Published Online, 6 June 2006, www.theannals.com, DOI 10.1345/aph.1G034.
The Annals of Pharmacotherapy: Vol. 40, No. 7, pp. 1301-1310. DOI 10.1345/aph.1G034
© 2006 Harvey Whitney Books Company.
FORMULARY FORUM
Fosamprenavir: Drug Development for Adherence
E Kelly Hester, PharmD BCPS
Assistant Clinical Professor, Department of Pharmacy Practice, Harrison
School of Pharmacy, Auburn University, AL
Haley V Chandler, PharmD Student
Harrison School of Pharmacy
Kelli M Sims, PharmD Student
Harrison School of Pharmacy
Reprints: Dr. Hester, Harrison School of Pharmacy, 125 Walker Building,
Auburn University, AL 36849-5502, fax 334/844-4019,
hesteek{at}auburn.edu
 |
Abstract
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OBJECTIVE: To review the pharmacology, pharmacokinetics, virology,
safety, efficacy, and clinical use of fosamprenavir.
DATA SOURCES: A MEDLINE (1966-July 2005) search was conducted using
fosamprenavir, Lexiva, amprenavir, and GW433908 as key words. Abstracts from
infectious diseases and HIV scientific meetings were identified.
Bibliographies of cited articles were reviewed.
STUDY SELECTION AND DATA EXTRACTION: All publications, meeting
abstracts, and unpublished information were reviewed and relevant items
included. Information from in vitro, preclinical, and Phase II and III
clinical trials was included.
DATA SYNTHESIS: Fosamprenavir is a protease inhibitor (PI) prodrug
used for the treatment of HIV-1 infection. The active moiety, amprenavir, is
extensively metabolized by CYP3A4. In clinical trials, fosamprenavir was at
least as effective as amprenavir, with a reduced pill burden. Fosamprenavir
was developed with the intention of reducing the pill burden associated with
amprenavir. It has demonstrated comparable safety and efficacy with comparator
PIs and is associated with limited cross-resistance to other PIs.
CONCLUSIONS: Fosamprenavir is a promising antiretroviral agent with
favorable efficacy and tolerability. At this time, data indicate the utility
of fosamprenavir in treatment-naïve and PI-experienced HIV-infected
patients.
Key Words: fosamprenavir, GW433908, Lexiva
Published Online, June 6, 2006. www.theannals.com, DOI 10.1345/aph.1G034
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-06-015-H02
In the last 2 decades since HIV was first isolated, the medical management
of HIV and related outcomes have dramatically changed. Advances in drug
therapy have had a significant impact on the morbidity and mortality
associated with HIV infection. With the advent of protease inhibitors (PIs)
and their use in combination with other antiretroviral classes, highly active
antiretroviral therapy (HAART) has been associated with delayed disease
progression and reduced hospitalization and opportunistic infection
rates.1 While
these outcomes represent a tremendous milestone in treatment, management of
HIV infection has been complicated by antiretroviral resistance, short- and
long-term adverse effects of therapy, drug interactions, comorbid conditions,
and nonadherence to drug therapy. As a result, drug development has focused on
improving antiretroviral resistance profiles, tolerability, and adherence
strategies such as reduced pill burden and administration requirements.
