HIV

Amprenavir promotes the specific interactions between the nuclear receptor pregnane X receptor (PXR) and the coactivators SRC-1 and PBP. Amprenavir is docked into the high-resolution crystal structure of human PXR in complex with SR12813. Amprenavir occupies all four subpockets, and its hydroxyl group forms a hydrogen bond with Ser247, which is located in the connection region of PXR, to help to position the drug in the optimal orientation inside the receptor. Amprenavir forms direct contacts with one residue on αAF of the PXR activation function-2 (AF-2) surface, Phe429, which may stabilize the active AF-2 conformation of the receptor and contribute to the agonist activity of amprenavir on PXR. Amprenavir induces the expression of bona fide PXR target genes involved in phase I (CYP3A4), phase II (UGT1A1), and phase III (MDR1) metabolism in both HepaRG cells and LS180 cells.

Amprenavir increases atherogenic LDL cholesterol fractions in WT mice, but not in PXR−/− mice. Amprenavir stimulates expression of known PXR target genes, including CYP3A11, glutathione transferase A1, and MDR1a, in the intestine of WT mice but not in PXR−/− mice. Amprenavir-mediated PXR activation stimulates the expression of both LipF and LipA in the intestine of WT mice, but not in PXR−/− mice, indicating a possible role of intestinal PXR in mediating dietary lipid breakdown and absorption in mammals.

Amprenavir induced PXR target gene expression in both HepaRG hepatoma cells and LS180 intestinal cells.

Absorption, Distribution and Excretion
The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established. After administration of a single 1,400 mg dose in the fasted state, fosamprenavir oral suspension (50 mg/mL) and fosamprenavir tablets (700 mg) provided similar amprenavir exposures (AUC), however, the Cmax of amprenavir after administration of the suspension formulation was 14.5 % higher compared with the tablet.
Excretion of unchanged amprenavir in urine and feces is minimal. 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. Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system.
Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed. After administration of a single dose of fosamprenavir to HIV-1-infected patients, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established.
Administration of a single 1400 mg dose of fosamprenavir in the fed state compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax or AUC.
The following are areas under the curve (AUC) values of amprenavir based on the drug therapy regimen administered: Fosamprenavir 1400 mg twice per day: 27.6 to 39.2 ug/hr/mL (median 33 ug/hr/mL; Fosamprenavir 1400 mg once per day plus ritonavir 200 mg once per day: 59.7 to 80.8 ug/hr/mL (median 69.4 ug/hr/mL);Fosamprenavir 700 mg twice per day plus ritonavir 100 mg twice per day: 69 to 90.6 ug/hr/mL (median 79.2 ug/hr/mL). Fosamprenavir may be taken with or without food.
Peak plasma concentration (Cmax): The following Cmax values of amprenavir based on the drug therapy regimen administered: Fosamprenavir 1400 mg once per day plus ritonavir 200 mg once per day: 6.32 to 8.28 ug/mL (median 7.24 ug/mL); Fosamprenavir 1400 mg twice per day: 4.06 to 5.72 ug/mL (median 4.82 ug/mL); Fosamprenavir 700 mg twice per day plus ritonavir 100 mg twice per day: 5.38 to 6.86 ug/mL (median 6.08 ug/mL)...
For more Absorption, Distribution and Excretion (Complete) data for FOSAMPRENAVIR (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
In the gut epithelium during absorption, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system.
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 and 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.

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Biological Half-Life
The plasma elimination half-life of amprenavir (the active metabolite) is approximately 7.7 hours.
The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of fosamprenavir during breastfeeding. Fosamprenavir is not recommended during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Very high (approximately 90%); primarily bound to alpha 1 -acid glycoprotein. Higher amounts of unbound amprenavir present as amprenavir serum concentrations increase.

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Interactions
Amprenavir inhibits and induces cytochrome P-450 (CYP) isoenzyme 3A4; potential pharmacokinetic interactions (altered metabolism of the other drug). Caution is advised if fosamprenavir is used concomitantly with substrates, inhibitors, or inducers of CYP3A4. Concomitant use with drugs with a narrow therapeutic index that are CYP3A4 substrates is not recommended. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, or CYP2E1.
Pharmacokinetic interaction with antacids (decreased amprenavir peak concentrations and AUC). ... This pharmacokinetic interaction is not clinically important and there are no restrictions for concomitant use of fosamprenavir and antacids.
Pharmacokinetic interaction following concomitant use of ritonavir-boosted fosamprenavir with flecainide or propafenone (increased plasma concentrations of the antiarrhythmic agent). Potential for serious and/or life-threatening adverse effects (eg, cardiac arrhythmias). Concomitant use of ritonavir-boosted fosamprenavir with flecainide or propafenone is contraindicated.
Pharmacokinetic interaction with amiodarone, bepridil (no longer commercially available in US), systemic lidocaine, or quinidine (increased concentrations of the antiarrhythmic). Potential for serious and/or life-threatening adverse effects. Use concomitantly with caution and, if possible, monitor plasma concentrations of the antiarrhythmic agents.
For more Interactions (Complete) data for FOSAMPRENAVIR (37 total), please visit the HSDB record page.

