Date of approval.
Date of revision.
Instructions for Bicep Enbrel Tablets
Please read the instructions carefully and use under medical supervision
Warning: Acute exacerbation of hepatitis B following treatment
Severe acute exacerbations of hepatitis B have been reported in patients co-infected with HIV-1 and HBV who discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF) and may also occur when discontinuing Biclopirox tablets.
For patients with HIV-1 and HBV co-infection who discontinue Biceprofenor tablets, monitor liver function closely, including clinical and laboratory follow-up for at least several months. If appropriate, anti-hepatitis B virus therapy may be required. (See [Precautions])
Drug Name]
Generic name: Biceprinol Tablets
Trade name: Bictegravir® (Biktarvy®)
English Name: Bictegravir Sodium, Emtricitabine and Tenofovir Alafenamide Fumarate Tablets
Hanyu Pinyin：Bike’enbingnuo Pian
Ingredients
This product is a compound preparation, each tablet contains Bictegravir Sodium (Bictegravir) 50mg, Emtricitabine 200mg, Propofol Tenofovir Fumarate (Propofol Tenofovir) 25mg.
Properties
This product is a film-coated tablet, after removing the coating, it is a double-layer tablet, with one layer showing white or off-white and one layer showing yellow.
Indications
This product is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection as a complete regimen in adults with no current or previous evidence of viral resistance to integrase inhibitors, emtricitabine or tenofovir. (See [Dosage] and [Pharmacology and Toxicology]).
Specification
Each tablet contains bictegravir sodium (as bictegravir) 50mg, emtricitabine 200mg, tenofovir propofol fumarate (as propofol tenofovir) 25mg.
[Dosage].
Treatment should be initiated by a physician experienced in HIV disease management.
Dosage
Once daily, one tablet each time.
Missed dose
If a patient misses a dose of Bic Enbrelol within 18 hours of the usual dosing time, the patient should take a replacement dose of Bic Enbrelol as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Bic en propanol tablets for more than 18 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.
If a patient vomits within 1 hour of taking Bic Enbrelol tablets, the patient should take an additional Bic Enbrelol tablet. If a patient vomits more than 1 hour after taking Bic Enbrel, the patient does not need to take another dose of this product before the next dosing time.
Elderly people
There are limited data on the use of Biceprobamate Tablets in patients over 65 years of age. No dose adjustment is required in elderly patients (see [Pharmacology and Toxicology] and [Pharmacokinetics]).
Renal Impairment
No dose adjustment is required in patients with estimated creatinine clearance (CrCl) ≥ 30 mL/min.
For patients with an estimated CrCl below 30 mL/min, initiation of Bic Enbrel tablet therapy is not recommended due to insufficient data on the use of Bic Enbrel tablets in this population (see [Pharmacokinetics]).
Hepatic impairment
No dose adjustment of Biceprobenox tablets is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Biceprofenol Tablets have not been studied in patients with severe hepatic impairment (ChildPugh Class C); therefore, Biceprofenol Tablets are not recommended for use in patients with severe hepatic impairment (see [Precautions] and [Pharmacokinetics]).
Pediatric Population
The safety and efficacy of Biceprobamate Tablets in children under 18 years of age have not been established. No data are available.
Method of Administration
Oral.
Bic Enbrel tablets may or may not be taken with or without food (see [Pharmacokinetics]).
Film-coated tablets should not be chewed, crushed, or broken open.
[Adverse Reactions].
Summary of Safety Profile
Adverse reactions were evaluated based on safety data from all Phase 2 and Phase 3 studies of Biceprobenox tablets. In clinical studies of previously untreated patients treated with Bic Enbrel for 48 weeks, the most frequently reported adverse reactions were headache (5%), diarrhea (5%), and nausea (4%).
Summary Table of Adverse Reactions
Table 1 lists adverse reactions by system organ classification and frequency of occurrence. The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), occasional (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), or very rare (<1/10,000).
