Emtricitabine

Pharmacokinetic interactions with drugs metabolized by uridine diphosphate-glucuronosyltransferase are unlikely. Emtricitabine does not inhibit glucuronosyltransferase (uridine diphosphoglucuronosyltransferase, UDP-glucuronate B-d-glucuronosyltransferase (acceptor-unspecific)), an enzyme responsible for glucuronidation.

Pharmacokinetic interactions with drugs metabolized by hepatic microsomal enzymes are unlikely. In vitro studies indicate that emtricitabine does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.

At concentrations up to 14 fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5'-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

The potential for drug interactions with emtricitabine has been studied in combination with indinavir, stavudine, famciclovir, and tenovir disoproxil fumarate. There were no clinically significant drug interactions for any of these drugs.

There is little evidence for direct hepatotoxicity of emtricitabine and it has not been specifically implicated in cases of lactic acidosis with steatosis and hepatic failure. However, patients with chronic hepatitis B can experience a flare of the underlying hepatitis during emtricitabine therapy. These flares occur either at the start therapy (treatment flares), with the development of antiviral resistance (breakthrough flares), or when therapy is abruptly stopped (withdrawal flares). Treatment flares occur in 5% to 10% of patients, are usually transient and asymptomatic, and rarely require dose modification or discontinuation of therapy. In contrast, withdrawal flares occur in 15% to 30% of patients, but can be symptomatic and severe, in rare instances (~1%) leading to acute liver failure, death or requirement for emergency liver transplantation. Patients who develop emtricitabine resistance often have relapse of disease activity after the appearance of the mutant HBV strain and rise in HBV DNA levels; this relapse can initially be severe and associated with symptoms and jaundice.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 55(SRC), determined from a structure estimation method(2), indicates that emtricitabine is expected to have high mobility in soil(SRC). Volatilization of emtricitabine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.1X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Emtricitabine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 55(SRC), determined from a structure estimation method(2), indicates that emtricitabine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.1X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of -0.43(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Emtricitabine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), emtricitabine, which has an estimated vapor pressure of 1.7X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase emtricitabine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.6 hours(SRC), calculated from its rate constant of 1.3X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). The rate constant for the vapor-phase reaction of emtricitabine with ozone has been estimated as 7.0X10-19 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). This corresponds to an atmospheric half-life of about 16 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(4). Particulate-phase emtricitabine may be removed from the air by wet or dry deposition(SRC). Emtricitabine does not absorb UV light at wavelengths >290 nm(5) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

The adverse effects of emtricitabine are similar to those of other NRTIs. They may include headache, muscle weakness, arthralgia, fatigue, fever, abdominal pain, nausea, vomiting, diarrhea, depression, anxiety, insomnia, rhinitis, cough, and pharyngitis. More specifically, emtricitabine has been associated with skin discoloration. This dermatologic effect typically presents as hyperpigmentation of the palms and soles, occurring more frequently among African American patients. Less commonly, skin discoloration may also appear on the tongue, arms, lips, and nail beds. Emtricitabine has not been associated with any serious adverse events.

Emtricitabine is distributed into human milk in low concentrations.

EXPERIMENTAL: The aim was to evaluate emtricitabine (FTC) and tenofovir (TFV) neonatal ingestion through breast milk. Median TFV and FTC breast milk doses represented 0.03% and 2%, respectively, of the proposed oral infant doses. Neonatal simulated plasma concentrations were extremely low for TFV but between the half-maximal inhibitory concentration and the adult minimal expected concentration for FTC. The rare children who will acquire HIV despite TDF-FTC therapy will need to be monitored for viral resistance acquisition.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of November 15, 2013: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=143491-57-0]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of emtricitabine can be estimated to be 55(SRC). According to a classification scheme(2), this estimated Koc value suggests that emtricitabine is expected to have high mobility in soil.

/SIGNS AND SYMPTOMS/ Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs), including emtricitabine, in conjunction with other antiretroviral agents. Most reported cases have involved women; obesity and long-term therapy with a nucleoside analog also may be risk factors.

/SIGNS AND SYMPTOMS/ Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs), including emtricitabine, in conjunction with other antiretroviral agents. Most reported cases have involved women; obesity and long-term therapy with a nucleoside analog also may be risk factors.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Emtricitabine

Ambiguous-DILI-concern

2

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including emtricitabine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Antiviral Agents

Use (kg; approx.) in Germany (2009): >1000

Oral: Solution 10 mg/mL, Emtriva (Gilead).

Oral: Capsules: 200 mg Emtriva, (Gilead).

Trade name (emtricitabine): ETruvada (co-formulation tablet of emtricitabine and tenofovir disoproxyl fumarate) (Gilead Sciences Inc.)

Table: Emtricitabine Comination Preparations [Table#6925]