[1]. Mol Pharmacol.2013 Jun;83(6):1190-9.

[2]. J Clin Pharmacol. 2002 Aug;42(8):887-98.

Fosamprenavir is a sulfonamide with a structure based on that of sulfanilamide substituted on the sulfonamide nitrogen by a (2R,3S)-4-phenyl-2-(phosphonooxy)-3-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}amino)butyl group. It is a pro-drug of the HIV protease inhibitor and antiretroviral drug amprenavir. It has a role as a prodrug. It is functionally related to a sulfanilamide.
Fosamprenavir is a prodrug of amprenavir, an inhibitor of human immunodeficiency virus (HIV) protease.
Fosamprenavir is a Protease Inhibitor. The mechanism of action of fosamprenavir is as a HIV Protease Inhibitor.
Fosamprenavir is a prodrug form of amprenavir. In the body fosamprenavir is metabolized to amprenavir, a synthetic derivative of hydroxyethylamine sulfonamide that selectively binds to and inhibits human immunodeficiency virus (HIV) protease.
See also: Fosamprenavir Calcium (annotation moved to).

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Drug Indication
Indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission. The use of fosamprenavir is pending revision due to a potential association between the drug and myocardial infarction and dyslipidemia in HIV infected adults.
FDA Label

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Mechanism of Action
Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. During HIV replication, HIV protease cleaves viral polypeptide products of the Gag and Gag-Pol genes to form structural proteins of the virion core and essential viral enzymes. Amprenavir interferes with this process by binding to the active site of HIV-1 protease, thereby preventing the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.
Fosamprenavir is a prodrug of amprenavir, an inhibitor of HIV protease. ...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 noninfectious viral particles.

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Therapeutic Uses
Fosamprenavir is indicated in combination with other antiretroviral agents for the treatment of HIV infections in adults. /Included in US product labeling/

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Drug Warnings
Rash (usually maculopapular and of mild or moderate intensity, with or without pruritus) has been reported in about 19% of patients receiving fosamprenavir in clinical studies; manifestations occurred approximately 11 days after initiation of fosamprenavir and persisted for a median of 13 days. Severe or life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of patients receiving fosamprenavir in clinical studies.
Fosamprenavir contains a sulfonamide moiety, which may cause allergic-type reactions (e.g., rash) in certain susceptible individuals. The potential for cross-sensitivity between drugs with sulfonamide moieties and fosamprenavir is unknown. Use fosamprenavir with caution in patients with known hypersensitivity to sulfonamide-containing drugs.
Patients with chronic hepatitis B or C virus infection and those with marked increases in AST or ALT concentrations prior to fosamprenavir therapy may be at increased risk for further elevations in hepatic enzyme concentrations. Liver function tests should be performed prior to initiating therapy with fosamprenavir, and patients should be monitored closely during treatment. ... Increases in serum AST (SGOT) and/or ALT (SGPT) concentrations (more than 5 times the upper limit of normal) have been reported in approximately 4-8% of patients receiving fosamprenavir in clinical studies.
Possible amprenavir resistance. The possible effect of fosamprenavir therapy on subsequent therapy with other HIV protease inhibitors in unknown.
For more Drug Warnings (Complete) data for FOSAMPRENAVIR (14 total), please visit the HSDB record page.

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Pharmacodynamics
Fosamprenavir is hydrolyzed by cellular phosphatases to the antiretroviral protease inhibitor amprenavir. This hydrolysis allows for the slow release of amprenavir, reducing the number of pills a patient must take.

C25H36N3O9PS

585.61

585.19

226700-79-4

Fosamprenavir Calcium Salt;226700-81-8;Fosamprenavir-d4;1133702-41-6

131536

Light yellow to yellow solid powder

1.4±0.1 g/cm3

1.612

3.36

4

11

14

39

912

3

CC(C)CN(C[C@H]([C@H](CC1=CC=CC=C1)NC(=O)O[C@H]2CCOC2)OP(=O)(O)O)S(=O)(=O)C3=CC=C(C=C3)N

MLBVMOWEQCZNCC-OEMFJLHTSA-N

InChI=1S/C25H36N3O9PS/c1-18(2)15-28(39(33,34)22-10-8-20(26)9-11-22)16-24(37-38(30,31)32)23(14-19-6-4-3-5-7-19)27-25(29)36-21-12-13-35-17-21/h3-11,18,21,23-24H,12-17,26H2,1-2H3,(H,27,29)(H2,30,31,32)/t21-,23-,24+/m0/s1

[(2R,3S)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3S)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~170.76 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (4.27 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)