Table 1: List of adverse reactions1
Frequency Adverse reactions Blood and lymphatic system disorders occasional: anemia2
Psychiatric disorders common: depression, abnormal nightmares occasional: suicidal behavior, anxiety, sleep disorders neurologic disorders common: headache, dizziness gastrointestinal disorders common: diarrhea, nausea occasional: vomiting, abdominal pain, dyspepsia, flatulence hepatobiliary disorders occasional: hyperbilirubinemia skin and subcutaneous tissue disorders occasional: angioedema2,3, rash, pruritus musculoskeletal and connective tissue disorders occasional: arthralgia 3 Systemic disease and dosing site conditions common: fatigue1 With the exception of angioedema and anemia (see footnote 2), all adverse reactions were identified in clinical studies of emtricitabine + propofol tenofovir-containing drugs. Frequencies were derived from phase 3 clinical studies (GS-US-380-1489 and GSUS3801490) in previously untreated patients receiving 48 weeks of treatment.
2 This adverse reaction was not observed in clinical studies of products containing emtricitabine + propofol tenofovir, but was identified in clinical studies or postmarketing experience with emtricitabine in combination with other anti-retroviral agents.
3 This adverse reaction was identified in postmarketing surveillance of emtricitabine but was not observed in randomized controlled clinical studies in adults or clinical studies in children with HIV using emtricitabine. The frequency category “Occasional” was estimated by statistical calculation based on the total number of patients exposed to emtricitabine in these clinical studies (n=1563).
Suicidal ideation, suicide attempts, and depressive suicides occurred in 1% of subjects receiving bicucumber enanthate tablets< all events were serious and occurred primarily in subjects with a history of pre-existing depression, pre-existing suicide attempts, or psychiatric illness.
Description of specific adverse reactions
Metabolic parameters
Body weight and lipid and blood glucose levels may increase during anti-retroviral therapy (see [Precautions]).
Immune reconstitution inflammatory syndrome
Inflammatory responses due to asymptomatic or residual opportunistic infections may occur in HIV-infected patients with severe immunodeficiency at the time of CART initiation. Autoimmune diseases (e.g., Graves’ disease) have also been reported; however, the reported timing of onset is more variable, and these events may occur several months after treatment initiation (see [Caution]).
Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with recognized risk factors, advanced HIV disease, or long-term exposure to CART. The frequency of this adverse event is unknown (see [Precautions]).
Changes in serum creatinine
Bictegravir has been shown to increase serum creatinine because it inhibits renal tubular secretion of creatinine; however, these changes are not considered clinically relevant because they do not reflect changes in glomerular filtration rate. Serum creatinine increased by week 4 of treatment and remained stable by week 48. In studies GSUS3801489 and GSUS-3801490, median serum creatinine values (Q1,Q3) increased from baseline to week 48 by 0.10 (0.03, 0.17) mg/dL, 0.11 (0.03, There were no discontinuations due to renal adverse events by week 48 in the clinical study of Biceprobamate tablets.
Bilirubin Changes
In studies GSUS3801489 and GSUS3801490, elevations in total bilirubin were observed in 12% of previously untreated patients treated with Biceprobamate up to week 48. The elevations were primarily grade 1 (9%) and grade 2 (3%) (1.0 to 2.5 x upper limit of normal [ULN]) and were not associated with adverse liver reactions or other liver-related laboratory test abnormalities. There were no discontinuations due to hepatic adverse events in the clinical study of Biceprofloxacin tablets through week 48.
Other Special Populations
Patients with hepatitis B co-infection
In 21 HIV/HBV co-infected adults (8 treatment-naïve HIV/HBV-infected adults in study GSUS3801490; 8 HIV/HBV-suppressed adults in study GSUS3801878 and 5 HIV-HBV-suppressed women in study GS-US-380-1961) who received Bic Enbrel tablets, the The safety profile of Bicep enbrel tablets was similar to the corresponding profile in HIV-1 monoinfected patients (see [Clinical Trials]).
Report of Suspected Adverse Reactions
It is important to report suspected adverse reactions after drug authorization. This allows for continuous monitoring of the benefit/risk balance of the use of the drug. Healthcare professionals are required to report any suspected adverse reactions to the national reporting system.
Effects on the ability to drive and operate machinery
Patients should be informed that dizziness has been reported during treatment with Bic Enbrel tablet components.
[Contraindications
Contraindicated in hypersensitivity reactions to the active ingredient or any of the excipients.
Combination with rifampin or St. John’s Wort (Hypericum perforatum) is prohibited (see [Drug Interactions]).
Precautions]
Although effective viral suppression with ARV therapy has been shown to significantly reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Patients with HIV and hepatitis B or C virus co-infection
Patients with chronic hepatitis B or C on anti-retroviral therapy are at increased risk of serious and potentially fatal hepatic adverse reactions.