Current antiretroviral guidelines recommend initial combination therapy to
include dual nucleoside reverse transcriptase inhibitor (NRTI) therapy as the
antiretroviral backbone in combination with a PI or nonnucleoside reverse
transcriptase inhibitor
(NNRTI).2 The
preferred PI and NNRTI therapy in treatment-naïve patients includes
lopinavir/ritonavir and efavirenz, respectively. High rates of adherence to
antiretroviral therapy have been associated with greater durability of
virologic suppression, delayed progression to resistance, and improved
survival and are necessary to optimize therapeutic
outcomes.3-6
One of the most common barriers to adherence with antiretroviral therapy is
pill
burden.7
Fosamprenavir is a PI developed by GlaxoSmithKline Pharmaceuticals that was
approved by the Food and Drug Administration (FDA) for treatment of HIV-1
infection in October 2003. It is a prodrug converted to amprenavir and was
developed with an interest in reducing the pill burden yet maintaining the
unique resistance pattern associated with amprenavir administered as Agenerase
capsules. The pharmacokinetics of fosamprenavir and amprenavir have been
compared to evaluate the bioequivalence of this new
formulation.8,9
Virologic and immune response have been evaluated in clinical studies
providing comparisons of potency and durability with commonly prescribed PIs
(nelfinavir, lopinavir/ritonavir) in treatment-naïve and -experienced
patients.10-12
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Data Sources
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Publications were identified through a search of MEDLINE (1966-July 2005).
Fosamprenavir, GW433908, Lexiva, and amprenavir were used as key words.
Abstracts from significant HIV/AIDS and infectious diseases national and
international scientific meetings were reviewed (2000-2005), including the
Conference on Retroviruses and Opportunistic Infections, International AIDS
Society Conference on HIV Pathogenesis and Treatment, the Interscience
Conference on Antimicrobial Agents and Chemotherapy, and World AIDS
Conference. Scientific research was selected and reviewed based upon the
strength of the clinical trial design evaluating the safety and efficacy of
fosamprenavir. In vivo and in vitro data were included as they related to drug
development supporting clinical utility and antiretroviral resistance.
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Pharmacology and Virology
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Amprenavir, the active moiety of fosamprenavir, is an inhibitor of the
HIV-1 protease enzyme. In the course of viral replication, once transcription
and translation have occurred, the long newly formed polyproteins must be
cleaved by the protease enzyme for the new virion to mature and complete
formation. Inhibition of the viral HIV-1 protease enzyme prevents the
enzymatic interaction with the gag and gag-pol polyprotein precursors,
rendering a functionally immature, noninfectious virion. Fosamprenavir itself
has little antiviral activity in vitro. Results from in vitro testing of
amprenavir in infected lymphoblastic cells (MT-4, CEM-CCRF, H9) and peripheral
blood lymphocytes indicated that the concentration necessary to inhibit 50%
HIVIIIB replication in acutely infected cells is 0.012-0.08
µmol/L; the required concentration in chronically infected cells is 0.41
µmol/L.13
The relationship between in vitro and in vivo anti-HIV activity has not been
characterized.
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Resistance
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Resistance to PIs develops when amino acid substitutions occur in the HIV-1
protease gene. It can also occur with mutations to the p7/p1 Gag and Gag-pol
polyprotein cleavage
sites.13 In
vitro data have indicated minimal cross-resistance to other PIs when viral
mutations selected by amprenavir occur. In an effort to identify clinically
significant mutations conferring resistance to amprenavir, Maguire et
al.14
studied the resistance profiles of 48 PI-naïve HIV-infected patients
following 48 weeks of HAART treatment with amprenavir. Genotypic and
phenotypic assays were interpreted. Results demonstrated that 65% of these
patients developed protease mutations, and 4 key protease mutations were
selected during amprenavir treatment. The amino acid substitutions included
I50V, I54L/M, V32I+I47V, and, less commonly, I84V, which reduced amprenavir
susceptibility greater than fourfold compared with wild-type virus.
The variants exhibiting the I50V mutation were generally more resistant to
amprenavir than variants harboring any one of the other 3
mutations.14
This is consistent with in vitro data indicating that the I50V mutation is the
most frequent mutation associated with amprenavir resistance in PI-naïve
patients conferring a two- to threefold reduced
susceptibility.15-17
Viruses with reduced susceptibility to other PIs due to protease mutations,
such as V82A/F/T, I54V, and L90M, remained fully sensitive to amprenavir.
