エムトリシタビン

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Anti infectives for systemic use -> Antivirals for systemic use

log Kow = -0.43

-1.4

White to off white powder

White solid from ether and methanol

About 1.12X10+6 mg/L in water at 25 °C

2.00e+00 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Reverse Transcriptase Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

136-138

136-140 °C

136 - 140 °C

2.65

pKa = 2.65 (amine)

This chemical does not meet GHS hazard criteria for 100% (6 of 6) of all reports.

Not Classified

Aggregated GHS information provided per 6 reports by companies from 1 notifications to the ECHA C&L Inventory.

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.

Bang LM, Scott LJ; Emtricitabine: An Antiretroviral Agent for HIV Infection; Drugs 63 (22): 2413-24 (2003)

Zapor MJ et al; Antiretrovirals, Part II: Focus on Non-protease Inhibitor Antiretrovirals (NRTIs, NNRTIs, and Fusion Inhibitors); Psychosomatics 45 (6): 524-35 (2004)

Mjodrzejewski KA, Herman RA; Emtricitabine: A Once-Daily Nucleoside Reverse Transcriptase Inhibitor; Ann Pharmacother 38 (6): 1006-14 (2004)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

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.

J05AF09

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

Emtricitabine is a cytidine analog that competes with the natural substrate of HIV-1 reverse transcriptase to be incorporated into newly formed DNA, terminating its transcription. It is administered once daily so it has a long duration of action. Patients should be counselled regarding the risk of lactic acidosis and hepatomegaly with steatosis.

Emtricitabine is a cytidine analog which, when phosphorylated to emtricitabine 5'-triphosphate, competes with deoxycytidine 5'-triphosphate for HIV-1 reverse transcriptase. As HIV-1 reverse transcriptase incorporates emtricitabine into forming DNA strands, new nucleotides are unable to be incorporated, leading to viral DNA chain termination. Inhibition of reverse transcriptase prevents transcription of viral RNA into DNA, therefore the virus is unable to incorporate its DNA into host DNA and replicate using host cell machinery. This reduces viral load.

Emtricitabine, a synthetic nucleoside analog of cytosine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon and mitochondrial DNA polymerase gamma.

The half life of emtricitabine is approximately 10 hours.

The plasma emtricitabine half-life is approximately 10 hours.

Emtricitabine is approximately 86% unmetabolized. Approximately 9% of a dose is metabolized to 3'-sulfoxide diastereomers, 4% to the 2'-O-glucuronide, and a minor amount is converted to 5-fluorocytosine.

The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). No other metabolites were identifiable. Emtricitabine is not metabolized by liver enzymes.

G70B4ETF4S

EMTRICITABINE

Established Pharmacologic Class [EPC] - Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor

Chemical Structure [CS] - Nucleosides

Mechanisms of Action [MoA] - Nucleoside Reverse Transcriptase Inhibitors

Emtricitabine is a Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor. The mechanism of action of emtricitabine is as a Nucleoside Reverse Transcriptase Inhibitor.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template.

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.

Emtricitabine reaches a Cmax of 1.8±0.7µg/mL with a Tmax of 1-2 hours, and has an AUC of 10±3.1µg\*hr/mL. The bioavailability of emtricitabine capsules is 93% and the bioavailability of the oral solution is 75%. Taking emtricitabine with food decreases the Cmax by 29%.[L9019

Emtricitabine is 86% recovered in the urine and 14% recovered in feces. 13% of the dose is recovered in the urine as metabolites; 9% as 3'-sulfoxide diastereomers and 4% as 2'-O-glucuronide.

The apparent central volume of distribution is 42.3L and the peripheral volume of distribution is 55.4L.

Emtricitabine has an apparent elimination rate of 15.1L/h. This rate is closely linked to creatinine clearance.

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1 to 2 hours post-dose. Following multiple dose oral administration of emtriva to 20 HIV-infected subjects, the (mean + or - SD) steady state plasma emtricitabine peak concentration (Cmax) was 1.8 + or 0.7 ug/mL and the area under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 + or - 3.1 hr/ug/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 ug/mL. The mean absolute bioavailability of emtriva was 93%.

In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02 to 200 ug/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was approximately 1.0 and the mean semen to plasma drug concentration ratio was approximately 4.0.

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]