There are limited data on the safety and efficacy of Biker enbrelnor tablets in patients co-infected with HIV-1 and hepatitis C virus (HCV).
Biclopirox tablets contain propofol tenofovir, which is active against hepatitis B virus (HBV).
In HIV-1 patients, the presence of chronic hepatitis B virus (HBV) infection should be tested prior to or at the initiation of anti-retroviral therapy, and discontinuation of Biclopirox treatment in HIV and HBV co-infected patients may result in a severe acute exacerbation of hepatitis. Patients with HIV and HBV co-infection who discontinue treatment with Bicaprofloxacin should be closely monitored through clinical and laboratory follow-up for at least several months after discontinuation of treatment.
Liver disease
The safety and efficacy of Bicaprofloxacin tablets in patients with significant underlying liver disease have not been established.
In patients with pre-existing liver dysfunction, including chronic active hepatitis, the increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) should be monitored according to standard practice. If signs of exacerbation of liver disease develop in these patients, treatment interruption or discontinuation must be considered.
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogs including emtricitabine (a component of bicaprofloxacin tablets) and tenofovir disoproxil fumarate (another drug precursor of tenofovir) alone or in combination with other anti-retroviral agents. Treatment with Biceprinol tablets should be suspended in any patient with clinical or laboratory findings suggestive of lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even if transaminases are not significantly elevated).
Body weight and metabolic parameters
Weight gain and elevated lipid and blood glucose levels may occur during anti-retroviral therapy. These changes may be related to disease control and lifestyle to some extent. There is evidence in some cases that lipids are affected by treatment, while there is no strong evidence that weight gain is associated with any particular treatment. Refer to established HIV treatment guidelines for lipid and glucose monitoring. Lipid disorders should be managed appropriately in the clinic.
Mitochondrial dysfunction after intrauterine exposure
Nucleoside (acid) analogs may affect mitochondrial function to varying degrees, most notably with stavudine, dehydroxyeosin, and zidovudine. Mitochondrial dysfunction has been reported in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues: these reports of mitochondrial dysfunction were primarily associated with treatment with zidovudine-containing regimens. The main adverse reactions reported were hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipaseemia). These events were usually transient in nature. More rarely, some delayed neurological disorders (hypertonia, spasticity, behavioral abnormalities) have been reported. It is not known whether such neurological disorders are transient or permanent events. These findings should be considered in any child exposed in utero to a nucleoside (acid) analogue who presents with severe clinical examination abnormalities of unknown etiology (especially neurological abnormalities). These findings will not affect current national recommendations for the use of anti-retroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune reconstitution inflammatory syndrome
An asymptomatic or residual conditioned pathogen-induced inflammatory response may occur in HIV-infected patients with severe immunodeficiency at the time of CART initiation, and this response may result in the development of severe clinical conditions or worsening of symptoms. Typically, such reactions are observed within the first few weeks or months after initiation of CART. Relevant examples include cytomegalovirus retinitis, systemic and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment initiated if necessary.
In addition, autoimmune diseases (e.g., Graves’ disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have been reported during immune reactivation; however, the reported timing of onset is more variable, and these events may occur several months after treatment initiation.
Opportunistic infections
Patients should be informed that neither Bic Enbrel tablets nor any other anti-retroviral therapy will cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, such patients should continue to be under close clinical observation by a physician experienced in the treatment of HIV-related disease.
Osteonecrosis
Although the etiology is thought to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, and high body mass index), cases of osteonecrosis have been reported (particularly common in patients with advanced HIV disease and/or long-term exposure to CART). Patients are advised to seek medical attention in the event of joint pain, joint stiffness, or difficulty with movement.
Nephrotoxicity
The potential risk of nephrotoxicity due to prolonged exposure to low levels of tenofovir as a result of propofol tenofovir therapy cannot be excluded (see [Pharmacologic Toxicology]).
Combination with other drugs
Bicaproflox tablets should not be combined with antacids containing magnesium/aluminum or iron supplements on an empty stomach. Bic Enbrel tablets should be taken at least 2 hours before or 2 hours after the administration of antacids containing magnesium and/or aluminum with food. Bic Enbrel tablets should be taken at least 2 hours prior to the administration of iron supplements or with food (see [Drug Interactions]).
The following drugs are not recommended for use in combination with Bic Elfenox tablets: atazanavir, boceprevir, carbamazepine, cyclosporine (for intravenous use or oral administration), oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, or aluminum thioglycollate.
