Saquinavir Chemical Properties

alpha 

D20 -55.9° (c = 0.5 in methanol)

Boiling point:

1015.0±65.0 °C(Predicted)

Density 

1.211±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,Store in freezer, under -20°C

solubility 

DMSO : 100 mg/mL (149.07 mM; Need ultrasonic)

form 

Powder

pka

11.05±0.46(Predicted)

color 

White to off-white

Water Solubility 

35.8mg/L(25 ºC)

BCS Class

4

CAS DataBase Reference

127779-20-8(CAS DataBase Reference)

Safety Information

Hazardous Substances Data

127779-20-8(Hazardous Substances Data)

Saquinavir Usage And Synthesis

Description

Saquinavir mesylate, the first HIV protease inhibitor to reach the market, was launched in the U.S.A.. It is indicated for use in combination with approved nucleoside analogs for the treatment of advanced HIV infection. Saquinavir, a transition state analog of Phe-Pro, is a very potent and competitive inhibitor of HIV-1 and HIV-2 proteases with high specificity. Saquinavir inhibits the last stage in the replication process of HIV and prevents virion maturation in both acute and chronically infected cells. Combination of saquinavir with the nucleoside analogs such as zidovudine (AZT) or/and zalcitabine which inhibit the enzyme reverse transcriptase and target at an earlier stage in the HIV replication process, shows a greater than additive effect in increase in CD4 cell counts and reduction in viral load, with the combination delaying the onset of resistance to either drug alone. Saquinavir is well tolerated alone and in combination with A n .

Originator

Roche (Switzerland)

Uses

Antiviral (HIV protease inhibitor).

Definition

ChEBI: An aspartic acid derivative obtained by formal condensation of the primary amino group of (2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydroisoquinolin- (1H)-yl]-3-hydroxy-1-phenylbutan-2-ylamine with the carboxy group of N2(-quinolin-2-ylcarbonyl)-L-asparagine. An inhibitor of HIV-1 protease.

Indications

Saquinavir is a potent inhibitor of HIV-1 and HIV-2 protease. Fortovase, a soft gel preparation of saquinavir, has largely replaced saquinavir mesylate capsules (Invirase) because it has improved bioavailability. Saquinavir is usually well tolerated and most frequently produces mild gastrointestinal side effects.

brand name

Fortovase (Roche).

Acquired resistance

Resistance is associated with an amino acid substitution at position 48 in the HIV protease (G48V). An L90M mutation also confers resistance, as it does for most protease inhibitors. Saquinavir-resistant isolates from patients on long-term therapy often show cross-resistance to other protease inhibitors.

General Description

Saquinavir (Invirase) is well tolerated following oral administration.Absorption of saquinavir is poor but is increasedwith a fatty meal. The drug does not distribute intothe CSF, and it is approximately 98% bound to plasma proteins.Saquinavir is extensively metabolized by the firstpasseffect. Bioavailability is 4% from a hard capsule and12% to 15% from a soft capsule. Saquinavir lowers p24antigen levels in HIV-infected patients, elevates CD4⁺counts, and exerts a synergistic antiviral effect when combinedwith RT inhibitors such as AZT and ddC.Although HIV-1 resistance to saquinavir and other HIVPIs occurs in vivo, it is believed to be less stringent andless frequent than resistance to the RT inhibitors.Nevertheless,cross-resistance between different HIV PIsappears to be common and additive,suggesting thatusing combinations of inhibitors from this class would notconstitute rational prescribing. The drug should be used incombination with at least two other antiretroviral drugs tominimize resistance. Dosage forms are Invirase (hard capsule)and Fortovase (soft capsule).

Pharmaceutical Applications

A peptidomimetic protease inhibitor formulated as the mesylate for oral use.

Pharmacokinetics

Oral absorption: c. 4%
C_max 1200 mg thrice daily: c. 1–2.2 mg/L
C_min 1200 mg thrice daily: c. 0.1–0.22 mg/L
Plasma half-life: c. 7–12 h
Volume of distribution: c. 700 L
Plasma protein binding: c. 98%
Absorption and distribution
It is poorly absorbed and penetrates poorly into the CNS. The semen:plasma ratio is 0.04. It is not known if it is distributed into human breast milk.
Metabolism and excretion
It is metabolized via CYP3A4, principally to mono- and dihydroxylated derivatives. Around 88% of the dose is excreted in feces and 1% in urine. Caution should be exercised in severe renal impairment and moderate hepatic impairment; use in decompensated hepatic impairment is contraindicated.

