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Amprenavir
See also HIV protease inhibitors
General information
The marketing authorization of amprenavir (Agenerase) was withdrawn for commercial reasons at the request of the marketing authorization holder in 2011. Since fosamprenavir is still marketed and is a prodrug for amprenavir, adverse reactions to amprenavir are still relevant.
Amprenavir is an HIV protease inhibitor with an enzyme inhibitory constant of 0.6 nmol/l, similar to the inhibitory constants of other protease inhibitors. Its in vitro IC50 against wild-type clinical HIV isolates is 115 ng/ml. It has a long half-life (7–10 hours). It can be given twice-daily without food restrictions and had high potency when given as monotherapy in dose-finding studies [ ]. The recommended doses are 1200 mg bd for adults and 20 mg/kg bd or 15 mg/kg tds for children under 13 years of age or adolescents under 50 kg. Capsules and solution do not have equal systemic availability, and the recommended dose for amprenavir oral solution is 1.5 ml/kg bd or 1.1 ml/kg tds. The systemic availability increases with increasing doses. Amprenavir is about 90% bound to alpha1 acid glycoprotein and 40% to albumin. It does not penetrate the brain well, because it is exported by P glycoprotein. It is mainly metabolized by CYP3A4 and its clearance is reduced in liver disease. The clinical pharmacology of amprenavir has been reviewed [ ].
The use of amprenavir has been limited to patients who are highly motivated, because of the high capsule burden (16/day).
Fosamprenavir is a prodrug of amprenavir with better systemic availability. In large clinical trials the most common adverse events in patients taking fosamprenavir, with or without ritonavir, plus abacavir and lamivudine were diarrhea, nausea, vomiting, abdominal pain, drug hypersensitivity, and skin rashes [ ].
General adverse effects and adverse reactions
The adverse effects of amprenavir in patients treated with combination therapy included nausea, vomiting, diarrhea, epigastric pain, flatulence, paresthesia, headache, rash, and fatigue [ ]. The contribution of a single drug to the observed adverse effects is difficult to establish. Amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir [ ]. Co-administration with rifampicin and rifabutin should be avoided. Those who take amprenavir have complained of diarrhea, nausea, headache, and fatigue [ ]. The frequency of diarrhea may be as high as 50%.
Drug studies
Observational studies
In a monotherapy trial (n = 37), adverse effects were frequent but generally mild, and included rash, diarrhea or loose stools, and headache. In general, these adverse effects tend to disappear or weaken in severity within the first 2–4 weeks of treatment.
In a study of the pharmacokinetics of oral amprenavir administered as soft gelatin capsules to 20 HIV-positive children, the most common adverse event was nausea [ ]. The kinetics supported twice daily dosing with 20 mg/kg.
Comparative studies
In 249 patients fosamprenavir 1400 mg bd (n = 166) was compared with nelfinavir 1250 mg bd (n = 83), each combined with abacavir and lamivudine, the most common adverse event was diarrhea in both groups, but significantly more often with nelfinavir [ ]. There was increased lipase activity in 8% of the patients who took fosamprenavir but it was without clinical significance. There were rashes in 7% of the patients who took fosamprenavir. In all 14 patients withdrew from the study because of adverse events (9/166 in the fosamprenavir group; 5/83 in the nelfinavir group). There was a slight increase in total cholesterol in both groups. There were increases in LDL cholesterol requiring medical intervention in 18% of the patients in both groups; the ratio of total:HDL cholesterol was only slightly affected.
Placebo-controlled studies
Rashes and gastrointestinal disturbances were the most frequently reported adverse effects in a randomized controlled trial of fosamprenavir + ritonavir in treatment-naive HIV-infected patients [ ].
Organs and systems
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