elvitegravir/cobicistat/emtricitabine/tenofovir DF

Action and Spectrum

Actions and Spectrum: 

elvitegravir: 

Action: elvitegravir is an integrase strand transfer inhibitor (INSTI). It inhibits the activity of the viral integrase enzyme, which is responsible for integrating the viral DNA into the host cell DNA. By inhibiting this enzyme, elvitegravir prevents the replication of HIV-1. 

Spectrum: elvitegravir specifically targets the HIV-1 virus. 

cobicistat: 

Action: cobicistat is a pharmacokinetic enhancer or booster.  

Spectrum: cobicistat does not have antiviral activity on its own but enhances the effects of other antiretroviral drugs, such as elvitegravir. 

emtricitabine: 

Action: emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI). It inhibits the activity of the reverse transcriptase enzyme, which is essential for the replication of HIV-1. By blocking this enzyme, emtricitabine prevents the conversion of viral RNA into DNA, thereby inhibiting viral replication. 

Spectrum: emtricitabine targets the HIV-1 virus. 

tenofovir DF (disoproxil fumarate) 

Action: tenofovir DF is also a nucleoside reverse transcriptase inhibitor (NRTI) like emtricitabine. It works by inhibiting the reverse transcriptase enzyme and interfering with the replication of HIV-1.  

Spectrum: tenofovir DF targets the HIV-1 virus. 

Drug Interaction

Adverse Reaction

Frequency defined  

>10% 

Diarrhea (12%) 

Nausea (16%) 

Proteinuria (39%) 

1-10% 

Hematuria (3%) 

Creatine kinase increased ≥10 x ULN (5%) 

Serum lipids increased (4%) 

Insomnia (3%) 

Abnormal dreams (9%) 

Serum creatinine increased (7%) 

Fatigue (5%) 

Dizziness (3%) 

Rash (3%) 

Headache (7%) 

Black Box Warning

Black Box Warning:  

Post treatment acute exacerbation of hepatitis B 

Contraindication / Caution

Contraindication/Caution:  

Concomitant use of medications that rely heavily on CYP3A for metabolism and elimination, and are known to cause significant and potentially life-threatening effects when their plasma levels rise 

• triazolam, orally administered midazolam 
• St. John’s wort (Hypericum perforatum) 
• dihydroergotamine, ergotamine, methylergonovine 
• sildenafil when administered for pulmonary arterial hypertension 
• lurasidone, pimozide 
• carbamazepine, phenobarbital, phenytoin 
• lomitapide, lovastatin, simvastatin 
• rifampin 
• alfuzosin 
• cisapride 

Cautions: 

• Lactic acidosis and severe hepatomegaly accompanied by steatosis have been documented. 
• It is recommended to conduct tests on HIV-1 patients to detect chronic hepatitis B (HBV) before commencing antiretroviral therapy. 
• Fat redistribution and accumulation have been observed in association with antiretroviral therapy. 
• Instances of immune reconstitution syndrome have been reported, which may include the development of autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barre syndrome) with varying timeframes of onset. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned 

Lactation: Excreted into human milk: Yes (emtricitabine) Unknown (cobicistat, elvitegravir, tenofovir alafenamide) 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.   

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category  

Pharmacology

Pharmacology:  

elvitegravir/cobicistat/emtricitabine/tenofovir DF is a fixed-dose combination medication used to treat human immunodeficiency virus type 1 (HIV-1) infection in adults. 

Pharmacodynamics:  

elvitegravir is an integrase inhibitor that targets the catalytic activity of HIV-1 integrase, an enzyme essential for viral replication. It acts by inhibiting strand transfer. Additionally, elvitegravir is metabolized by the enzyme CYP3A4. 

cobicistat, on the other hand, is a CYP3A4 inhibitor that functions as a mechanism-based pharmacoenhancer. It was specifically developed and submitted as a pharmacokinetic booster for elvitegravir.

cobicistat enhances the systemic exposure of CYP3A substrates, including elvitegravir, mainly when their bioavailability is limited and their half-life is shortened due to CYP3A-dependent metabolism. 

emtricitabine is a synthetic nucleoside analog of cytidine. Cellular enzymes phosphorylate it to form emtricitabine 5′-triphosphate, an active compound. It exerts its antiviral effect by inhibiting the activity of HIV-1 reverse transcriptase. emtricitabine competes with the natural substrate deoxycytidine 5′-triphosphate and gets incorporated into the growing viral DNA chain, leading to chain termination. 

tenofovir is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. tenofovir disoproxil fumarate, its prodrug form, undergoes diester hydrolysis to convert to tenofovir. Subsequent phosphorylation by cellular enzymes results in the formation of tenofovir diphosphate.  

