Saquinavir

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking saquinavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication.

/HUMAN EXPOSURE STUDIES/ Limited information is available on the acute toxicity of saquinavir. The acute lethal dose of the drug in humans is not known. In a phase II study, patients receiving a saquinavir dosage of 1.2 g every 4 hours as hard gelatin capsules (7.2 g daily) had no evidence of serious toxicity through the first 25 weeks of therapy. There was no evidence of acute toxicities or sequelae in a patient who ingested a single 8-g dose of saquinavir as hard gelatin capsules; emesis was induced within 2-4 hours of ingestion. One patient who ingested 2.4 g of saquinavir as hard gelatin capsules in conjunction with 600 mg of ritonavir experienced throat pain which lasted 6 hours and then resolved.

/HUMAN EXPOSURE STUDIES/ Substantial increases in serum concentrations of AST (SGOT) or ALT (SGPT) (more than 5 times the upper limit of normal) has occurred in 1.2-5.7% of patients receiving saquinavir liquid-filled capsules in conjunction with other antiretroviral agents. Substantial increases in total serum bilirubin concentrations (more than 2.5 times the upper limit of normal) has occurred in 1.6% of patients receiving saquinavir. Increased serum Gamma-glutamyltransferase (GGT, Gamma-glutamyltranspeptidase, GGTP) concentrations have been reported in 5.7-7.1% of patients receiving saquinavir.

/HUMAN EXPOSURE STUDIES/ Pancreatitis occurred in less than 2% of patients receiving saquinavir alone or in conjunction with other antiretroviral agents; pancreatitis resulting in death has been reported. Pancreatitis resulting in death has been reported in a few patients receiving didanosine, stavudine, and an HIV protease inhibitor (i.e., indinavir, nelfinavir). Pancreatitis also has been reported in patients receiving other HIV protease inhibitors (e.g., lopinavir). In clinical studies evaluating saquinavir in conjunction with other antiretroviral agents, substantial increases in serum amylase concentrations (more than 2 times the upper limit of normal) occurred in up to 1.9% of patients.

/HUMAN EXPOSURE STUDIES/ A severe cutaneous reaction associated with increased liver function test results, substantial increases in liver function test results (more than 10 times the usual normal value) in association with exacerbation of chronic liver disease, isolated increases in transaminase values, jaundice, upper left and right quadrant abdominal pain, ascites, hepatitis, hepatomegaly, or hepatosplenomegaly have occurred rarely in patients receiving saquinavir. Although a causal relationship to saquinavir has not been established, exacerbation of chronic liver dysfunction, including portal hypertension, has occurred in patients with hepatitis B or C, cirrhosis, or other liver abnormalities receiving the drug. Cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, and sclerosing cholangitis have occurred in less than 2% of patients receiving saquinavir in clinical studies.

For more Human Toxicity Excerpts (Complete) data for SAQUINAVIR (7 total), please visit the HSDB record page.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

saquinavir

Invirase®

Antivirals

3

less-DILI-concern drugs

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats or rabbits at saquinavir exposure levels (based on measurements of the area under the plasma concentration-time curve (AUC)) of approximately 50 or 40%, respectively, of those achieved in individuals receiving the recommended dosage of saquinavir liquid-filled capsules have not revealed evidence of embryotoxicity or teratogenicity.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats using saquinavir from late pregnancy through lactation at exposure levels (based on AUC measurements) approximately 50% of those achieved in individuals receiving the recommended dosage of saquinavir liquid-filled capsules have shown no effect on survival, growth, or development of offspring to weaning.

Treatment of overdose: To decrease absorption: Patients may benefit from treatment with activated charcoal. Monitoring: Patient's vital signs should be monitored. Supportive care: Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. There are no specific antidotes for these agents. Administer activated charcoal.

Saquinavir is extensively metabolized in the liver following oral administration, and _in vitro_ studies have shown that >90% of its biotransformation is mediated by the CYP3A4 isoenzyme. Saquinavir is rapidly metabolized to a number of inactive mono- and di-hydroxylated compounds.

Results of in vitro studies indicate that saquinavir is rapidly metabolized in the liver to several monohydroxylated and dihydroxylated inactive metabolites. Metabolism of saquinavir is mediated by cytochrome P450; the isoenzyme CYP3A4 is involved in more than 90% of this metabolism. Orally administered saquinavir appears to undergo substantial metabolism on first pass through the liver.

Saquinavir is metabolized primarily by hepatic CYP3A4. The metabolites of saquinavir are not active against HIV-1.

Saquinavir has known human metabolites that include (2S)-N-[(2S,3R)-4-[(3S,4aR,8aS)-3-(tert-butylcarbamoyl)-6-hydroxy-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide, (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-7-hydroxy-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide, and (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-[(1-hydroxy-2-methylpropan-2-yl)carbamoyl]-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide.

L3JE09KZ2F

SAQUINAVIR

Mechanisms of Action [MoA] - HIV Protease Inhibitors

Established Pharmacologic Class [EPC] - Protease Inhibitor

Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors

Saquinavir is a Protease Inhibitor. The mechanism of action of saquinavir is as a HIV Protease Inhibitor and Cytochrome P450 3A Inhibitor.

Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP3A.

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 AUC24h at steady-state was 39026 ng.h/mL.

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.

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

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

Following administration of saquinavir in a dosage of 1200 mg 3 times daily as liquid-filled capsules, mean steady-state AUC at 3 weeks was 7249 ngh/mL compared with an AUC of 866 ngh/mL reported following administration of saquinavir hard gelatin capsules in a dosage of 600 mg 3 times daily. While the AUC of saquinavir in adults receiving liquid-filled capsules was lower at week 61-69 compared with the AUC at week 3, the AUC at week 61-69 was greater than the AUC at the same time point in HIV-infected adults receiving saquinavir as hard gelatin capsules (600 mg 3 times daily).

The relative oral bioavailability of saquinavir from liquid-filled (soft gelatin) capsules is estimated to average 331% (range: 207-530%) of that achieved with hard gelatin capsules of the drug when single 600-mg doses are administered. This would represent a calculated average oral bioavailability from the liquid-filled capsules of about 13% based on an average absolute bioavailability of 4% from the hard capsules; however, these are calculated estimates and not based on actual determination of absolute oral bioavailability from the liquid-filled capsules.