Biceprofenol Tablets should not be used in combination with other anti-retroviral drugs.
For Pregnant and Lactating Women
Pregnancy
There are no or very limited data on the use of bictegravir or propofol tenofovir in pregnant women (less than 300 pregnancy outcomes). A large body of data on pregnant women (more than 1,000 exposure outcomes) suggests that no malformations or fetal/neonatal toxicity associated with emtricitabine have occurred.
Results from animal studies suggest that emtricitabine does not have direct or indirect deleterious effects on fertility parameters, pregnancy, fetal development, delivery or postpartum development. Studies in animals with bictegravir and propofol tenofovir administered alone have shown no evidence of harmful effects on fertility parameters, pregnancy or fetal development (see [Pharmacologic Toxicology]).
Bictegravir tablets should be used during pregnancy only if the potential benefits to the fetus outweigh the potential risks.
Lactation
It is not known whether bictegravir or propofol tenofovir is secreted into human emulsion. Emtricitabine is secreted into human milk. In animal studies, bictegravir was detected in the plasma of lactating rat pups, which may be due to the presence of bictegravir in the milk, with no effect on lactating pups. The results of animal studies have shown that tenofovir can be secreted into the milk.
There is insufficient information on the effects of all components of Bicteplavir in neonates/infants and therefore Bicteplavir should not be used during breastfeeding.
To avoid transmission of HIV to the infant, HIV-infected women are advised not to breastfeed under any circumstances.
Fertility
There are no relevant data on the effect of Bictebanol Tablets on human fertility. Animal studies have shown no effect of bictegravir, emtricitabine or propofol tenofovir on mating or fertility (see [Pharmacology and Toxicology]).
Pediatric Dosage]
The safety and efficacy of Bictegravir tablets in children under 18 years of age have not been established. There are no available data.
Geriatric Use]
There are limited data on the use of Biceprobamate Tablets in patients over 65 years of age. No dose adjustment of Biceprobenox tablets is required in elderly patients (see [Pharmacology and Toxicology] and [Pharmacokinetics]).
Drug Interactions]
Interaction studies have been conducted in adults only.
Bicteporanol tablets should not be used in conjunction with propofol tenofovir, tenofovir disoproxil, lamivudine, or adefovir-containing drugs used in the treatment of HBV infection.
Bictegravir
Bictegravir is a substrate for CYP3A and UGT1A1. Combination of bictegravir with drugs that potently induce CYP3A and UGT1A1 (e.g., rifampin or St. John’s wort) may significantly reduce the plasma concentration of bictegravir, resulting in loss of efficacy and resistance to bictegravir, and is therefore contraindicated (see [Contraindications]). Combination of bictegravir with drugs that potently inhibit both CYP3A and UGT1A1 (e.g., atazanavir) may significantly increase plasma concentrations of bictegravir and is therefore not recommended.
Bictegravir is a substrate for P-gp and BCRP. The clinical relevance of this feature has not been established. Therefore, caution is recommended when combining bictegravir with drugs known to inhibit P-gp and/or BCRP (e.g., macrolides, cyclosporine, verapamil, dronedarone, Glecaprevir/Pibrentasvir) (see table below).
In vitro, bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin efflux transport protein 1 (MATE1). The combination of Bictegravir tablets with the OCT2 and MATE1 substrate metformin did not result in a clinically meaningful increase in metformin exposure. Bictepanol tablets can be combined with the OCT2 and MATE1 substrates.
In vivo, bictegravir is not an inhibitor or inducer of CYP.
Emtricitabine
In vitro and clinical pharmacokinetic drug-drug interaction studies indicate that the potential for CYP-mediated interactions between emtricitabine and other drugs is low. Co-administration of emtricitabine with drugs that are actively secreted by the renal tubules for clearance may increase the concentration of emtricitabine and/or the co-administered drugs. Drugs that decrease renal function may increase concentrations of emtricitabine.
Propofol Tenofovir
Propofol tenofovir is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Combination of Biclotrimide tablets with drugs that have a strong effect on P-gp and BCRP activity may result in altered absorption of propofol tenofovir. Drugs that are expected to induce P-gp activity (e.g., rifabutin, carbamazepine, phenobarbital) reduce the absorption of propofol tenofovir, resulting in a decrease in the plasma concentration of propofol tenofovir, which may lead to loss of efficacy and development of resistance to Biclopirox tablets. Combination of Bicnpranolol Tablets with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentrations of propofol tenofovir.
