| Reference | 1. Drugs. 2000 Dec;60(6):1383-410.
<br>
Amprenavir: a review of its clinical potential in patients with HIV infection.
<br>
Noble S(1), Goa KL.
<br>
Author information: <br>
(1)Adis International Limited, Mairangi Bay, Auckland, New Zealand.
[email protected]
<br>
The virological/immunological efficacy of amprenavir-containing combination
regimens has been evaluated in a small number of clinical trials in patients with
HIV infection. Amprenavir plus 2 nucleoside reverse transcriptase inhibitors
(NRTIs) was more effective than 2 NRTIs (in treatment-naive patients) or
amprenavir monotherapy (in treatment-naive or -experienced patients) in
double-blind trials. In the only direct comparison with another protease
inhibitor as part of triple therapy, amprenavir was less effective than indinavir
in treatment-experienced (protease inhibitor-naive) patients. Amprenavir was as
effective as other protease inhibitors when given with abacavir in a small
nonblind trial. Amprenavir is generally well tolerated (most events are mild or
moderate). GI disturbance and rash are the principal treatment-limiting effects.
Preclinical data suggest that amprenavir may have a low potential for metabolic
disturbances (e.g. lipodystrophy, fat redistribution); such effects have been
infrequent in patients treated to date, but longer term experience is needed.
150V is the major HIV protease substitution associated with amprenavir
resistance; this mutation is not seen in isolates from patients receiving other
available protease inhibitors. Amprenavir-resistant isolates evaluated to date
showed no significant cross-resistance to most other protease inhibitors,
although some cross-resistance to ritonavir was noted. Many isolates from
patients previously treated with other protease inhibitors are susceptible to
amprenavir. Amprenavir offers the convenience of twice-daily administration with
no food-timing or fluid restrictions, but this may be offset by the large number
and size of the capsules. However, pharmacokinetic data support the use of
co-administration of amprenavir and ritonavir at reduced dosages, thereby
allowing a reduction in the number of amprenavir capsules.CONCLUSIONS:
Amprenavir-containing combination regimens have shown virological efficacy, and
have generally been well tolerated, in patients with HIV infection (primarily
treatment-naive or protease inhibitor-naive). The limited number of studies
available and the absence of well controlled comparisons with other triple
therapies limits the conclusions that can be drawn at present. The clinical value
of amprenavir for patients with isolates which are resistant to other protease
inhibitors but sensitive to amprenavir, and in treatment-experienced patients in
general, requires further investigation. Further evaluation of the
amprenavir/ritonavir combination is awaited with interest. Like other members of
its class, amprenavir has a particular profile of tolerability, resistance and
administration characteristics which should be carefully considered in relation
to the needs of individual patients.
<br>
2. Clin Ther. 2000 May;22(5):549-72.
<br>
Amprenavir: a new human immunodeficiency virus type 1 protease inhibitor.
<br>
Fung HB(1), Kirschenbaum HL, Hameed R.
<br>
Author information: <br>
(1)Pharmacy Service, Veterans Affairs Medical Center, Bronx, New York 10468, USA.
<br>
OBJECTIVE: This paper reviews the pharmacologic properties and clinical
usefulness of amprenavir, a new human immunodeficiency virus type 1 (HIV-1)
protease inhibitor.<br>
BACKGROUND: Amprenavir, the most recent HIV-1 protease inhibitor to receive
marketing approval from the US Food and Drug Administration, is a potent
competitive inhibitor of HIV-1 protease and a relatively weak inhibitor of HIV-2
protease. Inhibition of the HIV-1 protease enzyme results in immature and
noninfectious viral particles. Amprenavir is rapidly absorbed following oral
administration. The time to peak concentration (Tmax) in adults is between 1 and
2 hours, the area under the plasma concentration versus time curve is roughly
proportional to the dose, the half-life is approximately 8 hours, and the volume
of distribution is approximately 430 L. The Tmax in children 4 to 12 years of age
is between 1.1 and 1.4 hours. The bioavailability of the solution is 86% relative
to the capsule formulation. It is metabolized by the cytochrome P-450 isozyme
CYP3A4 and to a lesser extent by CYP2D6 and CYP2C9.<br>
METHODS: We searched MEDLINE (1966 to January 2000), AIDSLINE (1980 to January
2000), International Pharmaceutical Abstracts (1970 to January 2000),
PharmaProjects (January 2000 version), and Web sites of major HIV/acquired
immunodeficiency syndrome conferences for appropriate published references (1996
to February 2000).<br>
RESULTS: Data reported to date indicate that amprenavir is efficacious in the
treatment of HIV disease in patients with primary HIV infection,
antiretroviral-naïve patients, protease inhibitor-naïve patients, protease
inhibitor-experienced patients, and pediatric patients. Adverse effects were
usually of early onset (range, 2 to 21 days) and transient (range, 3 to 46 days),
although the incidence of metabolic abnormalities such as lipodystrophy,
hyperlipidemia, and diabetes mellitus has not yet been defined. Amprenavir should
be avoided in patients with a known sulfonamide allergy. Concomitant use of other
medications that are CYP3A4 inducers or inhibitors should be done cautiously and
only if the potential benefit clearly outweighs potential risk. The dose should
be reduced in patients with significant hepatic impairment (Child-Pugh score, >
or = 5). Amprenavir probably should not be administered with rifabutin, rifampin,
astemizole, midazolam , triazolam, bepridil, dihydroergotamine, ergotamine, or
cisapride. The recommended adult dose is 1200 mg twice daily. For patients
between 4 and 12 years of age or between 13 and 16 years of age who weigh < 50
kg, the recommended dosage of the capsule form is 20 mg/kg (22.5 mg/kg for oral
solution) twice daily or 15 mg/kg (17 mg/kg for oral solution) 3 times a day to a
maximum dose of 2400 mg (2800 mg for oral solution). Patients should not take
vitamin E supplements because amprenavir is formulated with a large amount of
vitamin E (109 IU/capsule and 46 IU/mL oral solution) to improve oral absorption.
Amprenavir may be administered with or without food, but a high-fat meal (> 67 g
fat) should be avoided.<br>
CONCLUSIONS: Published clinical data are limited, but amprenavir appears to be
efficacious and generally well tolerated in patients with HIV infection.
Pharmacoeconomic data are not yet available. The introduction of amprenavir
appears to be important, since it provides an additional treatment option as a
component of both initial and salvage combination therapies for patients with
HIV.
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