CLINICAL TRIALS PROFILE FOR AMPRENAVIR

505(b)(2) Clinical Trials for Amprenavir

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials

Trial Type	Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
New Combination	NCT00196625 ↗	Salvage Therapy With Amprenavir, Lopinavir and Ritonavir in HIV-Infected Patients in Virological Failure.	Completed	French National Agency for Research on AIDS and Viral Hepatitis	Phase 2	2000-11-01	HIV infected patients are treated with highly active antiretroviral therapy (HAART). Side effects and the great number of pills reduces adherence to the treatment, and induces therapeutic failure. In order to maintain efficacy of HAART, new combination is evaluated. The aim of the study is to compare the antiviral efficacy of this salvage therapy combining lopinavir and amprenavir with 200 mg/d or 400 mg/d ritonavir, together with nucleoside reverse transcriptase inhibitors, over a 26-week period in HIV-infected patients in whom multiple antiretroviral regimens had failed.

All Clinical Trials for Amprenavir

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00000903 ↗	Addition of Efavirenz or Nelfinavir to a Lamivudine/Zidovudine/Indinavir HIV Treatment Regimen	Completed	National Institute of Allergy and Infectious Diseases (NIAID)	Phase 3	1969-12-31	To compare time to a virologic failure (first of 2 consecutive plasma HIV RNA levels greater than or equal to 200 copies/ml at or after Week 24) of each 4-drug regimen vs the 3-drug regimen. To determine the safety, tolerance, and virologic benefits of either nelfinavir (NFV) or efavirenz (EFV) with indinavir/lamivudine/zidovudine (IDV/3TC/ZDV) vs IDV/3TC/ZDV alone, in the treatment of patients with advanced HIV disease who have received limited or no prior antiretroviral therapy. Prior ACTG studies have shown that the 3-drug combination regimen (IDV/ZDV/3TC) resulted in improved clinical outcomes and therefore may prolong the effects of therapy. The enhanced effects seen with combination therapies are likely related to a greater suppression of RNA replication and alterations in resistance patterns. Due to the progressive success of combination regimens, it is possible that more potent regimens will further enhance viral suppression and provide more durable treatment responses. In light of the additive suppression of HIV replication determined by pharmacological, immunological, and virological results, nelfinavir (NFV) as an addition to IDV/ZDV/3TC will be evaluated. Based on the potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to suppress viral replication and the effectiveness of 3-drug regimens containing NNRTIs, efavirenz (EFV) will also be evaluated as an addition to IDV/ZDV/3TC.
NCT00000912 ↗	A Study on Amprenavir in Combination With Other Anti-HIV Drugs in HIV-Positive Patients	Completed	National Institute of Allergy and Infectious Diseases (NIAID)	Phase 2	1969-12-31	The purpose of this study is to compare 4 different combinations of anti-HIV drugs and to determine the number of people whose HIV blood levels decrease to 200 copies/ml or less while on the treatment. This study evaluates the safety of these drug combinations, which include an experimental protease inhibitor (PI), amprenavir. Despite the success that many patients have had with PI treatment regimens, there is still a possibility that patients receiving PIs may continue to have high HIV blood levels. Because of this possibility, alternative drug combinations containing PIs are being studied. It appears that amprenavir, when taken with 3 or 4 other anti-HIV drugs, may be effective in patients with prior PI treatment experience.
NCT00000918 ↗	A Study to Compare The Ability of Different Anti-HIV Drugs to Decrease Viral Load After Nelfinavir (an Anti-HIV Drug)Treatment Failure	Completed	National Institute of Allergy and Infectious Diseases (NIAID)	Phase 2	1969-12-31	The purpose of this study is to determine the safety and effectiveness of combining several anti-HIV drugs in order to decrease plasma viral load (level of HIV in the blood) in HIV-positive patients who have failed nelfinavir (NFV) treatment. In order to determine the ability of a drug regimen to decrease viral load after drug treatment has failed, it is best to test a variety different of drug "cocktails" (drug regimens). The drug cocktails in this study include 2 new nucleoside reverse transcriptase inhibitors (NRTIs), efavirenz (an NNRTI, non-nucleoside reverse transcriptase inhibitor), and either 1 or 2 protease inhibitors. It is important to include multiple drugs from different groups in a drug cocktail since combinations containing fewer drugs are likely to fail.
NCT00000919 ↗	A Study to Evaluate Various Combinations of Anti-HIV Medications to Treat Early HIV Infection	Completed	National Institute of Allergy and Infectious Diseases (NIAID)	N/A	1969-12-31	The purpose of this study is to compare the effectiveness of various combinations of anti-HIV drugs in HIV-positive men and women. Patients receive specific combinations of 3 or 4 of the following 6 drugs: didanosine (ddI), stavudine (d4T) efavirenz (EFV), nelfinavir (NFV), lamivudine (3TC), or zidovudine (ZDV). Anti-HIV therapy is effective in preventing the spread of HIV in the body. However, patients often experience unpleasant side effects and have difficulties following the dosing schedule. This study looks for combinations of anti-HIV drugs ("cocktails") which will be the most effective with the fewest problems.
NCT00000940 ↗	Five-Drug Anti-HIV Treatment Followed by Treatment Interruption in Patients Who Have Recently Been Infected With HIV	Completed	National Institute of Allergy and Infectious Diseases (NIAID)	Phase 2	1999-05-01	This study will determine what effect taking a combination of five anti-HIV drugs during the early stage of HIV infection, then temporarily stopping them once or twice, may have on the amount of HIV virus in the blood (viral load). The study will also evaluate the safety and effectiveness of this anti-HIV drug combination.