Genotypic analysis of isolates from amprenavir-treated patients has identified
the major protease mutations conferring resistance to fosamprenavir to include
amino acid substitutions at positions I50V and I84V. Minor mutations include
L10F/I/R/V, V32I, M46I/L, I47V, I54L/V/M, G73S, and
L90M.18
Resistance data with the fosamprenavir formulation were evaluated in
patients experiencing virological failure (n = 86) in the SOLO
trial.11,19
No resistance mutations were identified in 84% and 31% of patients receiving
fosamprenavir/ritonavir (FPV/r) and nelfinavir, respectively, at the first
failure
timepoint.19
In addition, primary or secondary protease mutations were identified in 50% of
subjects treated with nelfinavir, while no protease mutations were identified
in the FPV/r group. The development of NRTI mutations observed with the FPV/r
group was also less common. Lamivudine resistance (M184I/V) was identified in
69% of nelfinavir-treated patients compared with 13% in the FPV/r group.
Differences between groups for each of these parameters were statistically
significant (p < 0.001). These differences in rates of resistance have been
attributed to a higher genetic barrier produced by the high drug exposure
associated with the ritonavir-boosted fosamprenavir combination, thereby
delaying the emergence of resistance to both PIs and NRTIs.
Greater drug exposure and subsequent selective pressure exerted by the
ritonavir-boosted fosamprenavir suppress viral replication to restrict the
development of resistance to antiretroviral therapy. Adherence data for this
study were evaluated and did not attribute to differences in the observed
resistance profiles between treatment
groups.20
This higher genetic barrier was also supported in evaluating unboosted and
ritonavir-boosted fosamprenavir in that the unboosted group developed
characteristic amprenavir
mutations.21
Another unique characteristic observed in vivo with amprenavir is that, in
some cases, viral variants with resistance to one or more PIs retain
susceptibility to
amprenavir.22,23
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Pharmacokinetics
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Amprenavir was marketed in 1999 as the first PI without food
restrictions.24
The dose approved by the FDA was 1200 mg (8 capsules) twice daily. The primary
goal in the development of fosamprenavir was to attain high water solubility,
thereby reducing the pill burden associated with its active and less-soluble
form, amprenavir. To improve water solubility, the hydroxyl group of the
parent drug amprenavir was converted to a calcium phosphate ester in
fosamprenavir. Other differences from the previous formulation include organic
additives to minimize the pill burden of this prodrug and lack of vitamin E
compared with 109 IU per capsule of
amprenavir.24,25
Fosamprenavir is rapidly and extensively hydrolyzed by alkaline
phosphatases in the intestinal brush border of the epithelium to form
amprenavir and inorganic phosphates, with minimal systemic
absorption.8,9,13
The median peak amprenavir concentration occurs 2.5 hours following
administration. Plasma protein binding with amprenavir is estimated to be 90%,
with binding primarily to 
1-acid
glycoprotein.13
Amprenavir is metabolized in the liver by the CYP3A4 enzyme system primarily
by oxidation but also undergoes conjugation to a lesser extent. Amprenavir and
its metabolites are excreted in the urine and feces. Unchanged amprenavir
accounts for approximately 1% of the dose in the urine and is undetectable in
the feces. The plasma terminal elimination half-life of amprenavir is
approximately 7.7 hours.
The pharmacokinetics of fosamprenavir tablets have been studied in
HIV-infected individuals and have shown comparable results to amprenavir
capsules (Table
1).13
Differences in the fosamprenavir pharmacokinetic parameters were minimal
between the fasting and fed (high-fat meal) conditions for maximum
concentration, time to maximum concentration, and
AUC0-
. The pharmacokinetic enhancement of
fosamprenavir with ritonavir has been studied comparing once- and twice-daily
administration.13,26
Healthy volunteers were randomized to receive either FPV/r 1400/200 mg once
daily or FPV/r 700/100 mg twice daily. Coadministration of ritonavir increased
the AUC24 and minimum concentration compared with
pharmacokinetic parameters for unboosted amprenavir or fosamprenavir
(Table 1). The greatest
pharmacokinetic difference observed between the once- and twice-daily boosted
regimens was the higher minimum concentrations (1.45 and 2.12 µg/mL,
respectively). The greater drug exposure attained by the twice-daily
ritonavir-boosted fosamprenavir regimen is necessary in PI-experienced
patients to suppress viral replication and restrict the development of
resistance to antiretroviral therapy.
