Amprenavir: A new human immunodeficiency virus type 1 protease inhibitor

Objective: This paper reviews the pharmacologic properties and clinical use fulness of amprenavir, a new human immunodeficiency virus type 1 (HIV-1) pr otease inhibitor. Background: Amprenavir, the most recent HIV-1 protease inhibitor to receive marketing approval from the US Food and Drug Administration, is a potent c ompetitive inhibitor of HIV-1 protease and a relatively weak inhibitor of H IV-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 (T-max) in adults is b etween 1 and 2 hours, the area under the plasma concentration versus time c urve is roughly proportional to the dose, the half-life is similar to 8 hou rs, and the volume of distribution is similar to 430 L. The T-max in childr en 4 to 12 years of age is between 1.1 and 1.4 hours. The bioavailability o f the solution is 86% relative to the capsule formulation. It is metabolize d by the cytochrome P-450 isozyme CYP3A4 and to a lesser extent by CYP2D6 a nd CYP2C9. Methods: We searched MEDLINE(R) (1966 to January 2000), AIDSLINE(R) (1980 t o January 2000), International Pharmaceutical Abstracts (1970 to January 20 00), PharmaProjects (January 2000 version), and Web sites of major HIV/acqu ired immunodeficiency syndrome conferences for appropriate published refere nces (1996 to February 2000). Results: Data reported to date indicate that amprenavir is efficacious in t he treatment of HIV disease in patients with primary HIV infection, antiret roviral-naive patients, protease inhibitor-naive patients, protease inhibit or-experienced patients, and pediatric patients. Adverse effects were usual ly 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 potenti al risk. The dose should be reduced in patients with significant hepatic im pairment (Child-Pugh score, greater than or equal to 5). Amprenavir probabl y should not be administered with rifabutin, rifampin, astemizole, midazola m, triazolam, bepridil, dihydroergotamine, ergotamine, or cisapride. The re commended 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 recomm ended 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 ma ximum 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 a bsorption. Amprenavir may be administered with or without food, but a high- fat meal (>67 g fat) should be avoided. 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 amprenav ir appears to be important, since it provides an additional treatment optio n as a component of both initial and salvage combination therapies for pati ents with HIV.