Research Initiative Treatment Action (RITA!); Vol 5, No. 3 July 1999
Paul Simmons, RN, ACRN
Amprenavir brand Agenerase (ah-GEN-er-ase) received accelerated approval from the U.S. Food and Drug Administration (FDA) on April 16, 1999, making it the sixteenth agent licensed for the treatment of HIV infection. The FDA based its approval on the results of two controlled surrogate marker studies of 24 weeks duration.
Vertex Pharmaceuticals discovered and initially developed amprenavir, but GlaxoWellcome acquired manufacturing and marketing rights to the drug and set its annual wholesale price at $6,132.
Background and indication. An inhibitor of HIV protease, amprenavir binds to the enzyme's active site, disrupting its normal function. The result is immature, non-infectious virions. Amprenavir is indicated, in combination with other antiretrovirals, for the treatment of HIV infection.
How supplied and description. Amprenavir is supplied in 50 mg and 150 mg capsules and as an oral solution of 15 mg/ml. The 150 mg soft gelatin capsules are large, cream white, oblong and imprinted in edible red ink with GX CC2 on one side. The solution is clear in appearance, yellow in color and grape bubblegum/peppermint in flavor. Since the bioavailability of the capsules differs from that of the solution, the two are not interchangeable on a milligram per milligram basis.
Storage. Both the capsules and solution should be stored at a room temperature of 68º to 77ºF.
Dose. The appropriate dose of amprenavir is 1200 mg—eight 150 mg capsules—twice daily by mouth.
Food restrictions. Amprenavir may be taken with or without food, although a meal high in fat decreases the drug's absorption and should be avoided.1 Patients taking amprenavir should not take supplemental vitamin E since the drug's vitamin E content exceeds the recommended daily allowance; however, the continued use of multivitamins is safe.2
Side effects. The side effects most frequently associated with amprenavir therapy are nausea, vomiting, diarrhea, rash and perioral paresthesia. Stevens-Johnson syndrome, a life-threatening skin reaction, may occur in one percent of treated patients. Amprenavir therapy should be discontinued for patients with Stevens-Johnson syndrome and for those with moderate rashes accompanied by systemic symptoms.3
Drug interactions. Amprenavir is metabolized in the liver by cytochrome P450 CYP34A enzymes. Amprenavir is an inhibitor of CYP34A metabolism and is contraindicated with certain other drugs metabolized by the same pathway. Amprenavir should not be concurrently administered with the following drugs:
Concentration monitoring is recommended whenever amprenavir is coadministered with any of the following agents:4
When administered concomitantly with amprenavir, the dose of rifabutin (Mycobutin) should be cut in half.
Interactions with other antiretrovirals. The interactions between amprenavir and nevirapine (Viramune) or amprenavir and delavirdine (Rescriptor) are not yet known. Data presented at the 5th Conference on Retroviruses indicate that the trough level of amprenavir may be reduced by 43% in the presence of efavirenz (Sustiva). If so, such a reduction is clinically significant and may warrant an increase in the amprenavir dose when the drug is coadministered with efavirenz.5
Until adequate data are available, clinicians may wish to avoid combining amprenavir with nevirapine, delavirdine or efavirenz, all of which are non-nucleoside reverse transcriptase inhibitors (NNRTIs).
In vitro, amprenavir exhibits synergistic activity against HIV when combined with abacavir (Ziagen), zidovudine (Retrovir) or didanosine (Videx).
The interactions between amprenavir and nelfinavir (Viracept) or amprenavir and indinavir (Crixivan) may be clinically significant and are the subject of ongoing study.6 Saquinavir (Fortovase) may reduce amprenavir area under the curve by 36%. Clinicians may wish to avoid combining amprenavir with these drugs until more data are available.
Because of potential problems with drug absorption, amprenavir should be taken at least one hour before or after an antacid or didanosine.
Resistance and cross-resistance. Clinical isolates recovered from patients failing amprenavir demonstrate mutations in the protease gene with the following amino acid substitutions: M46I/L, I47V, I50V, I54L/V and I84V. Additionally, mutations in the viral protease p1/p6 cleavage site have been identified.
This pattern of mutations is unique; it is rare even among subjects heavily experienced with other protease inhibitors (PIs), which suggests to some that amprenavir can be used as either a component of initial treatment or as part of second or third-line therapy. In study CNA2007, 101 heavily treated subjects were given a regimen of abacavir, efavirenz and amprenavir. Sixty percent of these patients had taken 3 or 4 PIs. After 16 weeks of treatment, only 1 in 4 participants had an unquantifiable viral load (less than 400 copies). Subjects naive to NNRTIs with a baseline viral load of less than 40,000 copies faired best, which suggests that amprenavir's anti-viral contribution to the regimen was modest.
