Bictegravir

Uses

Bictegravir is an integrase inhibitor used to treat HIV infections.

Bictegravir is indicated in the management of HIV-1 infection in patients not previously treated with antiretroviral therapy. Additionally, Bictegravir is indicated in the management of HIV-1 infection in patients who are virologically suppressed (HIV-1 RNA 3,4.

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.

This is used for the treatment of:

• Chronic hepatitis B virus infection in adults
• HIV infected adults in combination with other anti retroviral agents

Bictegravir is also used to associated treatment for these conditions: Stable antiretroviral regimen, less than 50 HIV-1 RNA copies HIV-1, Untreated with antiretrovirals HIV-1HIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Human Immunodeficiency Virus Type 1 (HIV-1), Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Bictegravir works

This single dose medication inhibits the strand transfer of viral DNA into the human genome, preventing HIV-1 virus replication and propagation .

In vitro, bictegravir has shown powerful antiviral activity against HIV-2 and various subtypes of HIV-1. It has shown synergistic effects when combined with other ARVs, including tenofovir alafenamide (TAF), emtricitabine (FTC), and darunavir (DRV) . The three components of the first USA approved medication ( trade name: Biktarvy ) are as follows:

Bictegravir: integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme necessary for viral replication. Inhibition of the integrase enzyme prevents the integration of HIV-1 into host DNA, blocking the conversion of the HIV-1 provirus and progression of the virus .

Emtricitabine: FTC, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine is phosphorylated to form emtricitabine 5'-triphosphate intracellularly. This metabolite inhibits the activity of human immunodeficiency virus (HIV) reverse transcriptase by competing with the substrate deoxycytidine 5'-triphosphate and by incorporating itself into viral DNA preventing DNA chain elongation .

Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine monophosphate analog). Plasma exposure to TAF leads to leakage into cells and then TAF is intracellularly converted to tenofovir by hydrolysis by cathepsin. Tenofovir is subsequently phosphorylated by cellular kinases to the metabolite tenofovir diphosphate, which is the active form of the drug. Tenofovir diphosphate inhibits HIV-1 replication by incorporating into viral DNA by the HIV reverse transcriptase, resulting in DNA chain-termination. Tenofovir diphosphate also weakly inhibits mammalian DNA polymerases .

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.

Once tenofovir is activated by a bi-phosphorylation it acts as an antiviral acyclic nucleoside phosphonate. It is a potent inhibitor of the viral reverse transcriptase with an inhibitory constant of approximately 0.022 micromolar.

Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase causing chain termination and the inhibition of viral synthesis. All these activities are attained by its competition with deoxyadenosine 5'-triphosphate in the generation of new viral DNA. Once tenofovir is incorporated in the chain, it induces a chain termination which in order inhibits viral replication. The safety of tenofovir relies on its low affinity towards the cellular DNA polymerase including the mitochondrial DNA polymerase gamma.

Dosage

Bictegravir dosage

The recommended dose of Tenofovir in chronic hepatitis B virus infection in adults 18 years of age and older with adequate renal function is 300 mg once daily with or without food.

Side Effects

The most common side effects are nausea, vomiting, diarrhea and flatulence.

Toxicity

Those with renal disease and creatinine clearance of Label. Patients with hepatic disease should not take bictegravir.

Most common adverse reactions include diarrhea, nausea, and headache .

Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms/laboratory findings suggesting lactic acidosis or hepatotoxicity.

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.

There haven't been reports regarding the LD50 of the parent compound nor the effects of an overdose. However, based on the reports with the derivative that most rapidly transforms into tenofovir, tenofovir disoproxil, it is recommended to monitor overdose patients. As well, it is widely known that tenofovir is efficiently removed by hemodialysis.

Administration of high doses of tenofovir has been reported to produce bone toxicity reported as osteomalacia and reduced bone mineral density and to produce some degree of renal toxicity.

