Lexiva Pharmacology, Pharmacokinetics, Studies, Metabolism - Fosamprenavir Calcium

Lexiva Pharmacology, Pharmacokinetics, Studies, Metabolism - Fosamprenavir Calcium

CLINICAL PHARMACOLOGY

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.

Figure 1. Mean (±SD) Steady-State Plasma Amprenavir Concentrations and Mean IC₅₀ Values Against HIV from Protease Inhibitor-Naive Patients (in the Absence of Human Serum)

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-∞.

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 of ¹⁴C-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.

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-∞ 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-∞ and C_max were significantly greater in patients with severe cirrhosis (AUC_0-∞: 38.66 ± 16.08 mcg· hr/mL; C_max: 9.43 ± 2.61 mcg/mL) compared with healthy volunteers (AUC_0-∞: 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.

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 Cmin, respectively.