Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amprenavir is a new peptidomimetic inhibitor of the HIV protease enzyme. Amprenavir has a twice daily dosing schedule and can be administered with or without food making it a convenient dosing regimen among the protease inhibitors (PIs). It is currently being investigated in combination with various nucleoside reverse transcriptase inhibitors (NRTIs) and initial results are promising. Amprenavir may also be useful for salvage therapy in patients failing PI-containing regimens as little cross-resistance has been observed so far with nelfinavir, indinavir or saquinavir. However, amprenavir resistant strains show cross-resistance with ritonavir. Clinical evidence indicates amprenavir is generally well tolerated. However, there is little information to date regarding the ability of amprenavir to cause lipodystrophy or other disturbances of lipid metabolism.
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PMID:Coming therapies: amprenavir. 1062 44

Amprenavir is a novel protease inhibitor with antiviral activity, and was approved in the U.S. (AGEN-ERASE) in 1999 for use in combination with other antiretrovirals for the treatment of HIV infection. The drug is developed by Kissei Pharmaceuticals Co., Ltd. in Japan, approved in the same year, and has been distributed by them (PROZEI). Amprenavir achieves a viral load of less than 400 copies/ml when it is given in triple combination therapy in both therapy-naive patients and patients previously treated with nucleoside reverse transcriptase inhibitors (NRTI). The recommended dose of amprenavir is eight 150-mg capsules, twice daily, or 1200 mg, b.i.d. Amprenavir may be taken with or without a meal; however, it should not to be taken with high-fat meals because its oral bioavailability may possibly be affected by fat. One of the major concerns associated with anti-HIV agents is the resistance mutation development, and the presence of I50V, M46I/L, I47V, I54L/V and I84V genotype has been observed in amprenavir therapy experienced subjects. Differences in resistance patterns and resistance mutation interactions may have amprenavir recognized as an alternative choice of drugs in maintaining efficacy. Therefore, amprenavir is believed to add an important treatment option in HIV infection therapy. It should be noted that P450 isozyme CYP3A4 is responsible for amprenavir; thus, care must be taken to avoid combined amprenavir with drugs that affect the action of CYP3A4, that act on the production CYP3A4 substrates, or that are metabolized by CYP3A4 metabolism. Amprenavir is the fifth protease inhibitor approved in Japan, and it is important to understand its differential and identical properties from other protease inhibitors to maximize its efficacy.
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PMID:[Pharmacological study and clinical effect of HIV protease inhibitor amprenavir]. 1123 98

Four new drugs have been developed to overcome the limitations of the currently available anti-HIV drugs, including inconvenient schedules, side effects, and drug interactions. It is hoped that abacavir, efavirenz, adefovir dipivoxil, and amprenavir will be widely available in the near future. Abacavir, a nucleoside reverse transcriptase inhibitor with a twice-daily schedule, offers good bioavailability and generally mild side effects. Efavirenz, a non-nucleoside reverse transcriptase inhibitor with a once daily schedule, may produce side effects such as rash and dizziness. Adefovir dipivoxil, a nucleotide analog with once daily dosing, can cause carnitine depletion and carnitine supplementation is recommended. Amprenavir, a protease inhibitor with twice-daily dosing, has rather mild side effects. Information on efficacy, availability, and resistance for each of these drugs is given.
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PMID:Antiretroviral agents: the next generation. 1136 27

Since many new anti-HIV drugs are variations of currently available drugs, they may be more effective for people who are beginning treatment. One study shows favorable results when using efavirenz in triple combination therapy; however, it is recommended that this therapy be reserved for people who are treatment-naive and symptom-free. It is still unclear if all non-nucleoside RT inhibitors (NNRTIs) are as potent as efavirenz and whether the long-term potential for them is as promising as standard combinations. Researchers caution against pairing an NNRTI with a protease inhibitor in the event that resistance to the combination develops. That resistance may eliminate the option of using any other protease inhibitor or NNRTI in future therapies. Conversely, abacavir, an NARTI, has been effective in combination with many protease inhibitors. Amprenavir shows good antiviral activity; although studies show that it may not be successful as a salvage therapy with protease inhibitors. Nucleotide analogue reverse transcriptase inhibitors, such as adefovir and bis-poc PMPA, showed moderate anti-HIV potency. A study evaluating FTC alone showed a good reduction in viral load. FTC also fights hepatitis B and requires only one dose daily. Information is included about expanded access programs for abacavir, adefovir, and efavirenz.
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PMID:New drugs on the horizon. 1136 12

None of the studies conducted on people who have reduced the number of antivirals taken in their regimen have shown good results. Research has consistently shown that these people have an increased viral load count when one or more drugs are discontinued. Results from a French study show some promise in switching from a protease inhibitor to a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) such as Viramune (Nevirapine) or Sustiva (efavirenz). Fifteen out of sixteen participants maintained viral load levels below 200 copies when they changed to an NNRTI regimen. The one person whose viral load increased had taken an NNRTI drug before, although its use was prohibited in eligibility requirements. The strategy may work for people at varying stages of the disease, but larger studies are needed to confirm the results. Also, a fifth protease inhibitor, Amprenavir (Agenerase) has received FDA approval. Trial results are summarized, and side effects and drug interactions with Amprenavir are described.
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PMID:New treatment options. 1136 13

