TAFEBRA

Tenofovir alafenamide is a novel tenofovir prodrug developed in order to improve renal safety when compared to the counterpart tenofovir disoproxil.

Both of these prodrugs were first created to cover the polar phosphonic acid group on tenofovir by using a novel oxycarbonyloxymethyl linkers to improve the oral bioavailability and intestinal diffusion.

Tenofovir alafenamide is an alanine ester form characterized for presenting low systemic levels but high intracellular concentration.

It has been reported to produce a large antiviral efficacy at doses ten times lower than tenofovir disoproxil.

Tenofovir alafenamide is indicated to treat chronic hepatitis B, 9 treat HIV-1, 11, 12, 13, 14 and prevent HIV-1 infections. 11, 17 Tenofovir alafenamide was developed by Gilead Sciences Inc and granted FDA approval on 5 November 2015.

Tenofovir alafenamide is indicated for the treatment of hepatitis B virus infection in adults and pediatric patients 12 years of age and older with compensated liver disease.

In combination with emtricitabine and other antiretrovirals, it is indicated for the treatment of HIV-1 infection in adolescent and adult patients with a weight higher than 35 kg.

This combination is also indicated to prevent HIV-1 infections in high-risk adolescent and adult patients, excluding patients at risk from receptive vaginal sex. 11, 17 When combined with antiretrovirals other than protease inhibitors that require a CYP3A inhibitor, it can be used to treat pediatric patients weighing 25-35 kg.

In the with emtricitabine and bictegravir, tenofovir alafenamide is considered a complete treatment regimen for HIV-1 infections for treatment-naive patients or patients virologically suppressed for at least three months with no history of treatment failure. 12, 20, 19 This is also used to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known or suspected substitutions associated with resistance to bictegravir or tenofovir. 21, 22 Additionally, the including elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide and the including emtricitabine, rilpivirine and tenofovir alafenamide can be used in the treatment of HIV-1 infection in patients older than 12 years with no previous antiretroviral therapy history or who are virologically suppressed for at least 6 months with no history of treatment failure.

The including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for the treatment of HIV-1 infection in adults without prior antiretroviral therapy or in patients virologically suppressed for 6 months and no reported resistance to darunavir or tenofovir.

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.

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. 1, 5 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.

In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L.

To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound tenofovir by the activity of cathepsin A or carboxylesterase 1.

Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells.

After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid.

Hover over products below to view reaction partners Tenofovir alafenamide Tenofovir alanine Tenofovir Tenofovir Monophosphate Tenofovir Diphosphate.

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.

The reported half-life for tenofovir alafenamide is of 0.51 hours.

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.

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LD 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.

is contraindicated to be co-administered with: dofetilide due to the potential for increased dofetilide plasma concentrations and associated serious and/or life-threatening events. rifampin due to decreased BIC plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to BIKTARVY.

BIKTARVY is contraindicated to be co-administered with: dofetilide. rifampin.

Prior to or when initiating BIKTARVY test for hepatitis B virus infection.

Prior to or when initiating

BIKTARVY, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate.

In patients with chronic kidney disease, also assess serum phosphorus.

Recommended dosage in adults and pediatric patients weighing at least 25 kg: One tablet containing 50 mg BIC, 200 mg FTC, and 25 mg TAF taken once daily with or without food.

Recommended dosage in pediatric patients weighing at least 14 kg to less than 25 kg: One tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food.

Renal impairment

BIKTARVY is not recommended in patients with estimated creatinine clearance of to below 30 mL/min, or below 15 mL/min who are not receiving chronic hemodialysis, or below 15 mL/min who have no antiretroviral treatment history.

Hepatic impairment

BIKTARVY is not recommended in patients with severe hepatic impairment. 2.1 Testing When Initiating and During Treatment with BIKTARVY Prior to or when initiating BIKTARVY, test patients for hepatitis B virus infection.

BIKTARVY, and during treatment with BIKTARVY, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients as clinically appropriate.

In patients with chronic kidney disease, also assess serum phosphorus. 2.2 Recommended Dosage in Adults and Pediatric Patients Weighing at Least 25 kg BIKTARVY is a three-drug fixed dose containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF).

The recommended dosage of

BIKTARVY is one tablet containing 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF taken orally once daily with or without food in: adults and pediatric patients weighing at least 25 kg with an estimated creatinine clearance greater than or equal to 30 mL/min; or virologically-suppressed adults with an estimated creatinine clearance below 15 mL/min who are receiving chronic hemodialysis.

On days of hemodialysis, administer the daily dose of BIKTARVY after completion of hemodialysis treatment. 2.3 Recommended Dosage in Pediatric Patients Weighing at Least 14 kg to Less than 25 kg The recommended dosage of BIKTARVY is one tablet containing 30 mg of BIC, 120 mg of FTC, and 15 mg of TAF taken orally once daily with or without food in: pediatric patients weighing at least 14 kg to less than 25 kg with an estimated creatinine clearance greater than or equal to 30 mL/min.