In vivo, propofol tenofovir is not an inhibitor or inducer of CYP3A.
Other interactions
Interactions between Biclipramine Tablets or its single component and co-administered drugs are listed in Table 2 below (“↑” indicates an increase, “↓” indicates a decrease, and “↔” indicates no change; all no-effect limits range from 70% to 143%).
Table 2: Interactions between Biceprobamate tablets or its single components and other drugs
Effect of drugs on drug levels by therapeutic area/possible mechanism of interaction
Mean percentage change in AUC, Cmax, Cmin regarding Biceprobamate Tablets combined
Suggested herb St. John’s wort (Hypericum perforatum)
(CYP3A, UGT1A1 and P-gp induced) Interactions with any component of Bictebanol Tablets were not studied.
Combination may reduce plasma concentrations of bictegravir and propofol tenofovir. Combination with St. John’s Wort is contraindicated due to its effect on the bictegravir component of Bictebanovir Tablets. Anti-infective agents Anti-branched bacteriophage rifampicin (600 mg once daily),
Bictegravir 1
(CYP3A, UGT1A1 and P-gp induction) Bictegravir.
AUC: ↑75%
Cmax: ↓28%
Interaction with propofol tenofovir has not been studied.
Combination with rifampicin may decrease the plasma concentration of propofol tenofovir. Combination is contraindicated due to the effect of rifampicin on the bictegravir component of Bictegravir tablets. Rifabutin (300 mg once daily), bictegravir 1
(CYP3A and P-gp induced) Bictegravir.
AUC: ↓38%
Cmin: ↓56%
Cmax: ↓20%
Interaction with propofol tenofovir has not been studied.
Combination with rifabutin may decrease the plasma concentration of propofol tenofovir. Combination is not recommended because of the expected decrease in propofol tenofovir. Rifapentine
(CYP3A and P-gp induced) Interaction with any component of Biclopirox tablets has not been studied.
Combination with rifapentine may reduce plasma concentrations of bictegravir and propofol tenofovir. The combination of the HIV-1 antiviral agents atazanavir (300 mg once daily), cobicistat (150 mg once daily), and bictegravir 1 (CYP3A, UGT1A) is not recommended.
(CYP3A, UGT1A1 and P-gp/BCRP inhibition) Bictegravir.
AUC: ↑306%
Cmax: ↔ Combination is not recommended. Atazanavir (400 mg once daily), bictegravir 1
(CYP3A and UGT1A1 inhibition) bictegravir.
AUC: ↑315%
Cmax: ↔ Interaction between Boceprevir, a hepatitis C virus antiviral, and any component of Bictegravir tablets was not studied.
Based on in vitro data, co-administration with Boceprevir may adversely affect the intracellular activation and clinical antiviral efficacy of propofol tenofovir. Combination is not recommended. Ledipavir/sofosbuvir (90 mg/400 mg once daily), bictegravir/emtricitabine/propofol tenofovir 2 bictegravir.
AUC: ↔
Cmin: ↔
Cmax: ↔
Emtricitabine.
AUC: ↔
Cmin: ↔
Cmax: ↔
Propofol tenofovir.
AUC: ↔
Cmax: ↔
Ledipavir.
AUC: ↔
Cmin: ↔
Cmax: ↔
Sofosbuvir.
AUC: ↔
Cmax: ↔
Sofosbuvir metabolite GS331007.
AUC: ↔
Cmin: ↔
Cmax: ↔ No dose adjustment is required when combined. Sofosbuvir/vipatasvir/vosiravir (400/100/100+100mg3 once daily), bictegravir/emtricitabine/propofol tenofovir
(P-gp/BCRP inhibition) bictegravir.
AUC: ↔
Cmin: ↔
Cmax: ↔
Emtricitabine.
AUC: ↔
Cmin: ↔
Cmax: ↔
Propofol tenofovir.
AUC: ↑57%
Cmax: ↑28%
Sofosbuvir.
AUC: ↔
Cmax：↔
Sofosbuvir metabolite GS331007.
AUC: ↔
Cmin: ↔
Cmax: ↔
Vipatavir.
AUC: ↔
Cmin: ↔
Cmax: ↔
Vospiravir.