Pharmacokinetics: 

Absorption 

elvitegravir 

The Peak Plasma Time of the drug is 4 hours whereas the Peak Plasma Concentration is 1.7 mcg/mL. The Trough Plasma Concentration is 0.45 mcg/mL. 

cobicistat 

The Peak Plasma Time of the drug is 3 hours whereas Peak Plasma Concentration is 1.1 mcg/mL. The Trough Plasma Concentration is 0.05 mcg/mL. 

emtricitabine 

The Peak Plasma Time of the drug is 3 hours whereas the Peak Plasma Concentration is 1.9 mcg/mL. The Trough Plasma Concentration is 0.14 mcg/mL. 

tenofovir 

The Peak Plasma Time of the drug is 1 hours with fasting and 2 hours with food whereas thePeak  Plasma Concentration is  0.45 mcg/mL. The Trough Plasma Concentration is 0.1 mcg/mL. 

Distribution 

elvitegravir 

The Bound Protein is 98-99%. 

cobicistat 

The Bound Protein is 97-98%. 

emtricitabine 

The Bound Protein is <4%. 

tenofovir 

The Bound Protein is <0.7. 

The volume of distribution is 1.2-1.3 L/kg. 

Metabolism 

elvitegravir 

The drug is metabolized by CY3A4 and also undergoes glucuronidation via UGT1A1/3 enzymes. 

cobicistat 

The drug is metabolized by CYP3A4 and CYP2D6 (minor) CYP3A4 inhibitor. 

emtricitabine 

The drug is not significantly metabolized The drug metabolism occurs by the oxidation process. 

tenofovir 

The drug is not significantly metabolized 

converted intracellularly by hydrolysis to tenofovir, then phosphorylated to active tenofovir diphosphate. 

Excretion and Elimination 

elvitegravir 

The half-life of the drug is 12.9 hours. 

The drug was excreted in 94.8% feces and 6.7% urine. 

cobicistat 

The half-life of the drug is 3.5 hours. 

The drug was excreted in 86.2% feces and 8.2% urine. 

emtricitabine 

The half-life of the drug is 10 hours. 

The drug is 30% removed by hemodialysis 

The drug excreted in the form of 86% urine and  14% feces. 

tenofovir 

The drug excretion is 70-80% in urine via filtration and active secretion, primarily as unchanged tenofovir. 

Adminstartion

Administration:  

The drug is administered orally in form of tablets in prescribed dosage. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: elvitegravir/cobicistat/emtricitabine/tenofovir DF  

Why do we use elvitegravir/cobicistat/emtricitabine/tenofovir DF?  

elvitegravir: It is an integrase strand transfer inhibitor (INSTI). drug works by blocking the integrase enzyme, which is essential for the replication of HIV.  

cobicistat: It is a pharmacokinetic enhancer or booster. drug does not have antiviral activity itself but is included in the combination to increase the effectiveness of elvitegravir. It works by inhibiting certain liver enzymes that metabolize elvitegravir, thus increasing the concentration and duration of its effectiveness in the body. 

emtricitabine: drug inhibits the activity of reverse transcriptase, an enzyme required for the replication of HIV. By blocking this enzyme, emtricitabine helps to reduce viral replication and slows down the progression of the HIV infection. 

tenofovir disoproxil fumarate: It is also a nucleoside reverse transcriptase inhibitor (NRTI). tenofovir disoproxil fumarate is converted into its active form, tenofovir diphosphate, within the cells. tenofovir diphosphate inhibits the reverse transcriptase enzyme, preventing the conversion of viral RNA into DNA. This action helps to reduce viral replication and control the HIV infection.