To know more about the carcinogenicity and mutagenic potential of tenofovir, as well as the effect on fertility, please visit the drug entries for the derivatives tenofovir disoproxil and tenofovir alafenamide.

Precaution

Co-administration with other drugs: Tenofovir should not be administered concurrently with Emtricitabine & Tenofovir combination or Adefovir Dipivoxil.

Lactic Acidosis & Severe Hepatomegaly with Steatosis: Though the risk of occurrence of lactic acidosis is low for Tenofovir, treatment should be suspended in any patient who develops lactic acidosis or hepatotoxicity.

Exacerbation of hepatitis after discontinuation of treatment: Discontinuation of Tenofovirtherapy may be associated with severe acute exacerbation of hepatitis.

Interaction

Co-administration of Tenofovir with anti-retroviral, entecavir, lamivudine, methadone, oral contraceptives, ribavirin and tacrolimus did not result in significant drug interactions. The effects of co-administration of Tenofovir with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.

Volume of Distribution

0.2 L/Kg in humans

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

Accumulation of tenofovir in plasma is related to the presence of nephrotoxic effects. It is reported that tenofovir presents a volume of distribution of 0.813 L/kg.

Elimination Route

Bictegravir is rapidly absorbed within the body. Tmax= 2.0-4.0h

Emtricitabine reaches a C_max of 1.8±0.7µg/mL with a T_max 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 C_max by 29%.[L9019

Tenofovir as the active moiety presents a very low bioavailability when orally administered. Hence, the administration of this active agent is required to be under its two prodrug forms, tenofovir disoproxil and tenofovir alafenamide. This reduced absorption is suggested to be related to the presence of two negative charges among its structure. This negative charge limits its cellular penetration, and its passive diffusion across cellular membranes and intestinal mucosa hindering its availability for oral administration.

Intravenous tenofovir has been shown to produce a maximum plasma concentration of 2500 ng/ml with an AUC of 4800 ng.h/ml.

Half Life

1. 3h

The half life of emtricitabine is approximately 10 hours.

The reported half-life of tenofovir is of 32 hours.

Clearance

Bictegravir is mainly cleared by the kidneys. Those with renal clearance Label

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

The clearance of tenofovir is highly dependent on the patient renal stage and hence the clearance rate in patients with renal impairment is reported to be of 134 ml/min while in patients with normal function the clearance rate can be of 210 ml/min.

Elimination Route

BIC is mainly eliminated through UGT1A1 glucuronidation and CYP3A4 oxidation, equally . About 1% of the bictegravir dose is excreted in the urine, unchanged [1218,1219].

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 is eliminated in the urine by tubular secretion and glomerular filtration. The elimination of this compound is driven by the activity of the human organic anion transporters 1 and 3 and its secretion is mainly ruled by the activity of the multidrug resistance-associated protein 4.

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy category B. It should be used during pregnancy only if clearly needed.

Lactation: It is not known whether it is excreted in human milk. Mothers should be instructed not to breast feed if they are taking Tenofovir.

Contraindication

Tenofovir is contraindicated in patients with known hypersensitivity to Tenofovir or any component of the product.

Special Warning

Pediatric use: Safety and effectiveness of Tenofovir in pediatric patients below the age of 18 years have not been established.Geriatrics use: Clinical studies of Tenofovir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. But care should be taken in dose selection, and it may be useful to monitor renal function.Renal Impairment: Haemodialysis patients: 300 mg once every 7 days or after a cumulative total of 12 hr of dialysis.

• CrCl (10-29 mL/min): 300 mg 72-96 hrly.
• CrCl (30-49 mL/min): 300 mg 48 hrly.

Hepatic impairment

: No dose adjustment is required in patients with hepatic impairment.

Acute Overdose

There is no experience of Tenofovir overdose reported in patients

Storage Condition

Store in a cool and dry place, protected from light and moisture. Keep the medicine out of the reach of children.

Innovators Monograph

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