A small crossover study compared the pharmacokinetic enhancement of
ritonavir 100 and 200 mg once daily with fosamprenavir 1400 mg once
daily.27
Comparable steady-state AUC24 and maximum plasma
concentrations were achieved; however, the ritonavir 100 mg regimen resulted
in 38% lower minimum concentrations (0.86 and 1.40 mg/mL, respectively).
Compared with unboosted fosamprenavir, this represents a 2.5-fold increase in
minimum concentration; however, this is not an FDA-approved dosing
regimen.
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Clinical Trials
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Two clinical trials
(NEAT10 and
SOLO11) of
fosamprenavir have been conducted in antiretroviral-naïve patients, and
one trial (CONTEXT) has been conducted in antiretroviral-experienced
patients12
(Table 2).
ANTIRETROVIRAL-NAÏVE SUBJECTS
The NEAT study (protocol APV30001) was a prospective, multicenter,
international, randomized (2:1), open-label trial evaluating the efficacy,
safety, and tolerability of fosamprenavir 1400 mg twice daily (n = 166)
compared with nelfinavir 1250 mg twice daily (n = 83) in
antiretroviral-naïve
patients.10
All subjects received abacavir 300 mg twice daily and lamivudine 150 mg twice
daily as the NRTI backbone. The patients in this study had advanced HIV
disease with 44% having a baseline HIV RNA viral load (vRNA) greater than 100
000 copies/mL and 48% having a CD4+ cell count less than 200
cells/mm3. At 48 weeks, the percentage of patients achieving
vRNA less than 400 copies/mL was higher for the fosamprenavir group than the
nelfinavir group, as well as the percentage of those achieving less than 50
copies/mL as determined by intent-to-treat analysis. Divergence between groups
in terms of virologic response was observed in patients with higher baseline
viral loads (vRNA >100 000). More patients in the fosamprenavir group (67%
and 55%) than the nelfinavir group (35% and 24%) achieved vRNA less than 400
copies/mL and less than 50 copies/mL at 48 weeks, respectively.
Treatment failure, defined as inability to achieve vRNA less than 400
copies/mL, a vRNA rebound to greater than 400 copies/mL, or treatment
discontinuation for any reason, was higher in the nelfinavir group. Immune
response was significant and comparable between groups at the end of the
study.10 At
120 weeks, 76% (intent-to-treat) of patients on fosamprenavir 1400 mg twice
daily maintained RNA less than 400 copies/mL and 71% less than 50 copies/mL
(personal communication, Maribeth Day Case JD, Trademark Counsel,
GlaxoSmithKline, January 25, 2006).
This head-to-head study of fosamprenavir and nelfinavir was designed
primarily to evaluate safety and tolerability results. The 2:1 randomization
resulted in a small comparator group (n = 83) and inadequate power to assess
differences between treatment groups in achieving undetectable vRNA relative
to therapeutic efficacy. As a result, comparisons were made based on the
secondary endpoint (mean vRNA average AUC minus baseline), allowing for
analysis of noninferiority. Noninferiority was defined as an upper limit of
the mean treatment differences of less than 0.5 log10
copies/mL. Comparisons at 48 weeks indicated similar results between the
treatment groups (-2.41 and -2.32 log10 copies/mL,
respectively) and demonstrated noninferiority with the mean treatment
difference of -0.082 (95% CI -0.333 to 0.169). However, a true treatment
difference is suggested by the 95% CI reported to the right of
zero.10
In contrast to the NEAT study, the SOLO trial compared ritonavir-boosted
fosamprenavir with nelfinavir in therapy-naïve patients
(Table
2).11
SOLO (study protocol APV30002) was an open-label, randomized, multicenter
study evaluating the safety and efficacy of once-daily dosing of FPV/r
1400/200 mg once daily compared with nelfinavir 1250 mg twice daily in 649
patients. Both treatment groups also received abacavir 300 mg twice daily and
lamivudine 150 mg twice daily. This study was powered to detect differences in
proportions of patients achieving vRNA less than 400 copies/mL at week 48. The
48 week data, based on an intent-to-treat analysis, indicated that the
percentage of patients achieving a vRNA less than 400 copies/mL was comparable
between the FPV/r and nelfinavir treatment groups. Treatment failure, defined
as vRNA 400 or more copies/mL, a vRNA rebound greater than 400 copies/mL,
missing data, or discontinuation of treatment, was observed to a greater
extent in the nelfinavir arm (17%) than the FPV/r arm (7%).
