Protease inhibitors fosamprenavir

Fosamprenavir is a protease inhibitor. Fosamprenavir is a prodrug of amprenavir that inhibits HIV protease, the enzyme required to form functional proteins in HIV-infected patients. It is indicated in the treatment of HIV infections in combination with other antiretroviral agents. 

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

Protease inhibitor (Pl)-expehenced patients Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Once-daily administration of fosamprenavir plus ritonavir is not recommended in Pl-experienced patients. 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

Amprenavir is a nonpeptide protease inhibitor that is active against both HIV-1 and HIV-2 fosamprenavir is the prodrug for amprenavir and has better bioavailability. After binding to the active site of the viral protease, it inhibits the processing of viral gag and gag-pol polyprotein precursors, resulting in the production of immature HIV particles that lack the capability to infect other cells. The resistance to the drug results from site-directed mutagenesis primarily at codons 50 and 84, and also at codons 10, 32, 46, 54 and 90. 

Ellis JM, Ross JW, Coleman Cl. 2004. Fosamprenavir A novel protease inhibitor and prodrug of amprenavir. Formulary. 19 151-160. 

Clinically important, potentially hazardous interactions with amphetamines, aprepitant, astemizole, atazanavir, azithromycin, azole antifungals, clarithromycin, darunavir, dirithromycin, erythromycin, fluoxetine, fosamprenavir, grapefruit juice, imatinib, indinavir, itraconazole, ketoconazole, methylphenidate, nefazodone, nelfinavir, nilotinib, pemoline, phenothiazines, protease inhibitors, quinidine, ritonavir, saquinavir, sertraline, sparfloxacin, sulpiride, telithromycin, thioridazine, tipranavir, tricyclic antidepressants, troleandomycin, voriconazole, zileuton, ziprasidone... 

Clinically important, potentially hazardous interactions with amiodarone, amprenavir, anisindione, antacids, anticoagulants, aprepitant, atazanavir, atovaquone, beclomethasone, buprenorphine, corticosteroids, cortisone, cyclosporine, cyproterone, dabigatran, dapsone, darunavir, delavirdine, dexamethasone, dicumarol, digoxin, eszopiclone, flunisolide, fosamprenavir, gadoxetate, gestrinone, halothane, imatinib, isoniazid, itraconazole, ketoconazole, lapatinib, lorcainide, methylprednisolone, midazolam, nelfinavir, nifedipine, oral contraceptives, phenylbutazone, prednisone, protease inhibitors, pyrazinamide, ramelteon, ritonavir, saquinavir, solifenacin, sunitinib, tacrolimus, telithromycin, temsirolimus, tipranavir, tolvaptan, trabectedin, triamcinolone, triazolam, voriconazole, warfarin, zaleplon... 

The protease inhibitors (Pis) are a potent class of antiretrovirals that includes amprenavir, atazanavir, fosamprenavir, indinavir, Iopinavir, nelfinavir, ritonavir, and saquinavir. Tipranavir is an investigational PI at the time of this writing. The pharmacology, safety, and efficacy of these drugs are reviewed elsewhere. " Briefly, Pis block the maturation process, thereby resulting in the production of immature, noninfectious virions. ... 

Fosamprenavir Fosamprenavir is a prodrug that is converted to amprenavir, a nonpeptide HIV protease inhibitor the increased aqueous solubility of the prodrug markedly improves bioavail-ability. The drug is active against both HIV-1 and HIV-2. Amprenavir is the HIV protease inhibitor that is most likely to produce rash, possibly because it contains a sulfonamide moiety. It generally is combined with ritonavir. 

HIV Protease Inhibitors Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir, Atazanavir, Fosamprenavir, Tipranavir and Darunavir as Drugs against HIV Infection... 

Atazanavir (BMS-232632) and fosamprenavir (phosphate prodrug of amprenavir)followed in 2003, as well as tipranavir (PNU-140690) and darunavir (TMC-114) ° in 2005 and 2006 respectively. Therefore, there are currently 10 FDA approved HIV protease inhibitors on the market. After the X-ray structure of HIV protease was published in 1989 by several labora-... 