Clinical Trial Conditions for Amprenavir

Condition Name

Condition Name for Amprenavir
Intervention	Trials
HIV Infections	46
HIV Infection	5
Healthy	5
Infection, Human Immunodeficiency Virus	4

Condition MeSH

Condition MeSH for Amprenavir
Intervention	Trials
HIV Infections	54
Infections	16
Infection	15
Acquired Immunodeficiency Syndrome	13

Clinical Trial Locations for Amprenavir

Trials by Country

Trials by Country for Amprenavir
Location	Trials
United States	354
Canada	12
Puerto Rico	9
Italy	5
Brazil	5

Trials by US State

Trials by US State for Amprenavir
Location	Trials
California	29
New York	28
North Carolina	23
Florida	21
Pennsylvania	17

Clinical Trial Progress for Amprenavir

Clinical Trial Phase

Clinical Trial Phase for Amprenavir
Clinical Trial Phase	Trials
Phase 4	6
Phase 3	7
Phase 2/Phase 3	2

Clinical Trial Status

Clinical Trial Status for Amprenavir
Clinical Trial Phase	Trials
Completed	57
Terminated	2
Unknown status	2

Clinical Trial Sponsors for Amprenavir

Sponsor Name

Sponsor Name for Amprenavir
Sponsor	Trials
National Institute of Allergy and Infectious Diseases (NIAID)	20
Glaxo Wellcome	18
GlaxoSmithKline	10

Sponsor Type

Sponsor Type for Amprenavir
Sponsor	Trials
Industry	46
NIH	25
Other	18

Amprenavir: Clinical Trials, Market Analysis, and Projections

Introduction

Amprenavir, a human immunodeficiency virus (HIV) protease inhibitor, has been a significant component in the treatment of HIV-1 infection. This article will delve into the clinical trials, market analysis, and future projections for amprenavir, providing a comprehensive overview of its role in HIV treatment.

Clinical Trials Overview

Early Clinical Trials

One of the pivotal clinical trials involving amprenavir was conducted by the AIDS Clinical Trials Group 347 Study Team. This trial compared the efficacy of amprenavir monotherapy with a combination therapy of amprenavir, zidovudine, and lamivudine in adults with HIV infection. The results showed that the combination therapy significantly reduced HIV RNA levels more effectively than amprenavir monotherapy. Specifically, the median decrease in HIV RNA was 2.04 log10 copies/mL at 24 weeks, with 63% of subjects achieving less than 500 HIV RNA copies/mL[1].

Efficacy and Safety

The trial highlighted that amprenavir, when used in combination with other antiretroviral agents, is highly effective in reducing viral load. However, the amprenavir monotherapy arm was terminated due to inferior efficacy compared to the combination therapy. This study underscored the importance of combination antiretroviral therapy (cART) in managing HIV infection[1].

Mechanism of Action and Pharmacology

Mechanism of Action

Amprenavir works by inhibiting the HIV-1 protease enzyme, which is crucial for the processing of viral Gag and Gag-Pol polyprotein precursors. By binding to the active site of HIV-1 protease, amprenavir prevents the formation of mature, infectious viral particles[2].

Pharmacokinetics

Amprenavir is often administered as its prodrug, fosamprenavir, which is hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium. This conversion allows for a slower release of amprenavir, reducing the number of pills a patient must take. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 enzyme system and has a plasma elimination half-life of approximately 7.7 hours[2].

Market Analysis

Current Market Status

Amprenavir, particularly through its prodrug fosamprenavir (marketed as Lexiva or Telzir), has been approved for the treatment of HIV-1 infection in combination with other antiretroviral agents. The drug has been widely used due to its favorable pharmacokinetic profile and good in vitro activity against HIV-1[2].

Market Trends

The global antiretroviral therapy market has seen significant growth due to the increasing prevalence of HIV/AIDS and advancements in treatment options. However, the market for amprenavir specifically has been influenced by the development of newer antiretroviral drugs with improved profiles and fewer side effects. Despite this, amprenavir remains a viable option, especially in regions where access to newer drugs is limited[2].