(1) The reference antiretroviral treatment for HIV-infected patients is a three-drug regimen combining drugs from different families, namely two nucleoside reverse transcriptase inhibitors + a protease inhibitor or a non nucleoside reverse transcriptase inhibitor. In our opinion, indinavir is the first-choice protease inhibitor. (2) The clinical file on amprenavir is limited. In particular, it is not known whether the recommended dose regimen (1 200 mg twice a day) is the best one. A 48-week trial involving 232 patients previously untreated with antiretrovirals showed that the combination of amprenavir (1 200 mg) + lamivudine (150 mg) + zidovudine (300 mg), administered twice a day, was more effective than lamivudine + zidovudine on viral load. (3) An unblinded trial involving 504 patients, who had already received a reverse transcriptase inhibitor but no protease inhibitor, compared three-drug regimens consisting of amprenavir (1 200 mg twice a day) and two reverse transcriptase inhibitors, or indinavir (800 mg three times a day) and two reverse transcriptase inhibitors, for 48 weeks. Changes in viral load and the CD4+ lymphocyte count did not favour the amprenavir-containing regimen. (4) Laboratory studies suggest that the risk of cross-resistance between amprenavir and other HIV protease inhibitors is lower than with other compounds of this class. However, it is unclear whether this means that amprenavir would be clinically effective after failure of one or several other protease inhibitors. (5) The main adverse effects of amprenavir are gastrointestinal disorders and paraesthesias. Overall, the safety profile resembles that of the other protease inhibitors. (6) Like other protease inhibitors, amprenavir can potentially interact with many other drugs, owing to its hepatic metabolism. (7) Amprenavir is taken in two daily doses irrespective of meal times, but this advantage over other protease inhibitors is cancelled out by the fact that patients have to swallow 8 large soft capsules at each intake. (8) In our opinion, pending further data, amprenavir should be used only in well-conducted clinical trials.
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PMID:Amprenavir: new preparation. Another HIV protease inhibitor: no proven advance. 1171 66

Amprenavir is an HIV-1 protease inhibitor, the first in vitro activity studies of which were published in 1995. During in vivo development, it became clear that the pharmacokinetics of the drug would result in patients taking a large number of pills daily. The first comparative studies of amprenavir versus other protease inhibitors showed it had comparatively weak activity. Thus, studies using low doses of ritonavir to enhance the pharmacokinetic profile of amprenavir were first communicated in 2000. Only a small number of clinical trials in HIV-1-infected patients have been published. The pharmacokinetics of amprenavir have been documented in both healthy individuals and in HIV-1-infected patients. Amprenavir trough plasma concentrations increase 3- to 10-fold and the area under the concentration-time curve (AUC) increases 2- to 3-fold when using amprenavir 450 or 600 mg combined with ritonavir 100mg twice daily. Peak concentrations of amprenavir are less influenced by ritonavir coadministration, with a 1- to 2-fold increase. As there is no pharmacokinetic advantage to increasing ritonavir doses, the combination has only been used with low doses of ritonavir (100mg twice daily or 200 mg once or twice daily). Concomitant use of currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs)--efavirenz or nevirapine--is possible when amprenavir is coadministered with ritonavir, despite the pharmacokinetic interactions described when they are used with amprenavir alone. Fosamprenavir (GW 433908) is a prodrug of amprenavir primarily metabolised to amprenavir in the epithelial cells of the intestine. At steady state, plasma trough concentrations and AUC are slightly greater with fosamprenavir (two pills of 700 mg twice daily) than amprenavir (eight soft gel capsules of 150 mg twice daily). The clinical adverse effects of amprenavir are similar whether administered unboosted or in combination with ritonavir. Skin rashes do not appear to be more frequent. With regard to lipid profiles, the addition of ritonavir to amprenavir induces an increase in cholesterol and triglyceride levels; however, prospective comparative studies are lacking. In short-term prospective trials in antiretroviral-naive individuals, virological suppression with highly active antiretroviral therapy containing amprenavir plus ritonavir is similar to or higher than with unboosted amprenavir, with a smaller pill intake. Few comparative data are available in treatment-experienced patients. In several small studies, different salvage regimens which included amprenavir plus ritonavir achieved undetectable viral levels in half of the patients. Although the I50V amino acid substitution is the key mutation conferring resistance to amprenavir, the accumulation of several mutations is needed to increase the IC50 (concentration that produces 50% inhibition) of amprenavir. When used with ritonavir, the accumulation of six or more mutations among L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S and I84V leads to clear decrease in viral response to treatment. In salvage regimens, coadministration of amprenavir with lopinavir/ritonavir induces variations in lopinavir and amprenavir concentrations (decrease or increase in both drug concentrations) compared with the combination with ritonavir alone. Currently, close pharmacokinetic follow-up is mandatory when such combinations are used. There are sufficient data available today to support coadministration of reduced doses of amprenavir with low doses of ritonavir. Compared with amprenavir alone, this results in the administration of fewer pills with equivalent or higher efficacy, but without new clinical adverse effects. The concentrations of amprenavir achieved are high enough for use in treatment-experienced patients who have an accumulation of amino acid substitutions in the HIV-1 protease gene. It also allows combinations with NNRTIs. The pharmacokinetic properties of fosamprenavir and the first clinical trials in treatment-naive and treatment-experienced patients should allow it to be considered as a better alternative to amprenavir in countries where fosamprenavir is already available.
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PMID:Amprenavir or fosamprenavir plus ritonavir in HIV infection: pharmacology, efficacy and tolerability profile. 1574 98

Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1,400 mg twice daily, fosamprenavir 1,400 mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union. Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5-2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein. With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir. This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be co-administered with caution. However, fosamprenavir can be co-administered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.The extensive fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to co-administer fosamprenavir and fosamprenavir plus ritonavir with many other commonly co-prescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.
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PMID:Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. 1648 15

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