Emtricitabine and tenofovir alafenamide
Emtricitabine and tenofovir alafenamide Uses, Dosage, Side Effects, Food Interaction and all others data.
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) indicated for the treatment of HIV infection in adults or combined with tenofovir alafenamide for the prevention of HIV-1 infection in high risk adolescents and adults. Emtricitabine is a cytidine analogue. The drug works by inhibiting HIV reverse transcriptase, preventing transcription of HIV RNA to DNA.
Emtricitabine was granted FDA approval on 2 July 2003.
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.
Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Tenofovir alafenamide as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is then converted to tenofovir through hydrolysis primarily by carboxylesterase 1 (CES1) in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated by cellular kinases to the pharmacologically active metabolite tenofovir diphosphate.
Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination.Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication.
Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart tenofovir disoproxil. This improved safety profile seems to be related to a lower plasma concentration of tenofovir.
In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil.
| Trade Name | Emtricitabine and tenofovir alafenamide |
| Generic | Emtricitabine + tenofovir alafenamide |
| Type | Oral |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Emtricitabine is a nucleoside reverse transcriptase inhibitor used for the treatment and prophylaxis of HIV.
Emtricitabine is indicated in combination with other medications for the treatment of HIV-1 infections; treatment of HIV-1 infections in pediatric patients 25-35kg, treatment of HIV-1 infections in adult patients ≥35kg, for pre exposure prophylaxis of HIV-1 in adolescent and adult patients excluding those who have receptive vaginal sex; treatment of HIV-1 infections in pediatric and adult patients ≥17kg, pre exposure prophylaxis in adolescents and adults ≥35kg; treatment of HIV-1 in patients ≥12 years and ≥35kg; treatment of HIV-1 in patients weighing ≥35kg; treatment of HIV-1 in patients weighing ≥25kg; and treatment of HIV-1 in patients weighing ≥40kg.
Tenofovir Alafenamide is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is used for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.
Emtricitabine and tenofovir alafenamide is also used to associated treatment for these conditions: HIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Human Immunodeficiency Virus Type 1 (HIV-1), Human Immunodeficiency Virus Type 1 (HIV-1) InfectionHepatitis B Chronic Infection, Human Immunodeficiency Virus Type 1 (HIV-1), Human Immunodeficiency Virus Type 1 (HIV-1) Infection
How Emtricitabine and tenofovir alafenamide works
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.
Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil. This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate.
Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells.
Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis. To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir.
Dosage
Emtricitabine and tenofovir alafenamide dosage
Testing Prior To Initiation Of Tenofovir Alafenamide: Prior to initiation of Tenofovir Alafenamide, patients should be tested forHIV-1 infection. Tenofovir Alafenamide alone should not be used in patients with HIV infection
It is recommended that serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating Tenofovir Alafenamide and during therapy in all patients as clinically appropriate
Recommended Dosage In Adults: The recommended dosage of Tenofovir Alafenamide is 25 mg (one tablet) taken orally once daily with food
Side Effects
The following adverse reactions are discussed in other sections of the labeling:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Severe Acute Exacerbation of Hepatitis B
- New Onset or Worsening of Renal Impairment
The most common side effects are headache, stomach pain, tiredness, cough, nausea, back pain
Toxicity
The LD50 of emtricitabine is not readily available.[9019,L9818]
Symptoms of emtricitabine toxicity include hepatotoxicity with steatosis, as well as lactic acidosis. Treat overdose with symptomatic and supportive measures, including hemodialysis.
The LD50 of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%.
Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility.
Interaction
Tenofovir is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in Tenofovir absorption. Consult the full prescribing information prior to and during treatment for potential drug drug interactions.
Volume of Distribution
The apparent central volume of distribution is 42.3L and the peripheral volume of distribution is 55.4L.
In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L.
Elimination Route
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
As compared to the parent molecule, tenofovir, tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability.
Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation.
Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal exposure.
Half Life
The half life of emtricitabine is approximately 10 hours.
The reported half-life for tenofovir alafenamide is of 0.51 hours.
Clearance
Emtricitabine has an apparent elimination rate of 15.1L/h. This rate is closely linked to creatinine clearance.
The reported clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 L/h.
Elimination Route
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.
Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged tenofovir followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir.
Pregnancy & Breastfeeding use
Before you take Tenofovir Alafenamide, tell your healthcare provider about all of your medical conditions, including if you are pregnant or plan to become pregnant. It is not known if Tenofovir Alafenamide will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with Tenofovir Alafenamide.
Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.
Contraindication
None
Special Warning
Pediatric Use: Safety and effectiveness of Tenofovir Alafenamide in pediatric patients less than 18 years of age have not been established.
Geriatric Use: Clinical trials of Tenofovir Alafenamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Renal Impairment: No dosage adjustment of Tenofovir Alafenamide is required in patients with mild, moderate, or severe renal impairment. Tenofovir Alafenamide is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute)
Hepatic Impairment: No dosage adjustment of Tenofovir Alafenamide is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of Tenofovir Alafenamide in patients with decompensated cirrhosis (Child-Pugh B or C) have not been established; therefore Tenofovir Alafenamide is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment
Acute Overdose
If overdose occurs, monitor patient for evidence of toxicity. Treatment of overdosage with Tenofovir Alafenamide consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Tenofovir is efficiently removed by hemodialysiswith an extraction coefficient of approximately 54%
Storage Condition
Store below 86°F (30°C). Keep in its original container. Keep the container tightly closed.
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