226700-81-8 Usage
Description
Fosamprenavir calcium, also known as Lexiva, is an orally bioavailable prodrug of the HIV-1 protease inhibitor amprenavir. It is a highly soluble phosphate ester of amprenavir, which allows for more convenient dosing and a reduction in pill counts compared to amprenavir. Fosamprenavir calcium is typically administered in combination with other HIV drugs, such as reverse transcriptase inhibitors, for the treatment of HIV infection in adults and pediatric patients.
Uses
Used in HIV Treatment:
Fosamprenavir calcium is used as an HIV protease inhibitor for the treatment of HIV infection in adults and pediatric patients. It is particularly effective when used in combination with other antiretroviral agents, such as reverse transcriptase inhibitors. The improved solubility of fosamprenavir calcium compared to amprenavir allows for a less complex dosing schedule and fewer tablets, making it a more convenient option for patients.
Used in Initial Antiretroviral Therapy:
Fosamprenavir calcium is used as a water-soluble prodrug of amprenavir for adult and pediatric patients with HIV infection, especially as an initial antiretroviral therapy. Its improved solubility and pharmacokinetic properties make it a suitable choice for patients who are new to antiretroviral treatment.
Used in Combination Therapy with Ritonavir:
Fosamprenavir calcium is often used in combination with ritonavir, an HIV protease inhibitor, to enhance its antiviral potency and reduce the pill burden for patients. This combination therapy is typically administered at daily doses of 700–1400 mg.
Used in Monotherapy for Antiretroviral Therapy-Na?ve Patients:
In some cases, fosamprenavir calcium is used as monotherapy for antiretroviral therapy-na?ve patients. The dosing regimen for this application is 1400 mg twice daily.
Fosamprenavir calcium is used in the pharmaceutical industry for the development and formulation of HIV treatments, specifically for patients with HIV-1 infection. Its improved solubility and pharmacokinetic properties make it a valuable asset in the fight against HIV.
Originator
Vertex (US)
Clinical Use
Fosamprenavir calcium has been approved for the treatment of HIV in adults when used in combination
with other anti-HIV drugs. It is a prodrug that, on hydrolysis by serum phosphatases, gives rise to
amprenavir, which is a peptidomimetic transition-state inhibitor that targets HIV-1 protease and reduces
the viral replication and, thus, the infectiousness of HIV-1. It is commonly administered in combination
with RT inhibitors to produce excellent efficacy in patients with AIDS. The drug is administered as two
700 mg tablets twice daily or, in combination with ritonavir, can be given as two 700 mg tables once daily
or one 700 mg tablet twice daily. As a result, formaprenavir lowers the "pill burden" in patients with AIDS.
Synthesis
The synthesis of
fosamprenavir (X) started with a known amino alcohol 91. N,N-Dibenzyl-L-phenylalaninal (87) was prepared
by reduction of L-phenylalanine (86) to L-phenylalaninol
followed by N,N-dibenzylation and oxidation to the
aldehyde 87 using pyridine-sulfur trioxide complex at room
temperature. A large excess of lithium shot was stirred in a
solution of aldehyde 87 and bromochloromethane in THF at
-65°C. The reaction mixture was subsequently allowed to
warm up to room temperature to provide the diastereomeric
epoxide mixture (6:1) which was quenched with 6N aqueous
HCl and set standing overnight to provide the salt
precipitate. Recrystallization from methanol gave optically
pure dibenzylaminochlorohydrin hydrochloride (88) in 38-
45% yield. Hydrogenolysis under standard conditions gave
deprotected aminochlorohydrin hydrochloride 89 as a
crystalline white solid. Conversion to desired N-Bocepoxide
90 was accomplished by the introduction of the Boc
group followed by cyclization. N-Boc-epoxide 90 was
then converted to amino alcohol 91 by refluxing with isobutylamine
in EtOH. Treatment of the amino alcohol91 with p-nitrobenzene sulphonyl chloride in toluene at
80°C followed by acid hydrolysis of the Boc group
furnished sulphonamide 93 in 73% yield. The carbamate 95
was prepared by refluxing 93 with (S)-tetrahydrofuryl
imidazole carboxylate (94) in EtOAc. Treatment of the
sulphonamide 95 with POCl3 followed by aqueous HCl
hydrolysis provided the phosphate intermediate, which was
then reduced by hydrogenation and converted to
fosamprenavir calcium salt X in a one-pot process in 92%
yield.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: possibly increased concentration
of amiodarone, flecainide, lidocaine and propafenone
(increased risk of ventricular arrhythmias) - avoid.
