Fosamprenavir (Lexiva, GW433908)

Susa Coffey, MD
Published October 30, 2003

Class
Protease inhibitor

Background
U.S. Manufacturer
GlaxoSmithKline and Vertex Pharmaceuticals

Approval
Fosamprenavir received FDA approval in October 2003 for use in adults with HIV infection. It is a prodrug of amprenavir, which was previously licensed for treatment of HIV infection.
FDA approval was based on three Phase III studies, two in previously untreated patients and one in patients with prior protease inhibitor treatment. An open-label study compared fosamprenavir (without ritonavir boosting) to nelfinavir, each given twice daily with abacavir + lamivudine in previously untreated patients. At 48 weeks, higher rates of virologic suppression and CD4 T-lymphocyte increase were seen in the fosamprenavir treatment arm.(1) A second open-label study in previously untreated patients compared a once-daily combination of fosamprenavir + ritonavir to standard-dose nelfinavir, each in combination with twice-daily abacavir + lamivudine. Similar rates of virologic suppression and CD4 increase were observed in the two groups.

In patients with prior virologic failure on one or two regimens containing a protease inhibitor, two combinations of ritonavir-boosted fosamprenavir were compared with lopinavir/ritonavir (Kaletra). Each regimen included two active nucleoside analogues. Through week 48, similar rates of virologic suppression and CD4 increase were seen in the twice-daily fosamprenavir/ritonavir group and in the lopinavir/ritonavir group; higher rates of virologic failure were seen in the third treatment group, in which fosamprenavir/ritonavir was given once daily.

Formulation and Dosing
Fosmprenavir is available in tablet form.
Fosmprenavir is FDA approved for twice-daily dosing; it also is approved for once-daily dosing when used in combination with ritonavir. For treatment-experienced patients, approval of fosamprenavir is limited to twice-daily combination with ritonavir.

Usual Dosing of Fosamprenavir

*For protease inhibitor-experienced patients, only the combination of fosamprenavir 700 mg bid + ritonavir 100 mg bid is specifically approved.

• There are no food restrictions.
• Fosamprenavir interacts with a number of medications, including efavirenz, nevirapine, lopinavir/ritonavir, and other protease inhibitors; dose adjustments may be required and certain combinations are contraindicated. See the Database of Antiretroviral Drug Interactions for information on dose adjustments.
• No dose adjustment is necessary in renal insufficiency.
• Dose adjustment may be necessary in hepatic insufficiency.
• Please consult product labeling for detailed dosing information.
  
  

Clinical Use

Combinations
Like other antiretrovirals, fosamprenavir should be used only in combination regimens.
Amprenavir, the active metabolite of fosamprenavir, is metabolized by the cytochrome P450 3A4 (CYP3A4) isoenzyme, and may alter the concentrations of other drugs metabolized by this pathway, including rifabutin, hormonal contraceptives, ergot derivatives, certain benzodiazepines, antiarrhythmics, lipid-lowering agents, and others. Similarly, drugs or herbal preparations that induce or inhibit the action of this isoenzyme may cause therapeutically significant alterations in amprenavir levels. For example, rifampin induces CYP3A4, and markedly decreases amprenavir levels. Information on drug interactions should be consulted, as dose adjustments are frequently required and some combinations are contraindicated.

Fosamprenavir has not been thoroughly studied in combination with other protease inhibitors and nonnucleoside reverse transcriptase inhibitors; in most cases precise information on dosing in combination with other antiretrovirals is lacking. Coadministration of fosamprenavir with lopinavir/ritonavir causes reductions in levels of both amprenavir and lopinavir; it appears that this adverse interaction cannot be overcome by increasing ritonavir levels. Coadministration of fosamprenavir with efavirenz has been shown to decrease amprenavir levels, but boosting with sufficient doses of ritonavir may maintain therapeutic amprenavir levels in the presence of efavirenz.

Use in Initial vs Subsequent Therapy
Treatment guidelines of the DHHS do not include fosamprenavir, however, the guidelines were last published before FDA approval of fosamprenavir.
When used in initial therapy, fosamprenavir appears to compare favorably with nelfinavir, either when used as a single protease inhibitor or when boosted with ritonavir. In one Phase III study (see "Approval") of twice-daily fosamprenavir + abacavir + lamivudine versus nelfinavir + abacavir + lamivudine, similar rates of viral suppression were seen through 48 weeks (by intent-to-treat analysis, viral load <50 copies/mL in 55% of fosamprenavir recipients and 41% of nelfinavir recipients, (95% confidence interval [CI]: 2%, 28%). In patients with baseline viral loads >100,000 copies/mL, the fosamprenavir arm appeared to achieve higher rates of viral suppression to <400 copies/mL. Median CD4 increases were 201-216 cells/μL.

In the second study of initial therapy, a once-daily combination of fosamprenavir boosted with low-dose ritonavir was compared to standard twice-daily nelfinavir. Patients in both arms were also given twice-daily abacavir and lamivudine. Through week 48, by intent-to-treat analysis, comparable rates of viral suppression to <50 copies/mL were seen in the fosamprenavir/ritonavir group (55%) and the nelfinavir group (53%) (95% CI: -6%, 10%). In patients with baseline viral load >100,000 copies/mL, similar rates of viral suppression to <400 copies/mL were seen in the two treatment groups. Median CD4 increases were similar in the two groups (approximately 205 cells/μL). Fosamprenavir has not been compared to a boosted protease inhibitor or to a nonnucleoside reverse transcriptase inhibitor in initial therapy.

In patients with prior virologic failure on one or two protease inhibitors, a Phase III study compared two regimens containing fosamprenavir/ritonavir (a twice-daily combination and a once-daily combination) with fixed-dose lopinavir/ritonavir, each in combination with two active nucleoside analogues (dosed twice daily). At 48 weeks, similar rates of viral suppression to <400 copies/mL were seen in the fosamprenavir/ritonavir twice-daily group and the lopinavir/ritonavir group (58% and 61%, respectively; 95% CI for the difference: 16.6 -10.1), with comparable CD4 increases of approximately 85 cells/μL. In the once-daily fosamprenavir/ritonavir arm, patients had lower rates of viral suppression: 50% achieved HIV-1 RNA <400 copies/mL.


Factors Affecting Adherence
Symptomatic adverse effects of fosamprenavir include rash, nausea, and diarrhea. Fosamprenavir appears to induce fewer gastrointestinal adverse effects than amprenavir. Laboratory abnormalities include hyperlipidemia and increases in hepatic transaminase levels. Fosamprenavir is associated with a low pill burden and simple dosing regimen; these factors may increase adherence. It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with protease inhibitors is initiated.

Resistance
Resistance to fosamprenavir is associated with the selection of one or more of several resistance mutations.

Implications of fosamprenavir resistance for treatment with other antiretrovirals.
Mutations selected by fosamprenavir are also characteristic of amprenavir resistance, and include I50V, I54L/M, V32I, I47V, and M46I. These mutations do not appear to confer significant cross-resistance to other protease inhibitors. It appears that resistance to fosamprenavir may develop more readily during treatment with unboosted fosamprenavir than during treatment containing ritonavir-boosted fosamprenavir.
Results from clinical studies are needed to elucidate fosamprenavir resistance and its implications for subsequent therapy. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing fosamprenavir.

Implications of resistance to other antivirals for fosamprenavir treatment
Few data are available regarding the efficacy of fosamprenavir in individuals with HIV resistant to other protease inhibitors.
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to fosamprenavir following failure of regimens containing other antiretrovirals, but further clinical studies are needed to clarify this question.