Tissue distribution. Data presented at the 12th World AIDS Conference revealed that 8 of 9 PI naive subjects given an amprenavir-containing regimen reduced their viral load in cerebral spinal fluid to unquantifiable levels (less than 400 copies). Data presented at the 6th Conference on Retroviruses showed that 14 of 19 men given amprenavir monotherapy reduced their viral load in seminal plasma to unquantifiable levels. The clinical and epidemiological implications of these findings are unknown.
Clinical data in treatment naive patients. PROAB3001 is a double-blind, placebo-controlled study in which investigators randomized 232 patients to a regimen of amprenavir, zidovudine and lamivudine (Epivir) or to zidovudine and lamivudine alone, a two-drug combination known to produce inferior results. The participants were mostly white males who began study with a median CD4 cell count of 416 and a median viral load of 46,773 copies.
After 24 weeks of study, no difference in CD4 count between groups was observed; unsurprisingly, the proportion of patients in the amprenavir-containing arm who achieved viral loads below the level of quantification (400 copies) significantly outstripped that of patients in the weaker two-drug arm. Glaxo and Vertex hail these findings as significant, and the study remains in progress.7
Despite the advantage of comparison to a straw man competitor, amprenavir performed unimpressively in this study. At week 24, using the conservative intent-to-treat method of analysis, almost half (47%) of the subjects in the amprenavir-containing arm had withdrawn from study for toxicity or other reasons or failed virologically. Data on the percentage of amprenavir-treated subjects who achieved viral loads of less than 50 copies at week twenty-four, a predictor of durable treatment response, have not yet been reported. At week 16, 45% of the 116 participants in the three-drug arm had viral loads of less than 50.
Clinical data in treatment-experienced patients. PROA3006 is a randomized, open label study in which investigators assigned 504 patients to a regimen of amprenavir plus nucleoside reverse transcriptase inhibitors (RTIs) or indinavir plus RTIs. The patients, mostly white males, entered study with a median CD4 cell count of 399 and a median viral load of 8,511 copies. These patients were experienced with non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine), but naive to protease inhibitors.
After 24 weeks of therapy, 43% of subjects in the amprenavir-containing arm had achieved viral loads of less than 400 copies. Among patients in the indinavir-containing arm, 53% achieved the same result. (The amprenavir package insert does not disclose the statistical significance, if any, of the difference between the groups.)
Patient Assistance. For those who qualify, Glaxo offers a patient assistance program for amprenavir. For more information, call 800.513.3028.
Summary and analysis. The Antiviral Agents Bulletin describes amprenavir as "highly potent." But the potency of a drug can be contingent on the statistical method by which its performance is analyzed.
When analyzed by on treatment analysis, which counts just those patients who actually take their medication, amprenavir's antiviral performance—at least in the short-term—is comparable to that of other PIs. But an intent-to-treat analysis is less generous to the drug, and includes not only virologic failures but also patients who withdrew from amprenavir for side effects, pill burden or other reasons. By this method of analysis, almost half of the patients in the drug's pivotal study had withdrawn in as little as six months. In any event, amprenavir is yet another "me too" drug and its introduction to the HIV armamentarium is probably not a significant therapeutic advance.
Amprenavir is conveniently dosed twice daily without food effect, and it appears to be as relatively safe, effective and well-tolerated as any other drug in its class. Its unique chemical structure may make it less likely than other PIs to produce the so-called lipodystrophy syndrome, but this possibility awaits clinical confirmation.
Recommendation. The Center for AIDS recommends that The Panel on Clinical Practices for Treatment of HIV Infection classify amprenavir as a "preferred" therapy.
1 A high fat meal is defined as one containing 67 or more grams of fat.
2 Vertex Pharmaceuticals, personal communication.
3 Systemic symptoms include fever, chills and muscle and joint aches.
4 Agenerase package insert. As a practical matter, note that concentration monitoring is available only for warfarin.
5 When coadministering amprenavir 1200 mg twice daily and efavirenz 600 mg once daily, consider the addition of ritonavir (Norvir) 200 mg twice daily, or dose amprenavir at 1200 mg three times daily with standard dose efavirenz.
6 Vertex Pharmaceuticals, personal communication.
7 After 16 weeks of treatment, patients in the two-drug arm, their therapeutic options now constrained by a history of inferior therapy, were allowed to change to a standard of care regimen.
Accelerated approval: the abbreviated process under which the FDA grants conditional approval to a new drug.
Surrogate markers: a laboratory test, such as viral load, used to predict the future clinical condition of a patient.
Bioavailability: the amount of a drug that becomes available for activity in the target tissue.
Perioral paresthesia: a subjective sensation of numbness or tingling around the mouth.
In vitro: in the test tube.
Area under the curve: the amount of drug exposure over time.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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