AUC: ↔
Cmin: ↔
Cmax: ↔ No dose adjustment is required when combined. The antifungals voriconazole (300 mg twice daily), bictegravir 1
(CYP3A inhibition) bictegravir.
AUC: ↑61%
Cmax: ↔ No dose adjustment required when combined. Itraconazole
Posaconazole
(P-gp/BCRP inhibition) Interaction with any component of Bictegravir tablets has not been studied.
Combination with itraconazole or posaconazole may increase bictegravir plasma concentrations. Macrolide azithromycin
Clarithromycin
(P-gp inhibition)
Not studied.
Interactions were not studied. Combination with azithromycin or clarithromycin may increase bictegravir plasma concentrations. Because these agents may have an effect on the bictegravir component of Bictebanor tablets, caution is advised in combining them. The anticonvulsants carbamazepine (adjusted from 100 mg to 300 mg twice daily), emtricitabine/propofol tenofovir 4
(CYP3A, UGT1A1 and P-gp induction) propofol tenofovir.
AUC: ↓54%
Cmax: ↓57%
Interaction with bictegravir has not been studied.
Combination with carbamazepine may decrease plasma concentrations of bictegravir. Combination is not recommended. Oxcarbazepine
Phenobarbital
Phenytoin
(CYP3A, UGT1A1 and P-gp induced) Interaction with any component of Bictegravir tablets has not been studied.
Combination with oxcarbazepine, phenobarbital or phenytoin may decrease plasma concentrations of bictegravir and propofol tenofovir. Combination use is not recommended. Antacids, Supplements, and Buffered MedicationsMagnesium/aluminum-containing antacid suspension (20 mL, single dose5), bictegravir
(chelation with multivalent cations) Bictegravir (2 h before antacid suspension administration, fasting).
AUC: ↓52%
Cmax: ↓58%
Bictegravir (2 hours after antacid suspension administration, fasting).
AUC: ↔
Cmax: ↔
Bictegravir (concurrent dosing, fasting).
AUC: ↓79%
Cmax: ↓80%
Bictegravir (concomitant administration with food).
AUC: ↓47%
Cmax: ↓49% Because of the expected substantial reduction in bictegravir exposure (see [Precautions]), Bicteprenolol Tablets should not be taken concomitantly with supplements containing magnesium and/or aluminum.
Bicteporanol tablets should be taken at least 2 hours prior to the administration of antacids containing magnesium and/or aluminum or with food 2 hours after administration. Ferrous fumarate (324 mg, single dose), Bictegravir
(chelation with multivalent cations), bictegravir (concurrent administration, fasting).
AUC: ↓63%
Cmax: ↓71%
Bictegravir (concomitant administration with food).
AUC: ↔
Cmax: ↓25% Bictegravir tablets should be taken at least 2 hours prior to iron supplementation administration or with food. Calcium carbonate (1200 mg, single dose), bictegravir
(chelation with multivalent cations), bictegravir (concurrent administration, fasting).
AUC: ↓33%
Cmax: ↓42%
Bictegravir (concomitant administration with food).
AUC: ↔
Cmax: ↔ Bictegravir tablets and calcium-containing supplements taken together without regard to food factors. Aluminum thioglycollate.
(chelation with multivalent cations) Interaction with any component of Bictebanol tablets has not been studied.
Combination may decrease plasma concentrations of bictegravir. Combination use is not recommended. Antidepressants sertraline (50 mg single dose), propofol tenofovir 6 propofol tenofovir.
AUC: ↔
Cmax: ↔
Sertraline.
AUC: ↔
Cmax: ↔
No dose adjustment is expected when combined with bictegravir and emtricitabine without interaction. Immunosuppressant cyclosporine (IV or oral)
(P-gp inhibition) Interaction with any component of Bictegravir tablets has not been studied.
Combination with cyclosporine (IV or oral) is expected to increase plasma concentrations of bictegravir and propofol tenofovir. Coadministration with cyclosporine (IV or oral) is not recommended. If coadministration is required, clinical and biological monitoring is recommended, particularly for renal function. Opioid Methadone
Not studied.
(Inhibition of CYP1A2, 2B6, 2D6 by bictegravir metabolites cannot be excluded). Combination with caution is recommended. Oral antidiabetic drugs metformin (500 mg twice daily), bictegravir/emtricitabine/propofol tenofovir
(OCT2/MATE1 inhibition) Metformin.
