DRUG RESISTANCEAnalysis of viral isolates identified mutational patterns of unboosted fos-amprenavir. Protease mutations were consistent with the amprenavir profile. In patients who were experiencing virolog-ical rebound after treatment with un-boosted fosamprenavir, clinical isolates containing mutations at positions V32I, I47V, 154L/M, I50V, M46I/L, and I84V were identified. Mutations were also identified in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. The HIV clinical isolates with mutational patterns retained sensitivity to lopinavir, saquinavir (Fortovase®, Invi-rase®, Roche), and boosted (Merck).

ADVERSE DRUG EFFECTS

In clinical trials, the most commonly reported ADEs associated with the use of fosamprenavir were nausea, vomiting, diarrhea, headache, and rash (Table 2). These ADEs were usually described as mild to moderate in severity and did not require discontinuation of the drug. During clinical trials, only 6.4% of patients stopped drug therapy as a result of ADEs. Although 19% of the fosampren-avir patients experienced mild skin reactions, only one case of a severe, life-threatening dermatological effect, such as Stevens-Johnson syndrome, was reported.

Table 2  Adverse Events Associated with Antiretroviral Therapy

Fosamprenavir

1,400 mg b.i.d.

1,250 mg b.i.d.
Effect

(n = 166) (%)

(n = 83) (%)
Diarrhea

5

18
Drug hypersensitivity

9

5
Rash

7

2
Nausea

5

4
Vomiting

2

4
Fatigue

2

1
Headache

2

2
Weakness

2

1
Insomnia

2

1

DRUG INTERACTIONS

Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of CYP3A4 metabolism. Therefore, the concurrent administration of fosamprenavir and drugs that induce this isoenzyme, such as barbiturates, phenytoin, and rifampin, may decrease amprenavir concentrations and, ultimately, may reduce therapeutic efficacy. In contrast, when coadmin-istered with CYP3A4 inhibitors, such as (Nizoral canadian, Janssen), (e.g., Pfizer), and ser-traline (Zoloft®, Pfizer), amprenavir concentrations, as well as the incidence of ADEs, may increase. To prevent the loss of virological response, resistance to fosamprenavir, or resistance to the class of PIs, prescribers should avoid coadministration of fosamprenavir and delavirdine(Rescriptor®, Agouron/Pfizer) or rifampin (Table 3).

PRECAUTIONS AND CONTRAINDICATIONS

Fosamprenavir should be used with caution in patients with sulfa allergy, hepatic impairment, hemophilia, immune reconstitution, fat redistribution, and lipid elevations. This agent is contraindicated in patients with clinically significant hypersensitivity to any components of this product or to amprenavir. Fosamprenavir is also contraindicated with the coadministration of drugs that require CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious, life-threatening events (see Table 3).

Table 3 Fosamprenavir Drug Interactions

Drug Class Drug Name
Antiarrhythmic agents Antimycobacterial agents Ergot derivatives Gatrointestinal motility agents Herbal products HMG-CoA reductase inhibitors Neuroleptic agents Non-nucleoside reversetranscriptase inhibitors Sedative/hypnotic agents Flecainide* (Tambocor®, 3M), propafenone* (Rythmol®, Abbott) Rifampin (Rifadin®, Aventis)Dihydroergotamine* (Migranol®, Xcel), ergonovine*, ergotamine*, methylergonovine* Cisapride* (Propulsid®, Janssen) St. John’s wort

(Merck), (Merck) Pimozide* (Orap®, Gate) Delavirdine (Rescriptor®, Agouron)

Midazolam* (Versed®, Roche), triazolam* (Halcion®, Pfizer)

* These drugs are contraindicated with the coadministration of fosamprenavir. HMG-CoA = 3-hydroxyl-3-methylglutaryl-coenzyme A. Data from Lexiva™ package insert, GlaxoSmithKline.7

DOSAGE AND ADMINISTRATION

As a calcium phosphate ester prodrug of amprenavir, fosamprenavir is highly water-soluble. Each 700-mg fosampren-avir tablet is equivalent to 600 mg of amprenavir. Compared with amprenavir capsules, two 700-mg fosamprenavir tablets contain the same amount of amprenavir as eight 150-mg capsules. Fosamprenavir should be taken orally with or without food and in combination with ritonavir. Some of the advantages of fosamprenavir over amprenavir include a decreased pill burden and a flexible dosing regimen, both of which help to improve compliance.