The data demonstrated similar virologic potency and durability between
treatment groups regardless of baseline vRNA levels. However, differences in
efficacy were apparent in patients with a baseline vRNA greater than 500 000,
with a higher percentage achieving vRNA less than 400 copies/mL with FPV/r
(73%) than nelfinavir (53%). Median increases in CD4+ cell counts from
baseline were similar between treatment
groups.11
Long-term study results of FPV/r at 120 weeks indicated that 75% and 66% of
patients had vRNA levels less than 400 and less than 50 copies/mL,
respectively (personal communication, Maribeth Day Case).
Since administration requirements differed between groups (FPV/r once daily
vs nelfinavir twice daily), self-reported adherence was assessed to determine
whether the results could be explained by this factor. Better adherence was
reported with the once-daily regimen (78%) than with the twice-daily regimen
(67%), as well as a higher percentage of perfect adherence at week 48 (90% and
84%), respectively. Treatment with FPV/r resulted in a potent and durable
response for treatment-naïve, highly immunocompromised patients with
advanced
disease.11
ANTIRETROVIRAL-EXPERIENCED SUBJECTS
The CONTEXT study (protocol APV30003) was the first long-term trial
evaluating the virologic response of fosamprenavir in treatment-experienced
patients.12,13
This randomized, open-label study evaluated patients who had previously failed
a PI-containing regimen. The purpose of the study was to assess the efficacy,
durability, and noninferiority of FPV/r dosed either once or twice daily
compared with lopinavir/ritonavir (LPV/r). Patients were randomized to 1 of 3
treatment regimens: FPV/r 1400/200 mg once daily, FPV/r 700/100 mg twice
daily, or LPV/r 400/100 mg twice daily in combination with 2 active NRTIs
based on resistance testing. More than 40% of patients in each group had
previous experience with at least 2 PIs. This study was powered to show
noninferiority of FPV/r to LPV/r, with antiviral efficacy assessed by mean
time-averaged change in HIV RNA from baseline (AAUCMB).
At 24 weeks, the fosamprenavir/ritonavir treatment groups demonstrated
noninferiority to LPV/r based on mean
AAUCMB.12
However, at 48 weeks, the FPV/r treatment groups diverged based on mean AAUCMB
compared with the LPV/r group (-1.49, -1.53, and -1.76 log10
copies/mL,
respectively).23
At 48 weeks, virologic suppression less than 400 copies/mL was comparable
between the twice-daily treatment groups, with 58% and 61% in the FPV/r and
LPV/r groups,
respectively.13,23
The percentage of patients achieving HIV-1 RNA less than 50 copies/mL was 46%
and 50%, respectively. The FPV/r once-daily regimen achieved much lower
percentages for these outcomes (50% and 37%,
respectively).13
Virologic failure rates were also similar between the twice-daily dosing
treatment arms, with 29% in the FPV/r and 27% in the LPV/r arms. There were
also minimal differences between groups with respect to increases in CD4+ cell
counts from baseline. This study, however, was not large enough to
definitively conclude that FPV/r and LPV/r are clinically equivalent in
PI-experienced patients. The results of this trial provide the evidence
necessitating twice-daily dosing of fosamprenavir boosted with ritonavir in
this population to achieve optimal virologic outcomes. It also supports the
recommendation against once-daily FPV/r administration for PI-experienced
patients.
