Lexiva Online, Description, Chemistry, Ingredients - Fosamprenavir Calcium

Lexiva Online, Description, Chemistry, Ingredients - Fosamprenavir Calcium

LEXIVA^®

LEXIVA (fosamprenavir calcium) is a prodrug of amprenavir, an inhibitor of human immunodeficiency virus (HIV) protease. The chemical name of fosamprenavir calcium is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3S)(1S,2R⁾ configuration. It has a molecular formula of C₂₅H₃₄CaN₃O₉PS and a molecular weight of 623.7. It has the following structural formula:

Fosamprenavir calcium is a white to cream-colored solid with a solubility of approximately 0.31 mg/mL in water at 25°C.

LEXIVA Tablets are available for oral administration in a strength of 700 mg of fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir). Each 700-mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone K30. The tablet film-coating contains the inactive ingredients hypromellose, iron oxide red, titanium dioxide, and triacetin.

Mechanism of Action: Fosamprenavir is rapidly converted to amprenavir by cellular phosphatases in vivo. Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.

Antiviral Activity in Vitro: Fosamprenavir has little or no antiviral activity in vitro. The in vitro antiviral activity observed with fosamprenavir is not measurable due to trace amounts of amprenavir. The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC₅₀) of amprenavir ranged from 0.012 to 0.08 μM in acutely infected cells and was 0.41 μM in chronically infected cells (1 μM = 0.50 mcg/mL). Amprenavir exhibited synergistic anti–HIV-1 activity in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, and zidovudine, and the protease inhibitor (PI) saquinavir, and additive anti–HIV-1 activity in combination with the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine and PIs indinavir, lopinavir, nelfinavir, and ritonavir in vitro. These drug combinations have not been adequately studied in humans. The relationship between in vitro anti–HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.

Resistance: HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with fosamprenavir. Genotypic analysis of isolates from amprenavir-treated patients showed mutations in the HIV-1 protease gene resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as mutations in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated mutations have also been detected in HIV-1 isolates from antiretroviral-naive patients treated with LEXIVA. Of the 488 antiretroviral-naive patients treated with LEXIVA or LEXIVA/ritonavir, 61 patients (29 receiving LEXIVA and 32 receiving LEXIVA/ritonavir) with virological failure (plasma HIV-1 RNA >1,000 copies/mL on 2 occasions on or after Week 12) were genotyped. Five of the 29 antiretroviral-naive patients (17%) receiving LEXIVA without ritonavir had evidence of genotypic resistance to amprenavir: I54L/M (n = 2), I54L + L33F (n = 1), V32I + I47V (n = 1), and M46I + I47V (n = 1). No amprenavir-associated mutations were detected in antiretroviral-naive patients treated with LEXIVA/ritonavir.

Cross-Resistance: Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level <400 copies/mL) and PI-resistance mutations detected in baseline HIV-1 isolates from PI-experienced patients receiving LEXIVA/ritonavir twice daily (n = 88), or lopinavir/ritonavir twice daily (n = 85) in study APV30003 is shown in Table 1. The majority of subjects had previously received either one (47%) or 2 PIs (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily LEXIVA/ritonavir, 54% (55) had resistance to at least one PI, with 98% (54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (58) had resistance to at least one PI, with 97% (56) of those having resistance to nelfinavir.

The virologic response based upon baseline phenotype was assessed. Baseline isolates from PI-experienced patients responding to LEXIVA/ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild-type reference strain of 0.7 (range: 0.1 to 5.4, n = 62), and baseline isolates from individuals failing therapy had a median shift in susceptibility of 1.9 (range: 0.2 to 14, n = 29). Because this was a select patient population, these data do not constitute definitive clinical susceptibility break points. Additional data are needed to determine clinically relevant break points for LEXIVA.

Isolates from 15 of the 20 patients receiving twice-daily LEXIVA/ritonavir and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance-associated mutations were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V.