Fosamprenavir

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,400(SRC), determined from a structure estimation method(2), indicates that fosamprenavir is expected to have low mobility in soil(SRC). The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7 (3), indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from moist soil surfaces. Fosamprenavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-11 mm Hg(SRC), determined from a fragment constant method(4). No biodegradation data were available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,400(SRC), determined from a structure estimation method(2), indicates that fosamprenavir is expected to adsorb to suspended solids and sediment(SRC). The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7(3), indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from water surfaces and generally do not adsorb as strongly to organic carbon and clay than their neutral counterparts(4). According to a classification scheme(5), an estimated BCF of 9.4(SRC), from an estimated log Kow of 2.2(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(8). No biodegradation data were available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fosamprenavir, which has an estimated vapor pressure of 6.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase fosamprenavir may be removed from the air by wet and dry deposition(SRC). Fosamprenavir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for fosamprenavir can be estimated to be 1,400(SRC). According to a classification scheme(2), this estimated Koc value suggests that fosamprenavir is expected to have low mobility in soil. The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7(3), indicating that this compound will primarily be an anion under environmental conditions and anions generally do not adsorb as strongly to organic carbon and clay as their neutral counterparts(4).

An estimated BCF of 9.4 was calculated for fosamprenavir(SRC), using an estimated log Kow of 2.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7(1), indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from water or moist soil surfaces. Fosamprenavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-11 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Amprenavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in males of both species at the highest doses tested. Female mice and rats were not affected. These observations were made at systemic exposures equivalent to approximately 2 times (mice) and 4 times (rats) the human exposure (based on AUC 0-24 hr measurement) at the recommended dose...

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The effects of fosamprenavir on fertility and general reproductive performance were evaluated in male and female rats administered a dose 3 to 4 times higher than the maximum recommended human dose (MRHD). Fosamprenavir did not impair mating or fertility of male or female rats and did not affect the development and maturation of sperm from treated rats.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Embryo/fetal development studies were conducted in rats (dosed from day 6 to day 17 of gestation) and rabbits (dosed from day 7 to day 20 of gestation). Administration of fosamprenavir to pregnant rats and rabbits produced no major effects on embryo-fetal development; however, the incidence of abortion was increased in rabbits that were administered fosamprenavir. Systemic exposures (AUC 0-24 hr ) to amprenavir at these dosages were 0.8 (rabbits) to 2 (rats) times the exposures in humans following administration of the maximum recommended human dose (MRHD) of fosamprenavir alone or 0.3 (rabbits) to 0.7 (rats) times the exposures in humans following administration of the MRHD of fosamprenavir in combination with ritonavir. In contrast, administration of amprenavir was associated with abortions and an increased incidence of minor skeletal variations resulting from deficient ossification of the femur, humerus, and trochlea, in pregnant rabbits at the tested dose; approximately one twentieth the exposure seen at the recommended human dose.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The mating and fertility of the F1 generation born to female rats given fosamprenavir was not different from control animals; however, fosamprenavir did cause a reduction in both pup survival and body weights. Surviving F1 female rats showed an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights compared to control animals. Systemic exposure (AUC 0-24 hr ) to amprenavir in the F 0 pregnant rats was approximately 2 times higher than exposures in humans following administration of the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir.

/GENOTOXICITY/ Fosamprenavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays, including bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus and chromosome aberrations in human lymphocytes.

Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(1). Fosamprenavir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to fosamprenavir may occur through dermal contact with this compound at workplaces where fosamprenavir is produced or used. Exposure to the drug among the general population may be limited to those administered the Lexiva (an HIV drug) which contains fosamprenavir calcium as its active component. (SRC)

Fosamprenavir's production and use as the free acid of fosamprenavir calcium which is used in the treatment of AIDS may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.1 X10-11 mm Hg at 25 °C indicates fosamprenavir will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase fosamprenavir will be removed from the atmosphere by wet and dry deposition. Fosamprenavir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, fosamprenavir is expected to have low mobility based upon an estimated Koc of 1,400. The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7, indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from water or moist soil surfaces and generally do not adsorb as strongly to organic carbon and clay than their neutral counterparts. Fosamprenavir is not expected to volatilize from dry soil surfaces based upon its vapor pressure. If released into water, fosamprenavir is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Biodegradation data were not available. An estimated BCF of 9.4 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to fosamprenavir may occur through dermal contact with this compound at workplaces where fosamprenavir is produced or used. Exposure to the drug among the general population may be limited to those administered Lexiva (an HIV drug) which contains fosamprenavir calcium as its active component. (SRC)

WOU1621EEG

FOSAMPRENAVIR

Mechanisms of Action [MoA] - HIV Protease Inhibitors

Established Pharmacologic Class [EPC] - Protease Inhibitor

Fosamprenavir is a Protease Inhibitor. The mechanism of action of fosamprenavir is as a HIV Protease Inhibitor.

Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly.

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS.

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)...