Competitive Landscape

The HIV treatment market is highly competitive, with numerous antiretroviral drugs available. Amprenavir competes with other protease inhibitors like lopinavir, ritonavir, and darunavir, as well as with newer classes of antiretrovirals such as integrase inhibitors and non-nucleoside reverse transcriptase inhibitors. The choice of amprenavir often depends on factors like resistance profiles, side effect profiles, and patient compliance[5].

Projections and Future Outlook

Resistance and Mutations

One of the challenges facing amprenavir and other protease inhibitors is the development of drug resistance. Studies have identified specific mutations associated with reduced susceptibility to amprenavir, such as V82A and L90M. Monitoring and managing resistance through genotype testing and adjusting treatment regimens are crucial for maintaining efficacy[5].

Combination Therapy

The future of HIV treatment lies in combination therapy, and amprenavir is likely to continue being used as part of these regimens. The strategy of combining drugs that target different stages of the HIV life cycle reduces the risk of resistance and improves treatment outcomes[1].

Regulatory Considerations

Fosamprenavir, the prodrug of amprenavir, is under review due to potential associations with myocardial infarction and dyslipidemia in HIV-infected adults. These concerns may impact its future use and market position, although it remains an approved treatment option pending further revisions[2].

Adverse Effects and Safety

Common Adverse Effects

Amprenavir is associated with several adverse effects, including gastrointestinal disturbances, skin rash, and lipid abnormalities. The high protein binding of amprenavir (approximately 90%) can also lead to drug interactions, particularly with other drugs that are metabolized by the cytochrome P450 3A4 enzyme system[2].

Serious Adverse Effects

Serious adverse effects such as myocardial infarction and dyslipidemia have been noted, particularly in the context of fosamprenavir use. These risks necessitate careful patient monitoring and management to mitigate potential harm[2].

Key Takeaways

• Efficacy: Amprenavir is highly effective in reducing HIV RNA levels when used in combination with other antiretroviral agents.
• Mechanism: It inhibits the HIV-1 protease enzyme, preventing the formation of mature viral particles.
• Pharmacokinetics: Fosamprenavir, the prodrug, is hydrolyzed to amprenavir, allowing for slower release and fewer dosing requirements.
• Market: The drug competes in a highly competitive market but remains a viable option, especially in regions with limited access to newer drugs.
• Future Outlook: Combination therapy will continue to be the cornerstone of HIV treatment, with amprenavir likely to be used in these regimens despite potential regulatory and resistance challenges.

FAQs

What is amprenavir used for?

Amprenavir is used for the treatment and postexposure prophylaxis of human immunodeficiency virus (HIV-1) infection, typically in combination with other antiretroviral agents.

How does amprenavir work?

Amprenavir works by inhibiting the HIV-1 protease enzyme, preventing the processing of viral Gag and Gag-Pol polyprotein precursors and the formation of mature, infectious viral particles.

What are the common adverse effects of amprenavir?

Common adverse effects include gastrointestinal disturbances, skin rash, and lipid abnormalities. Serious adverse effects such as myocardial infarction and dyslipidemia have also been noted.

Why is fosamprenavir used instead of amprenavir?

Fosamprenavir is a prodrug of amprenavir, which is hydrolyzed to amprenavir in the gut epithelium. This allows for a slower release of amprenavir, reducing the number of pills a patient must take.

Is amprenavir still used in modern HIV treatment?

Yes, amprenavir is still used, particularly in combination therapy regimens. However, its use is influenced by the availability of newer antiretroviral drugs and concerns about resistance and side effects.

Sources

1. Murphy, R. L., et al. "Treatment with Amprenavir Alone or Amprenavir with Zidovudine and Lamivudine in Adults with Human Immunodeficiency Virus Infection." The Journal of Infectious Diseases, vol. 179, no. 4, 1999, pp. 808–816, doi: 10.1086/314668.
2. DrugBank. "Fosamprenavir: Uses, Interactions, Mechanism of Action - DrugBank." DrugBank, https://go.drugbank.com/drugs/DB01319.
3. ChemRxiv. "A Computational Drug Repurposing Study - ChemRxiv." ChemRxiv, 27 May 2020, https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/60c74c20702a9b35e618b5d7/original/simultaneous-inhibition-of-entry-and-replication-of-novel-corona-virus-by-grazoprevir-a-computational-drug-repurposing-study.pdf.
4. PubMed. "Amprenavir study results released - PubMed." PubMed, https://pubmed.ncbi.nlm.nih.gov/10743545/.
5. PLOS Computational Biology. "HIV-1 Subtype B Protease and Reverse Transcriptase Amino Acid Covariation." PLOS Computational Biology, 2006, doi: 10.1371/journal.pcbi.0030087.