Recommended doses of fosampren-avir, which are based on the patient’s previous use of PIs, are as follows:
• For therapy-naive patients:
• fosamprenavir 1,400 mg twice a day (without ritonavir)
• fosamprenavir 1,400 mg once a day plus ritonavir 200 mg once a day
• fosamprenavir 700 mg twice a day plus twice a day
• For PI-experienced patients:
• fosamprenavir 700 mg twice a day
plus ritonavir 100 mg twice a day 9 not recommended for PI-experienced patients: once-daily fosam-prenavir/ritonavir
• Fosamprenavir/ritonavir in combination with efavirenz: • When efavirenz (Sustiva®, Bristol-Myers Squibb) is administered with this combination once daily, an additional 100 mg/day (300 mg total) of ritonavir is recommended.

In patients with mild or moderate hepatic impairment, a reduced dose of fosamprenavir 700 mg twice daily is recommended if they are not receiving concurrent ritonavir. The use of doses below 700 mg is not recommended; therefore, patients with severe hepatic impairment should not use fosampren-avir. Currently, no data are available on the use of fosamprenavir/ritonavir in patients with any degree of hepatic impairment.

COST

A projected monthly cost of fosamprenavir 1,400 mg twice daily is approximately $960. Table 4 presents a comparison of the estimated monthly cost of fosamprenavir with typical daily doses of other currently available PIs.

Table 4 Overview of Protease Inhibitors

Name

Usual Unboosted Adult Daily Dosing

Food Requirement

Monthly Cost

Amprenavir

(Agenerase®, GlaxoSmithKline)

1,200 mg b.i.d. (16 caps/day)

Yes/No

$706.12

Atazanavir

(Reyataz™, Bristol-Myers Squibb)

400 mg q.d.(2 caps/day)

Yes

$808.20

Fosamprenavir

(Lexiva™, GlaxoSmithKline)

1,400 mg b.i.d. (4 tabs/day)

Yes/No

$960.00

Indinavir

(Crixivan®, Merck)

800 mg every 8 hours (6 caps/day)

Yes (one hour before or two hours after meals; no effect when taken with ritonavir)

$546.38

Lopinavir/ritonavir (Kaletra®, Abbott)

400/100 mg b.i.d. (6 caps/day)

Yes

$703.50

Nelfinavir

(Agouron)

750 mg t.i.d. (9 tabs/day) or1,250 mg b.i.d. (4 tabs/day)

Yes

$756.66

Ritonavir ((Norvir®, Abbott)

600 mg b.i.d.(12 caps/day)

Yes

$771.54

Saquinavir soft-gelatin (Fortovase®, Roche)

1,200 mg t.i.d. (18 caps/day)

Yes (unless taken with ritonavir)

$720.96

Saquinavir hard-gelatin (Invirase®, Roche)*

600 mg t.i.d.(9 caps/day)

No (no food effect when taken with ritonavir)

$699.30

* This drug should not be prescribed without ritonavir boosting. Price does not include ritonavir. b.i.d. = twice a day; q.d. = once a day; t.i.d. = three times a day.Data from Lexiva™ package insert;7 Bartlett G, Gallant JE. 2003 Medical Management ofHIV Infections. Johns Hopkins;14 Reyataz™ package insert, Bristol-Myers Squibb;15 and Korner E, et al. P&T 2003;28(8)532-542.16

SUMMARY

The advent of HAART has significantly improved the management of patients with HIV-1 infection. Fosamprenavir is a new alternative and offers some advantages over other agents in its class. The dosing flexibility and decreased pill burden associated with its use are clearly advantageous, compared with its predecessor, amprenavir capsules. On the basis of its ADEs and drug-drug interaction profiles, fosamprenavir is comparable to the other PIs currently available.

Preliminary data suggest that the combination of fosamprenavir and riton-avir is equivalent to lopinavir/ritonavir and that the use of fosamprenavir in both HAART-naive and HAART-experienced patients has successfully resulted in reduced HIV-1/RNA levels. Future clinical trials will provide more evidence on the exact role of fosamprenavir therapy in the management of HIV-1 infection.