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 .
Antiviral (HIV protease inhibitor).
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.
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.
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.
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.
Oral absorption: c. 4%
Cmax 1200 mg thrice daily: c. 1–2.2 mg/L
Cmin 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.
Treatment of HIV infection (in combination with other antiretroviral drugs)
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’.
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.
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.