AUC: ↑39%
Cmin: ↑36%
Cmax: ↔ No dose adjustment is required when combined in patients with normal renal function.
In patients with moderate renal impairment, close monitoring should be considered when initiating co-administration of bictegravir with metformin due to the increased risk of lactic acidosis in these patients. Dose adjustment of metformin should be considered when needed. Oral contraceptives norgestimate (0.180/0.215/0.250 mg once daily), ethinyl estradiol (0.025 mg once daily), and bictegravir 1 methyl progesterone.
AUC: ↔
Cmin: ↔
Cmax: ↔
Methylpregnanolone.
AUC: ↔
Cmin: ↔
Cmax: ↔
Ethinylestradiol.
AUC: ↔
Cmin: ↔
Cmax: ↔ No dose adjustment is required when combined. Norgestrel (0.180/0.215/0.250 mg once daily), ethinyl estradiol (0.025 mg once daily), emtricitabine/propofol tenofovir 4 sedative/sleeping medication midazolam (2 mg, oral syrup, single dose), bictegravir/emtricitabine/propofol tenofovir midazolam.
AUC: ↔
Cmax: ↔ No dose adjustment is required when combined.1 This study was conducted using bictegravir 75 mg as a single dose.
2 This study was conducted using bictegravir/emtricitabine/propofol tenofovir 75/200/25 mg administered once daily.
3 The study was conducted with an additional 100 mg of vosiravir to achieve the expected vosiravir exposure in HCV-infected patients.
4 This study was conducted using emtricitabine/propofol tenofovir 200/25 mg administered once daily.
5 The highest level of antacid per mL contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg dimethylsilicone oil.
6 This study was conducted using elvitegravir/cobicistat/emtricitabine/propofol tenofovir 150/150/200/10 mg administered once daily.
Based on drug interaction studies conducted using Biclopirox tablets or Biclopirox tablet components, no clinically meaningful drug interactions are expected with: amlodipine, atorvastatin, buprenorphine, drospirenone, famotidine, fluticasone, naloxone, norbuprenorphine, omeprazole, or reserpine.
[Drug Overdose].
If an overdose occurs, patients must be monitored for signs of toxicity (see [Adverse Reactions]). The treatment of BicEP overdose requires general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status.
There is no specific antidote for Bictebanol Tablets overdose. Because bictegravir is highly bound to plasma proteins, it is unlikely that the drug can be significantly removed by hemodialysis or peritoneal dialysis. Emtricitabine can be removed by hemodialysis, with approximately 30% of the emtricitabine dose being removed during a 3-hour dialysis period beginning within 1.5 hours of emtricitabine administration. Tenofovir can be effectively removed by hemodialysis with an extraction factor of approximately 54%. It is not clear whether peritoneal dialysis can remove emtricitabine or tenofovir.
[Clinical Trials].
The efficacy and safety of bicte enanthate tablets in treatment-naïve HIV-1-infected adults was determined based on 48-week data from two randomized, double-blind, active-controlled studies, GSUS3801489 (n=629) and GSUS3801490 (n=645).
The efficacy and safety of Bicep enbrel tablets in HIV-1-infected adults who achieved suppression of virologic features was determined based on 48-week data from a randomized, double-blind, active-controlled study GSUS3801844 (n=563) and a randomized, open-label, active-controlled study GSUS3801878 (n=577). A randomized, open-label, active-controlled study GS-US-380-1961 (n=470) was conducted in HIV-1-infected women who achieved suppression of virologic features.
Treatment-naïve HIV-1-infected patients
In study GSUS3801489, patients were randomized in a 1:1 ratio to receive either B/F/TAF (n=314) or abacavir/dotilaprevir/lamivudine (600/50/300 mg) (n=315) administered once daily. In study GSUS3801490, patients were randomized in a 1:1 ratio to receive either B/F/TAF (n=320) or dotilaprevir + emtricitabine/propofol tenofovir (50+200/25mg) (n=325) administered once daily.
