After administration, fosamprenavir is rapidly hydrolyzed to amprenavir and inorganic phosphate by cellular phos-phatases as it is absorbed by the gut epithelium. Its pharmacology is similar to that of amprenavir. Amprenavir inhibits HIV-1 protease by binding to the enzyme’s active site. HIV-1 protease enzyme is required for the cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Thus, by inhibiting this enzyme, amprenavir prevents the processing of viral Gag and Gag-pol poly-protein precursors. The result is the formation of immature and noninfectious viral particles.
The pharmacokinetic properties of fosamprenavir have been evaluated in healthy adult volunteers and in HIV-infected patients (Table 1). Fosampren-avir undergoes rapid hydrolysis to amprenavir and inorganic phosphate before entering the systemic circulation. After oral administration of a single dose of fosamprenavir, the time to peak concentration (Tmax) of amprenavir occurs between 1.5 and four hours. The plasma elimination half-life (T1/2) is 7.7 hours.
Table 1 Pharmacokinetic Parameters of Fosamprenavir: Geometric Mean (95% Confidence Interval)
1,400 mg b.i.d.
|RTV 200 mg q.d.||100 mg b.i.d.|
|C (mcg/ml)max о >||
|(mcg • hour/ml)||
|C . (mcg/ml)mm о >||
Amprenavir is 90% protein-bound in vitro and is metabolized in the liver by cytochrome P450 3A4 (CYP3A4). Along with its glucuronide conjugates, ampren-avir is minimally eliminated in the urine and feces. Because less than 1% of the administered dose is eliminated unchanged, a dosage adjustment would be unnecessary in patients with renal insufficiency.
Wood et al. evaluated the pharmaco-kinetics of fosamprenavir and ampren-avir following repeated dosing in patients with HIV-1 infection. The study compared the amprenavir area-under-the-concentration time curve (AUC) during a dosing interval, the minimum concentration at the end of a dosing interval at steady state (Cminss), and the maximum concentration at steady state (Cmax,ss) with those of amprenavir in combination with GlaxoSmithKline’s abacavir. The authors concluded that both fosam-prenavir and amprenavir delivered equivalent plasma drug concentrations.
The pharmacokinetics of amprenavir has also been evaluated in patients with hepatic insufficiency. Unlike healthy adult volunteers, patients with moderate-to-severe hepatic impairments had AUC and Cmax amprenavir concentrations that were significantly higher: 12 ± 4.38 mcg • hour/ml; 4.90 ± 1.39 mcg • hour/ml versus 38.66 ± 16.08 mcg • hour/ml; 9.43 ± 2.61 mcg • hour/ml. Subsequently, dosages might need to be adjusted in this patient population.
No data are available on the use of boosted fosamprenavir in patients with any hepatic impairment.