Clinical Use

Treatment of HIV infection (in combination with other antiretroviral drugs)

Side effects

The most frequently reported adverse effects include abdominal discomfort, diarrhea and nausea. Ritonavir-boosted saquinavir is associated with a dyslipidemic profile characteristic of those treated with a boosted protease inhibitor requiring 200 mg of the ritonavir ‘booster’.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: increased risk of ventricular arrhythmias with alfentanil, fentanyl and methadone - avoid.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with amiodarone, disopyramide, dronedarone, flecainide, lidocaine or propafenone - avoid.
Antibacterials: increased risk of ventricular
arrhythmias with clarithromycin, dapsone, erythromycin or moxifloxacin - avoid; increased risk of ventricular arrhythmias with delamanid; concentration of rifabutin increased; rifampicin and rifabutin can reduce saquinavir levels by 80% and 40% respectively (metabolism accelerated); increased hepatoxicity with rifampicin - avoid; concentration of both drugs increased with fusidic acid.
Anticoagulants: avoid with apixaban and rivaroxaban.
Antidepressants: increased risk of ventricular
arrhythmias with trazodone or tricyclics - avoid; concentration reduced by St John’s wort - avoid.
Antiepileptics: carbamazepine, phenobarbital, and phenytoin and possibly primidone can reduce saquinavir levels.
Antifungals: concentration increased by ketoconazole - avoid.
Antihistamines: increased risk of ventricular arrhythmias with mizolastine - avoid.
Antimalarials: avoid with piperaquine with artenimol; use artemether/lumefantrine with caution; increased risk of ventricular arrhythmias with quinine - avoid.
Antipsychotics: increased risk of ventricular arrhythmias with clozapine, haloperidol or phenothiazines - avoid; possibly increased risk of ventricular arrhythmias with pimozide and quetiapine - avoid; possibly inhibits aripiprazole metabolism - reduce aripiprazole dose; possibly increases lurasidone concentration - avoid.
Antivirals: tipranavir and efavirenz can reduce saquinavir levels; increased risk of ventricular arrhythmias with atazanavir or lopinavir - avoid; concentration increased by indinavir and ritonavir; reduced darunavir concentration; concentration of maraviroc increased, consider reducing dose of maraviroc.
Anxiolytics and hypnotics: midazolam concentration possibly increased (prolonged sedation) - avoid with oral midazolam.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol - avoid.
Ciclosporin: concentration of both drugs increased.
Cytotoxics: possibly increases concentration of axitinib, ibrutinib and panobinostat, reduce dose of axitinib, ibrutinib and panobinostat; possibly increases bosutinib, cabazitaxel, ceritinib and docetaxel concentration - avoid or consider reducing dose; possibly increases concentration of crizotinib and everolimus - avoid; avoid with lapatinib, olaparib and pazopanib; reduce dose of ruxolitinib.
Dapoxetine: increased risk of toxicity - avoid.
Domperidone: possibly increases risk of ventricular
arrhythmias - avoid. Ergot alkaloids: risk of ergotism - avoid.
Guanfacine: concentration possibly increased - halve guanfacine dose.
Lipid-lowering drugs: increased risk of myopathy with rosuvastatin and simvastatin - avoid; possibly increased myopathy with atorvastatin; avoid with lomitapide.
Naloxegol: possibly increases naloxegol concentration - avoid.
Orlistat: absorption possibly reduced by orlistat.
Pentamidine: increased risk of ventricular arrhythmias - avoid.
Ranolazine: possibly increases ranolazine concentration - avoid.

Metabolism

Saquinavir is absorbed to a limited extent (about 30%) after oral doses of the mesilate and undergoes extensive first-pass hepatic metabolism via cytochrome P450 isoenzyme, CYP3A4 to form a range of mono- and di-hydroxylated inactive compounds.
It is excreted mainly in the faeces.

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