|
Adverse Effects
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|---|
The safety of fosamprenavir has been evaluated in 700 patients in
controlled clinical
trials.10-13
The most common treatment-related adverse effects rated at least moderate in
severity in these studies were diarrhea (5-13%), nausea (3-9%), vomiting
(2-6%), headache (2-4%), and rash (19%). The incidence of moderate-to-severe
skin rash in treatment-naïve and experienced patients was 3-8% and led to
treatment discontinuation in fewer than 1% of subjects. However, other
coadministered antiretroviral agents (ie, abacavir) and antibiotics (ie,
trimethoprim/sulfamethoxazole) also have the potential to cause rash, which
may have confounded the results. Mild-to-moderate maculopapular rashes were
typically observed within the first 2 weeks of treatment and did not require
discontinuation of treatment. Recurrence of the rash was generally not
observed when treatment was interrupted and reinitiated.
There has been one case of Stevens-Johnson syndrome in clinical studies due
to
fosamprenavir.13
Fosamprenavir should be discontinued in cases of severe or life-threatening
rashes or in patients exhibiting systemic systems in addition to a rash.
Fosamprenavir and amprenavir both contain a sulfonamide moiety; therefore,
these agents should be used with caution in patients with a known sulfonamide
allergy. While the potential for cross-sensitivity between fosamprenavir and
other sulfonamides is not known, clinical studies have not consistently
demonstrated that patients with a history of sulfonamide allergy have a higher
incidence of rash compared with those without this allergy.
The most frequent grade 3/4 (severe to life threatening) laboratory
abnormalities in clinical studies with fosamprenavir were hypertriglyceridemia
(triglyceride levels >750 mg/dL in 0-6% pts.) and elevations (>5 times
the upper limit of normal) in transaminase levels (4-8% of pts.) and in serum
lipase levels (>2 times the upper limit of normal, 5-8% of pts.), which
were comparable between treatment groups in clinical studies. Comparatively,
hypertriglyceridemia (1-2%, 6% of pts.), elevated transaminases (5-8%, 2-4% of
pts.), and lipases (4%, 12% of pts.) were reported for nelfinavir/ritonavir
and lopinavir/ritonavir combinations, respectively. Hypertriglyceridemia
occurred more often in patients taking combination fosamprenavir and ritonavir
therapy or those having prior PI experience than in treatment-naïve
patients (6-11% and 6%,
respectively).12,13
Physical and metabolic abnormalities have been described in patients taking
HAART. The incidence of lipodystrophy, including dyslipidemia, hyperglycemia,
and peripheral fat redistribution, has been higher in HIV-infected individuals
following treatment with
PIs.28 In
the NEAT study, lipid alterations between treatment groups were evaluated.
There was a median increase in low-density lipoprotein cholesterol (LDL-C) of
24 mg/dL, total cholesterol of 39.9 mg/dL, and high-density lipoprotein
cholesterol (HDL-C) of 10.1 mg/dL in the fosamprenavir group. At the end of
the study, 18% of patients in both treatment groups had LDL-C levels that
warranted clinical intervention based on National Cholesterol Education
Program
guidelines.29
Normalization of HDL-C levels was observed in a greater proportion of patients
taking fosamprenavir than the comparator treatment in both the NEAT and SOLO
clinical
trials.10,11,30
At 48 weeks, HDL-C levels increased 37% and 22% in the fosamprenavir and
nelfinavir treatment groups,
respectively.31
The occurrence of hyperglycemia (blood glucose >251 mg/dL) was 2% in
PI-experienced subjects taking fosamprenavir and less than 1% in
antiretroviral-naïve patients.
