Lexiva (Fosamprenavir Calcium) - Description and Clinical Pharmacology

DESCRIPTION

LEXIVA (fosamprenavir calcium) is a prodrug of amprenavir, an inhibitor of human immunodeficiency virus (HIV) protease. The chemical name of fosamprenavir calcium is (3 S)-tetrahydrofuran-3-yl (1 S,2 R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium is a single stereoisomer with the (3 S)(1 S,2 R) 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 ingre-dients hypromellose, iron oxide red, titanium dioxide, and triacetin.

MICROBIOLOGY

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 up on 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.

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults: Fosamprenavir is a prodrug, which is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed.

The pharmacokinetic properties of amprenavir after administration of LEXIVA with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-infected patients; no substantial differences in steady-state amprenavir concentrations were observed between the 2 populations.

Absorption and Bioavailability: After administration of a single dose of LEXIVA to HIV-1-infected patients, the time to peak amprenavir concentration (T_max) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of LEXIVA in humans has not been established.

The pharmacokinetic parameters of amprenavir after administration of LEXIVA (with and without concomitant ritonavir) are shown in Table 2.

The median plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1.

Effects of Food on Oral Absorption: LEXIVA Tablets may be taken with or without food (see DOSAGE AND ADMINISTRATION). Administration of a single 1,400-mg dose of LEXIVA in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared to the fasted state was associated with no significant changes in amprenavir C_max, T_max, or AUC_0-(infinity) .

Distribution: In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha₁-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of 1 to 10 mcg/mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

Metabolism: After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.

Elimination: Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of¹⁴ C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for >90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Special Populations: Hepatic Insufficiency: The pharmacokinetics of amprenavir after administration of LEXIVA have not been studied in patients with hepatic insufficiency.

The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE® Capsules to adult patients with impaired hepatic function using a single 600-mg oral dose. The AUC_0-(infinity) of amprenavir was significantly greater in patients with moderate cirrhosis (25.76 ± 14.68 mcg·hr/mL) compared with healthy volunteers (12.00 ± 4.38 mcg·hr/mL). The AUC_0-(infinity) and C_max were significantly greater in patients with severe cirrhosis (AUC_0-(infinity) : 38.66 ± 16.08 mcg·hr/mL; C_max: 9.43 ± 2.61 mcg/mL) compared with healthy volunteers (AUC_0-(infinity) : 12.00 ± 4.38 mcg·hr/mL; C_max: 4.90 ± 1.39 mcg/mL). Based on these data, patients with impaired hepatic function receiving LEXIVA without concurrent ritonavir may require dosage reduction. There are no data on the use of LEXIVA in combination with ritonavir in patients with any degree of hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency: The impact of renal impairment on amprenavir elimination in adult patients has not been studied. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir.

Pediatric Patients: The pharmacokinetics of amprenavir after administration of LEXIVA to pediatric patients are under investigation. There are insufficient data at this time to recommend a dose.

Geriatric Patients: The pharmacokinetics of amprenavir after administration of LEXIVA to patients over 65 years of age have not been studied.

Gender: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between males and females.

Race: The pharmacokinetics of amprenavir after administration of LEXIVA do not differ between blacks and non-blacks.

Drug Interactions: See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions.

Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT).

Drug interaction studies were performed with LEXIVA and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, C_max, and C_min values are summarized in Table 3 (effect of other drugs on amprenavir) and Table 5 (effect of LEXIVA on other drugs). In addition, since LEXIVA delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from studies with AGENERASE are provided in Tables 4 and 6. For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions.

Nucleoside Reverse Transcriptase Inhibitors: There was no clinically significant effect of amprenavir after administration of AGENERASE on abacavir in subjects receiving both agents based on historical data.

In a Phase III clinical trial (APV30003), plasma amprenavir trough concentrations were similar for subjects receiving tenofovir disoproxil fumarate in combination with LEXIVA and ritonavir as compared to subjects not receiving tenofovir.

HIV Protease Inhibitors: In a 3-arm, randomized, cross-over study involving healthy volunteers, amprenavir pharmacokinetics were compared after administration of LEXIVA 1,400 mg twice daily plus lopinavir/ritonavir 533 mg/133 mg twice daily for 2 weeks versus LEXIVA 700 mg twice daily plus ritonavir 100 mg twice daily for 2 weeks. Amprenavir concentrations were lower with the regimen containing lopinavir/ritonavir: C_max was 13% lower, AUC was 26% lower, and C_min was 42% lower. In the same study, lopinavir pharmacokinetics were compared after administration of LEXIVA 1,400 mg twice daily plus lopinavir/ritonavir 533 mg/133 mg twice daily for 2 weeks versus lopinavir/ritonavir 400 mg/100 mg twice daily for 2 weeks. Lopinavir concentrations were similar (less than 10% change in C_max, AUC, and C_min values) with these 2 regimens.

The effect of amprenavir after administration of AGENERASE Capsules on concentrations of other HIV protease inhibitors in subjects receiving both agents was evaluated using comparisons to historical data. Indinavir steady-state C_max, AUC, and C_min were decreased by 22%, 38%, and 27%, respectively, by concomitant amprenavir. Similar decreases in C_max and AUC were seen after the first dose. Saquinavir steady-state C_max, AUC, and C_min were increased 21%, decreased 19%, and decreased 48%, respectively, by concomitant amprenavir. Nelfinavir steady-state C_max, AUC, and C_min were increased by 12%, 15%, and 14%, respectively, by concomitant amprenavir.

Methadone: Coadministration of amprenavir and methadone can decrease plasma levels of methadone.

Coadministration of amprenavir and methadone as compared to a non-matched historical control group resulted in a 30%, 27%, and 25% decrease in serum amprenavir AUC, C_max, and C_min, respectively.