Figure 5.4 Structures of marketed HIV protease inhibitors. Saquinivir (top left), ritonavir (top middle), indinavir (top right), nelfinavir (second row left), lopinavir (second row middle), tipranavir (second row right), atazanavir (third row left), darunavir (third row middle), fosamprenavir (third row right) and amprenavir (bottom).

Use of fosamprenavir, a sulfa-containing protease inhibitor, in HIV-infected patients with glucose-6-phosphate dehydrogenase deficiency. 

The data on the effect of protease inhibitors on ketoconazole are more limited. Amprenavir caused a modest increase in ketoconazole levels, and the UK manufacturer of amprenavir suggests that no ketoeonazole dose adjustment is necessary with amprenavir alone, although the US manufacturer recommends increased monitoring for adverse effeets and states that a dose reduction may be needed in patients receiving ketoconazole in doses of more than 400 mg daily. However, a marked effect was seen for ritonavir alone and for ritonavir combined with darunavir, fosamprenavir, lopinavir, saquinavir and theoretically tipranavir. This may increase the adverse effects of ketoconazole. Most protease inhibitor manufacturers say that doses greater than 200 mg a day of ketoconazole are not recommended. Similarly, the UK manufacturers of ketoconazole and ritonavir say that a dose reduction of ketoconazole should be considered when it is given with ritonavir. ... 

Based on the limited data with other protease inhibitors, the manufacturer of amprenavir also recommends it should not be given within 1 hour of antacids. The decrease in amprenavir levels seen when fosamprenavir is given with an antacid are not considered clinically relevant, and no fosamprenavir dose adjustments are likely to be neeessary. Greater decreases were seen with ranitidine, although the minimum levels were unehanged. The UK manufaeturer states that no fosamprenavir dose adjustment is needed with ranitidine or other H2-receptor antagonists however, the US manufacturer says the combination should be used with caution because fosamprenavir may be less effective. However, no interaction occurred with esomeprazole, and this, or other proton pump inhibitors may be given at the same time as fosamprenavir. 

The AUC, minimum, and maximum levels of amprenavir 1.2 g twice daily were increased by 131%, 484%, and 33%, respectively, by ritonavir 200 mg twice daily. This agrees with in vitro data. The manufacturer recommends that doses of both protease inhibitors be reduced when they are used together. Based on modelling of pharmacokinetic data, a dose of amprenavir 600 mg with ritonavir 100 mg, both twice daily, has been suggested. This combination has shown good clinical efficacy in at least one study, and resulted in satisfactory amprenavir levels when efavirenz was also used" (see also NNRTIs + ftotease inhibitors , p.785). Amprenavir levels with fosamprenavir/ritonavir 700/100 mg twice daily were similar to those achieved with amprenavir/ritonavir 600/100 mg twice daily. ... 

Rifabutin bioavailability is increased by amprenavir, atazanavir, fosamprenavir/ritonavir, indinavir, lopinavir/ritonavir, nelfinavir, tipranavir/ritonavir, and especially ritonavir, with an increased risk of toxicity. Rifabutin modestiy decreases the bioavailability of indinavir, neifinavir, and particuiarly saquinavir (with an increased risk of therapeutic faiiure), but has no effect on amprenavir, atazanavir, and ritonavir-boosted fosamprenavir. The combination of rifabutin with protease inhibitors may be used, but dosage adjustments of rifabutin or both drugs are often necessary. 

Protease inhibitors (Pis) target viral assembly by inhibiting the activity of protease. Protease inhibitors include Amprenavir, Atazanavir, Fosamprenavir, Indinavir, Lopinavir/Ritonavir, Nelfinavir, Ritonavir, Saquinavir, and Tipranavir. 

Halohydrins 11 can be used for the preparation of a number of pharmaceutically active compounds such as amprenavir, fosamprenavir, and atazanavir (Scheme 4.6), potent protease inhibitors employed against HIV. 

Treatment of AIDS often combines reverse transcriptase inhibitors with protease inhibitors such as saquinavir (Invirase), indinavir (Crixivan), fosamprenavir (Lexiva), nelfinavir (Viracept), and ritonavir (Norvir). The inhibition of a protease enzyme prevents the proper cutting and formation of proteins used by viruses to make more copies. Researchers are not yet certain how long protease inhibitors will be beneficial for a person with AIDS. 

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