For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes. 2.4 Not Recommended in Patients with Severe Renal Impairment BIKTARVY is not recommended in patients with: severe renal impairment (estimated creatinine clearance of to below 30 mL/min); or end stage renal disease (ESRD; estimated creatinine clearance below 15 mL/min who are not receiving chronic hemodialysis; or no antiretroviral treatment history and ESRD who are receiving chronic hemodialysis. 2.5 Not Recommended in Patients with Severe Hepatic Impairment BIKTARVY is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) .

50090-6247 NDC: 50090-6247-0 30 TABLET in a BOTTLE, PLASTIC.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BIKTARVY during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary There are insufficient human data on the use of BIKTARVY during pregnancy to inform a drug-associated risk of birth defects and miscarriage.

Dolutegravir, another integrase inhibitor, has been associated with neural tube defects (NTDs) .

Discuss the benefit-risk of using

BIKTARVY with individuals of childbearing potential, particularly if pregnancy is being planned.

BIKTARVY use during pregnancy has been evaluated in a limited number of women reported to the APR; consequently, there are insufficient BIC data from the APR to adequately assess the risk of major birth defects.

Reports of pregnant individuals treated with other drug products containing TAF or FTC contribute to APR's overall risk assessment for these components.

Available data from the

APR show no statistically significant difference in the overall risk of major birth defects for FTC or TAF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) .

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15–20%.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of BIKTARVY at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD) .

During organogenesis, systemic exposures (AUC) to BIC were approximately 36 (rats) and 0.6 times (rabbits), to FTC were approximately 60 (mice) and 108 times (rabbits), and to TAF were approximately 2 (rats) and 78 times (rabbits) the exposure at the RHD of BIKTARVY.

In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 30 times (BIC), 60 times (FTC), and 19 times (TDF) the exposures of each component in humans at the RHD.

Data Human Data Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of BIKTARVY are compared with a U.S. background major birth defect rate.

Methodological limitations of the APR include the use of MACDP as the external comparator group.

MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.

Bictegravir (BIC): Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy.

Data available to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to address this risk with BIC.

There are an insufficient number of reports to the APR to adequately assess the risk of major birth defects associated with BIC exposure.

APR has received prospective reports of 3 birth defects among 100 (3.0%) first trimester exposures to BIC-containing regimens during pregnancy resulting in live births.

No birth defects were reported among 40 exposures during the second/third trimester.

Emtricitabine (FTC): Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.

Alafenamide (TAF): Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-containing regimens.

BIC was administered orally to pregnant rats (5, 30, or 300 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) on gestation days 7 through 17, and 7 through 19, respectively.

No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (AUC) of up to approximately 36 (rats) and 0.6 (rabbits) times the exposure in humans at the RHD of BIKTARVY.

Spontaneous abortion, increased clinical signs [fecal changes, thin body, and cold-to-touch], and decreased body weight were observed at a maternally toxic dose in rabbits (1000 mg/kg/day; approximately 1.4 times higher than human exposure at the RHD).

In a pre/postnatal development study, BIC was administered orally to pregnant rats (up to 300 mg/kg/day) from gestation days to lactation/post-partum day 24.

No significant adverse effects were observed in the offspring exposed daily from before birth ( in utero ) through lactation at maternal and pup exposures (AUC) of approximately and 11 times higher, respectively, than human exposures at the RHD.

FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively).

No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the RHD.

In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD.

Tenofovir alafenamide

TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively).

No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures of approximately 2 (rats) and 78 (rabbits) times higher than the exposure in humans at the recommended daily dose of BIKTARVY.

TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 55 (rats) and 86 (rabbits) times higher than human tenofovir exposures at the RHD.

TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF.

Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 12 times higher than the exposures in humans at the RHD of BIKTARVY.

The safety and effectiveness of

BIKTARVY have been established as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric patients weighing at least 14 kg: who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known or suspected resistance to bictegravir or tenofovir.

Use of

BIKTARVY in pediatric patients weighing at least 14 kg is supported by the following: trials in adults an open-label trial in three age-based cohorts of virologically-suppressed pediatric subjects Cohort 1: 12 to less than 18 years of age and weighing at least 35 kg receiving BIKTARVY through Week 48 (N=50), Cohort 2: 6 to less than 12 years of age and weighing at least 25 kg receiving BIKTARVY through Week 24 (N=50), and Cohort 3: at least 2 years of age and weighing at least to less than 25 kg through Week 24 (N=22).

No pediatric subjects 2 years of age were enrolled; of the 6 pediatric subjects who were 3 years of age at enrollment, 3 subjects weighed between to less than 15 kg. The safety and efficacy of BIKTARVY in these pediatric subjects were similar to that in adults, and there was no clinically significant change in exposure for the components of BIKTARVY.

Safety and effectiveness of

BIKTARVY in pediatric patients weighing less than 14 kg have not been established.

Clinical trials in virologically-suppressed subjects (Trials 4449, 1844, and 1878) included 111 subjects aged 65 years and over who received BIKTARVY, including 86 patients from an open-label, single-arm trial of subjects aged 65 years and over who were switched from their previous antiretroviral regimen to BIKTARVY.

Of the total number of

BIKTARVY-treated patients in these trials, 100 (90%) were to 74 years of age, and 11 (10%) were to 84 years of age.

No overall differences in safety or effectiveness were observed between elderly subjects and adults between and less than 65 years of age, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.