Fat redistribution, characterized by central fat accumulation in the
abdominal area, increased adipose tissue in the neck and dorsocervical area
(buffalo hump), and breast enlargement, may be accompanied by lipoatrophy
involving the facial adipose tissue and
extremities.32,33
This metabolic complication has been observed in patients treated with
fosamprenavir.13
Fosamprenavir appears to be well tolerated, with a low incidence (6.4%) of
adverse events requiring treatment
discontinuation.13
Recommendations for monitoring fosamprenavir for safety include periodic liver
function tests and a baseline fasting lipid panel prior to initiation of
therapy, within 3 months, then annually or more frequently if
indicated.2,34
|
Drug Interactions
|
|---|
As with other PIs, many interactions must be considered when fosamprenavir
is administered with concomitant medications. Drug-drug interactions with
antiretroviral medications may reduce antiviral efficacy resulting in
virologic failure, compromise the efficacy of the concomitant medication,
worsen tolerability, or induce moderate-to-severe or life-threatening adverse
events (Table 3). Data suggest
that amprenavir both induces and inhibits CYP3A4; however, the majority of
clinically relevant drug interactions are due to inhibition. Caution is
advised with concomitant use of drugs that are substrates, inducers, or
inhibitors of CYP3A4, especially those with a narrow therapeutic index. Drugs
contraindicated with fosamprenavir are listed in
Table 3. Amprenavir does not
inhibit CYP2D6, 1A2, 2C9, 2C19, 2E1 or uridine
glucuronosyltransferase.13
Although the clinical role of fosamprenavir is yet to be defined, it is
likely to be coadministered with low-dose (100-200 mg) ritonavir for
pharmacokinetic enhancement. Ritonavir is a potent cytochrome P450 inhibitor
and has activity as an enzyme inducer (CYP3A, CYP1A2, CYP2C9); it will
therefore play a significant role regarding potential drug interactions. For
example, antiarrhythmics such as amiodarone and quinidine are contraindicated
with ritonavir due to the potential for cardiac arrhythmias secondary to
significant increases in plasma concentrations compared with fosamprenavir
alone. Conversely, with anticonvulsants such as phenytoin and divalproex,
plasma concentrations may be decreased with coadministration of ritonavir.
Coadministration of drugs or herbal products that induce CYP3A4 (eg,
rifampin, St. John's wort) could decrease concentrations of amprenavir,
resulting in a decrease in therapeutic effect. Use with drugs that are either
inducers or inhibitors of CYP3A4 requires close monitoring of therapeutic
effect or adverse events,
respectively.13
While evidence may exist for clinically significant drug-drug interactions
within an antiretroviral regimen, dosing recommendations may not be
established.
|
Pediatric Considerations
|
|---|
The safety and efficacy of fosamprenavir have not been evaluated in the
pediatric population. There have been 2 pediatric studies with Agenerase to
establish its safety and
efficacy.38,39
The incidence of treatment discontinuation as a result of an adverse event was
5%. The most common adverse effects were nausea, vomiting, diarrhea, and rash.
Agenerase solution is contraindicated in children less than 4 years of age due
to the large amounts of propylene glycol excipients in the formulation and
limited metabolic activity at this
age.24
|
Dosage and Administration
|
|---|
Fosamprenavir is available only as a 700 mg tablet that is equivalent to
600 mg of amprenavir (4
capsules).13
In antiretroviral-naïve patients, fosampenavir may be dosed with or
without ritonavir (fosamprenavir 1400 mg twice daily, FVP/r 700/100 mg twice
daily, or FVP/r 1400/200 mg once daily). Based on the pharmacokinetic data
from clinical trials, twice-daily ritonavir-boosted fosamprenavir is
recommended for PI-experienced patients. Dosing considerations with
concomitant nonnucleoside therapy are provided in
Table 3.
