.
Patients in these trials were randomized to receive treatment with either saquinavir+ZDV, saquinavir+ZDV+ ddC, or ZDV+ddC (Protocol NV14255); or, saquinavir monotherapy, ddC monotherapy, or saquinavir+ddC (Protocol NV14256). In NV14255, 197 patients were treated with saquinavir 600 mg t.i.d.; a total of 170 completed at least 24 weeks of treatment. In NV14256, 306 subjects from the surrogate analysis were treated with saquinavir 600 mg t.i.d.; a total of 259 completed more than 16 weeks of treatment. Table I summarizes the clinical adverse events (considered at least possibly related or of unknown relationship to study drug, and of moderate or greater intensity) which occurred in Â³2% of patients. The comprehensive safety database of 688 patients receiving saquinavir in all clinical trials also includes data from 185 patients in 3 double-blind, randomized European studies who completed at least 16 weeks of saquinavir treatment.
Although most adverse events reported during the above studies were mild or moderate in severity, the following serious adverse events have been reported during clinical trials and/or postmarketing experience with saquinavir and were considered possibly related to use of this drug: confusion, ataxia and weakness; acute myeloblastic leukemia; hemolytic anemia; attempted suicide; Stevens-Johnson syndrome; seizures; severe cutaneous reaction associated with increased liver function tests; isolated elevation of transaminases, thrombophlebitis; headache; exacerbation of chronic liver disease with Grade 4 elevated LFTs, jaundice, ascites and right/left upper quadrant abdominal pain; pancreatitis leading to death; nephrolithiasis; hepatitis; diabetes mellitus, bullous skin eruption and polyarthritis; portal hypertension.The clinical trial database for saquinavir consists of >6 000 patients, with over 100 patients followed for >2 years.
The following clinical adverse events (possibly or probably related to study drug, all severities) occurred with a frequency of:
- Body as a Whole: fever, wasting syndome, allergic reaction, chest pain, weight decrease, shivering.
- Cardiovascular: hypertension.
- Endocrine/Metabolic: hyperglycemia.
- Gastrointestinal: vomiting, constipation, eructation, stomatitis, discolored feces, glossitis, frequent bowel movements, gastralgia, gastritis, gastrointestinal inflammation, pancreatitis, tooth disorder.
- Hematologic: neutropenia, thrombocytopenia.
- Musculoskeletal: stiffness, arthralgia.
- Neurological: ataxia, confusion, dry mouth, convulsions, dysesthesia, tremor.
- Psychological: insomnia, euphoria, anxiety, reduced intellectual ability, irritability, agitation, hallucination, somnolence, depression.
- Resistance Mechanisms: staphylococcal infection.
- Respiratory: pharyngitis, dyspnea, laryngitis, rhinitis.
- Skin: sweating increased, hot flushes, skin pigment changes, acne, dermatitis, folliculitis.
- Special Senses: visual disturbances, taste alteration, xerophthalmia.
- Urinary: micturition disorder.
- Laboratory Values: No consistent alterations in standard laboratory tests have been associated with the use of saquinavir.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: One patient exceeded the recommended daily dose of 1 800 mg by ingesting 8 g in a single dose. The patient was treated with induction of emesis within 2 to 4 hours of ingestion. No toxicities or sequelae were noted. In exploratory clinical studies, oral doses of saquinavir up to 7 200 mg/day have been relatively well tolerated. In cases of saquinavir overdose, vital signs should be monitored, and symptoms treated as they arise. Patients may also benefit from treatment with activated charcoal.
Dosage And Administration: The recommended dosage is 600 mg (3´200 mg capsules) taken every 8 hours (q8h), anytime within 2 hours after a meal or substantial snack. Total daily dose is 1 800 mg. Saquinavir should be administered in combination with reverse transcriptase inhibitor nucleoside analogues.
Monitoring of Patients: Clinical chemistry tests should be performed prior to initiating therapy with saquinavir and reverse transcriptase inhibitor nucleoside analogues, and at appropriate intervals thereafter.
Dose Adjustments: For recipients of combination therapy with saquinavir and reverse transcriptase inhibitor nucleoside analogues, dose adjustments of any single drug should be based on the known toxicity profile of that individual drug.
Availability And Storage: Each hard gelatin, light brown and green capsule, imprinted with Roche and 0245 on opaque shells, contains: saquinavir 200 mg, present as saquinavir mesylate. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate and talc. Capsule shell: gelatin, indigotine, iron oxide and titanium dioxide. Glass or plastic (HDPE) bottles of 270. Keep in tightly closed container at room temperature (15 to 30°C).
INVIRASE Roche Saquinavir Mesylate HIV Protease Inhibitor – Antiretroviral Agent