Antibacterials: increases concentration of rifabutin
- reduce rifabutin dose; concentration significantly
reduced by rifampicin - avoid; avoid with
telithromycin in severe renal and hepatic impairment.
Anticoagulants: avoid with apixaban and
rivaroxaban.
Antidepressants: concentration reduced by St John’s
wort - avoid.
Antimalarials: use artemether/lumefantrine with
caution; possibly increases quinine concentration.
Antipsychotics: possibly inhibits aripiprazole
metabolism - reduce aripiprazole dose; possibly
increases quetiapine concentration - avoid; possibly
increases pimozide concentration (increased risk of
ventricular arrhythmias) - avoid.
Antivirals: avoid with boceprevir, raltegravir and
telaprevir; concentration of dolutegravir reduced;
concentration increased by etravirine, consider
reducing fosamprenavir dose; concentration
reduced by lopinavir, maraviroc and tipranavir,
effect on lopinavir unpredictable - avoid, avoid
with maraviroc; concentration possibly reduced by
nevirapine; avoid with raltegravir.
Anxiolytics and hypnotics: increased risk of
prolonged sedation and respiratory depression with
midazolam - avoid with oral midazolam.
Avanafil: concentration of avanafil possibly increased.
Cytotoxics: possibly increases concentration of
bosutinib and ibrutinib, avoid or consider reducing
bosutinib and ibrutinib dose.
Ergot alkaloids: increased risk of ergotism - avoid.
Immunosuppressants: monitor ciclosporin,
tacrolimus and sirolimus levels.
Lomitapide: avoid concomitant use.
Orlistat: absorption possibly reduced by orlistat.
Ranolazine: possibly increases ranolazine
concentration - avoid.
Statins: possibly increased risk of myopathy with
atorvastatin; possibly increased myopathy with
simvastatin and rosuvastatin - avoid.
Metabolism
Fosamprenavir is rapidly and almost completely
hydrolysed to amprenavir and inorganic phosphate as it
is absorbed through the gut epithelium, following oral
administration. The primary route of metabolism of
amprenavir is via the cytochrome P450 3A4 enzyme.
The primary route of elimination of amprenavir is
via hepatic metabolism with less than 1% excreted
unchanged in the urine and no detectable amprenavir
in faeces. Metabolites account for approximately 14%
of the administered amprenavir dose in the urine, and
approximately 75% in the faeces.
references
[1]. wire, m.b., et al., pharmacokinetics and safety of gw433908 and ritonavir, with and without efavirenz, in healthy volunteers. aids, 2004. 18(6): p. 897-907.[2]. hamada, y., et al., high incidence of renal stones among hiv-infected patients on ritonavir-boosted atazanavir than in those receiving other protease inhibitor-containing antiretroviral therapy. clin infect dis, 2012. 55(9): p. 1262-9.[3]. zheng, y., et al., antiretroviral therapy and efficacy after virologic failure on first-line boosted protease inhibitor regimens. clin infect dis, 2014. 59(6): p. 888-96.[4]. falcoz, c., et al., pharmacokinetics of gw433908, a prodrug of amprenavir, in healthy male volunteers. j clin pharmacol, 2002. 42(8): p. 887-98.
Check Digit Verification of cas no
The CAS Registry Mumber 226700-81-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,2,6,7,0 and 0 respectively; the second part has 2 digits, 8 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 226700-81:
(8*2)+(7*2)+(6*6)+(5*7)+(4*0)+(3*0)+(2*8)+(1*1)=118
118 % 10 = 8
So 226700-81-8 is a valid CAS Registry Number.
InChI:InChI=1/C25H36N3O9PS.Ca/c1-18(2)15-28(39(33,34)22-10-8-20(26)9-11-22)16-24(37-38(30,31)32)23(14-19-6-4-3-5-7-19)27-25(29)36-21-12-13-35-17-21;/h3-11,18,21,23-24H,12-17,26H2,1-2H3,(H,27,29)(H2,30,31,32);/q;+2/t21-,23-,24+;/m0./s1