Fosamprenavir has not been studied in elderly patients or patients with
renal or hepatic insufficiency. Administration of amprenavir (as Agenerase
capsules), however, in patients with hepatic impairment demonstrated
significant increases in the amprenavir
AUC.24
Patients with mild-to-moderate hepatic dysfunction (Child-Pugh score 5-8)
should have their fosamprenavir dosage reduced (700 mg twice daily without
ritonavir) and be monitored
closely.13
The use of fosamprenavir in patients with severe hepatic insufficiency
(Child-Pugh score 9-12) is not recommended. Since a minimal (
1%) amount
of amprenavir is eliminated unchanged in the urine following fosamprenavir
administration, renal insufficiency is not anticipated to result in
significant adverse events. At this time, the extent of amprenavir removed by
dialysis or hemodialysis is unknown.
|
Patient Counseling
|
|---|
Prior to initiation of any antiretroviral regimen, patients should be
counseled on the commitment to adherence that is required for optimal
therapeutic outcomes, and the patient's readiness to begin therapy should be
assessed. An understanding of the relationship between adherence and virologic
failure is imperative. In one study, adherence rates greater than 95% to
antiretroviral therapy were associated with significantly less virologic
failures compared with those with adherence rates less than 80% (22% and 80%,
respectively).6
Consistent, high levels of adherence have been the strongest predictor of
virologic and immunologic outcomes and are associated with the most
significant improvements in quality of
life.40,41
Adherence rates typically decline over time; therefore, the low pill burden
with fosamprenavir may encourage improved adherence as a PI-containing
regimen. Counseling on antiretroviral therapy should include specific
instructions on the individual agents regarding food-drug interactions and
prescribed dose, as well as the potential and anticipated adverse events with
initiation of therapy. Patients should be advised to notify all healthcare
providers of current prescription, nonprescription, and herbal medications
being taken concomitantly to minimize the potential of drug-drug interactions.
Lastly, the importance of routine laboratory monitoring for safety and
efficacy of antiretroviral therapy should be emphasized.
|
Therapeutic and Pharmacoeconomic Issues
|
|---|
Fosamprenavir is approved for treatment of HIV infection in combination
with other antiretroviral
agents.13
The current HIV treatment guidelines recommend the use of fosamprenavir as an
alternative treatment regimen in antiretroviral-naïve patients for whom
the preferred regimens are not an
option.2 In
the selection of patient-specific HAART regimens, the potency, tolerability,
resistance profile, and reduced pill burden of fosamprenavir make it a
favorable choice as alternative therapy with the likelihood of adherence to
encourage optimal outcomes. Ritonavir-boosted fosamprenavir produces higher
minimum concentrations than unboosted fosamprenavir and allows for once-daily
dosing in treatment-naïve
patients.13,26
These characteristics, coupled with a comparable adverse effect profile,
favorable resistance profile, and similar cost between the 2 prescribing
regimens, make the clinical utility of ritonavir-boosted fosamprenavir
preferable for both treatment-naïve and treatment-experienced
patients.42
The monthly average wholesale price for fosamprenavir is $1265.26 and $1249.86
for the ritonavir-containing fosamprenavir regimen
(Table
4).42
|
Summary/Formulary Recommendation
|
|---|
Fosamprenavir was developed with the intention of reducing the pill burden
associated with amprenavir. Fosamprenavir retains the dosing flexibility of
being administered without food restrictions, and the pharmacokinetics of this
formulation allow for once-daily dosing when boosted with ritonavir in
treatment-naïve patients. Additionally, the active moiety amprenavir has
a unique resistance profile that has demonstrated a high genetic barrier when
boosted with ritonavir and limited cross-resistance to other PIs, thus
preserving future treatment options. Evidence of noninferiority with
ritonavir-boosted regimens, comparable tolerability, and low pill burden make
fosamprenavir an attractive alternative to preferred regimens in
treatment-naïve patients and PI-experienced patients in the management of
HIV infection. It is therefore recommended that fosamprenavir be added to the
formulary. The AIDS Drug Assistance Program has already included fosamprenavir
on its formulary.
|
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Abstract
Data Sources
