Amprenavir/fosamprenavir

The oral absorption of amprenavir is rapid, and peak concentrations are reached between 1 and 2h administration of both amprenavir and fosamprenavir with food is not a concern. Fosamprenavir is dephosphorylated to amprenavir in intestinal mucosa. Amprenavir is 90% bound to plasma protein with most to ai-acid glycoprotein. It is metabolized by the cytochrome P-450 system, CYP3A4, in the liver, and more than 90% of the drug is excreted after its metabolism in feces. In combination with other antiretroviral agents, amprenavir/fosamprenavir are indicated for the treatment of HIV infection. 

Drug Exerting E ect Saquinavir Indinavir Ritonavir Nelfinavir Amprenavir Fosamprenavir Lopinavir Atazanavir... 

Food increases the bioavailability of atazanavir, darunavir, lopinavir/ritonavir soft capsules and solution, nelfinavir, saquinavir (all formulations) and tipranavir, but decreases that of indinavir. Food only minimally affects the bioavailability of amprenavir, fosamprenavir, lopinavir/ritonavir tablets and ritonavir. Mixing ritonavir with enteral feeds does not affect the pharmacokinetics of ritonavir. 

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. 

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],... 

Wire MB, Shelton MJ, Studenberg S (2006) Fosamprenavir Clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet 45 137-168. 

Concomitant therapy with efavirenz, nevirapine, fosamprenavir, or nelfinavir-Consider a dose increase to 533/133 mg lopinavir/ritonavir (4 capsules or 6.5 mL) twice daily taken with food when used in combination with efavirenz, nevirapine, amprenavir, or nelfinavir, or 600/150 mg (3 tablets) twice daily with or without food when used in combination with efavirenz, nevirapine, fosamprenavir without ritonavir, or nelfinavir in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). 

Pharmacology Fosamprenavir is a prodrug of amprenavir, an inhibitor of HIV protease. 

Absorption/Distribution - Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed. After administration of a single dose of fosamprenavir to HIV-1-infected patients, the... 

Metabolism/Excretion- Fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. 

CYP3A4 Amprenavir is metabolized by CYP3A4 and is an inhibitor (and possibly an inducer) of CYP3A4. Coadministration of fosamprenavir and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects. 

Abacavir (Ziagen) Amprenavir (Agenerase) Delavirdine (Rescriptor) Didanosine [ddl] (Videx) Efavirenz (Sustiva) Efavirenz/Emtricitabine/ Tenofovir (Atripla) Fosamprenavir (Lexiva)... 

Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir. 

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. 

Arvieux, C., and Tribut, O. Amprenavir or fosamprenavir plus ritonavir in HIV infection Pharmacology, efficacy and tolerability profile. Drugs 65(5) 633-659, 2005. 

A Atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin Amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice", verapamil Cimetidine... 

Fosamprenavir is a tabid phosphate prodmgof amprenavir. Amprenavir is available only as oral solution... 

Taltobulin, 11 Tamibarotene, 76 Tandutinib, 183 Tanomastat, 47 Tezacitabine, 131 Tipifamib, 172 Topixantrone, 227 Troxacitabine, 131 Vandetanib, 181 Antipsoriatic Ecalcidine, 38 Antiviral Amdoxovir, 199 Amprenavir, 4 Aplaviroc, 134 Atazanavir, 7 Capravirine, 95 Clevudine, 130 Daninavir, 5 Efavirenz, 177 Emivirine, 123 Emtricitabine, 132 Etravirine, 123 Fosamprenavir, 6 Lopinavir, 7 Maraviroc, 107 Maribavir, 158 Omaciclovir, 199 Oseltamivir, 25 Peramavir, 53 Rupinavir, 9 Tenofovir, 197 Tiprinavir, 120 Anxiolytic Sunepitron, 209 Apetite Supressant Rimonabant, 99 Cardiotonic Naxifylline, 203 Torborinone, 172 Collagenase Inhibitor Cipemastat, 99 Diuretic Lixivaptan, 222 Tolvaptan, 186 Elastase Inhibitor Sivelstat, 54... 

Fosamprenavir is a prodrug of amprenavir with better systemic availability. In large clinical trials the most common adverse events in patients taking fosamprenavir, with or without ritonavir, plus abacavir and lamivudine were diarrhea, nausea, vomiting, abdominal pain, drug hypersensitivity, and skin rashes (3). 

This class of agents affects a later part of the HIV cycle, by inhibiting the protease enzyme and leading to impaired assembly of mature HIV virions. Examples include amprenavir, atazanavir, darunavir, fosampre-navir indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. There have been no published reports of AKI or other direct kidney toxicity due to amprenavir, darunavir, fosamprenavir, and lopinavir. 

Clinically important, potentially hazardous interactions with abarelix, acenocoumarol, amisulpride, amprenavir, anisindione, anticoagulants, arsenic, astemizole, carbimazole, celiprolol, ciprofloxacin, dabigatran, degarelix, dicumarol, digoxin, diltiazem, enoxacin, fentanyl, fosamprenavir, gatifloxacin, grapefruit juice, lomefloxacin, methotrexate, moxifloxacin, nilotinib, norfloxacin, ofloxacin, oxprenolol, quinidine, quinolones, rifabutin, rifampin, rifapentine, ritonavir, simvastatin, sparfloxacin, sulpiride, tacrolimus, tipranavir, verapamil, warfarin, zuclopenthixol... 

Clinically important, potentially hazardous interactions with adefovir, alprazolam, amprenavir, anisindione, anticoagulants, buprenorphine, carbamazepine, dicumarol, dihydroergotamine, ergot, fosamprenavir, indinavir, ixabepilone, lovastatin, methadone, methysergide, midazolam, phenobarbital, phenytoin, quinidine, rifabutin, rifampin, sildenafil, simvastatin, triazolam, warfarin... 

Clinically important, potentially hazardous interactions with almotriptan, amprenavir, clarithromycin, darunavir, delavirdine, efavirenz, erythromycin, fosamprenavir, indinavir, naratriptan, nelfinavir, nilotinib, ritonavir, rizatriptan, saquinavir, sibutramine, sumatriptan, telithromycin, tipranavir, troleandomycin, zolmitriptan... 

Clinically important, potentially hazardous interactions with amprenavir, antiarrhythmics, cimetidine, fosamprenavir, mivacurium, nilutamide, oxprenolol... 

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