In studies GSUS3801489 and GSUS3801490, the mean age was 35 years (range 1877), 89% were male, 58% were white, 33% were black, and 3% were Asian. 24% of patients identified as Hispanic/Latino. The incidence of different subtypes was comparable among all three treatment groups, with subtype B predominating in both groups; 11% were non-subtype B. Mean baseline plasma HIV-1 RNA was 4.4log10 copies/mL (range: 1.36.6). The mean baseline CD4+ cell count was 460 cells/mm 3 (range: 0-1636), with 11% of patients having a CD4+ cell count less than 200 cells/mm 3. Baseline viral load was greater than 100,000 copies/mL in 18% of patients. In both studies, the baseline HIV-1 RNA levels (less than or equal to 100,000 copies/mL, greater than 100,000 copies/mL, and greater than 100,000 copies/mL) were determined by baseline HIV-1 RNA levels. greater than 100,000 copies/mL to less than or equal to 400,000 copies/mL or greater than 400,000 copies/mL), CD4+ cell count (less than 50 cells/μL, 50-199 cells/μL, or greater than or equal to 200 cells/μL), and region (US or outside the US) were used to stratify patients.
Treatment outcomes through week 48 for study GSUS3801489 and study GSUS3801490 are shown in Table 3.
Table 3: Week 48 for Study GSUS3801489 and GSUS3801490 in untreated patients
Summary of virological resultsa
B/F/TAF
(n=634)bABC/DTG/3TC
(n=315)cDTG+F/TAF
(n=325)dHIV-1 RNA<50 copies/mL91%93%93%Treatment difference (95% CI) between B/F/TAF and comparator – 2.1%
(-5.9% to 1.6%) -1.9%
(-5.6% to 1.8%) HIV-1 RNA ≥50 copies/mLe3%3%1% No virologic data at week 48 window6%4%6% Discontinued study drug due to AE or deathf<1%1%1% Discontinued study drug for other reasons and last obtained HIV-1 RNA<50 copies/mLg4%3%4% Missing data during window Percentage of patients with HIV-1 RNA<50 copies/mL by subgroup (%) h Baseline viral load, but still receiving study drug 2%<1%1%
≤100,000 copies/mL
>100,000 copies/mL
92%
87%
94%
90%
93%
94% Baseline CD4+ cell count
<200 cells/mm3
≥200 cells/mm3
90%
91%
81%
94%
100%
92% HIV-1 RNA<20 copies/mL 85% 87% 87% ABC=abacavir DTG=dotilavir 3TC=lamivudine F/TAF=emtricitabine/propofol tenofovir
a Week 48 window period is defined as days 295 to 378 inclusive.
b Pooled data from study GSUS3801489 (n=314) and study GSUS3801490 (n=320).
c Study GSUS3801489.
d Study GSUS3801490.
e Includes patients with a week 48 window of ≥50 copies/mL; patients who discontinued early due to lack or loss of efficacy; and patients who discontinued for reasons other than adverse events (AEs), death, or lack or loss of efficacy and had a viral value ≥50 copies/mL at discontinuation.
f Includes patients who discontinued treatment due to an AE or death that resulted in no treatment period virologic data for the specified window at any time point between Day 1 and that time window.
g Includes patients who discontinued treatment for reasons other than AE, death, or lack or loss of efficacy (e.g., withdrawal of consent, missed visits, etc.).
h Patients with a week 48 window of ≥50 copies/mL include patients who discontinued early due to lack or loss of efficacy (n=0) and those who discontinued for reasons other than AE, death, or lack or loss of efficacy (B/F/TAF n=12; ABC/DTG/3TC n=2; DTG+F/TAF n=3) and had a viral value ≥50 copies/mL at discontinuation. Patients.
The B/F/TAF group was not inferior to the abacavir/dotilaprevir/lamivudine and dotilaprevir+emtricitabine/propofol tenofovir groups in achieving HIV-1 RNA<50 copies/mL at week 48. Treatment outcomes were similar between subgroups by age, sex, race, baseline viral load, baseline CD4+ cell count, and region.
In studies GSUS3801489 and GSUS3801490, the mean increases in CD4+ cell counts relative to baseline at week 48 were 207, 229 and 201 cells/mm3 in the pooled B/F/TAF, abacavir/dotiravir/lamivudine and dotiravir + emtricitabine/coproterenol tenofovir groups, respectively.
HIV-1-infected patients who achieved suppression of virological features
In study GSUS3801844, the efficacy of switching from dolutegravir + abacavir/lamivudine or abacavir/dolutegravir/lamivudine therapy to B/F/TAF therapy was evaluated by conducting a randomized, double-blind study in adult patients (n=563) infected with HIV-1 who achieved virologic suppression (HIV-1 RNA<50 copies/mL) and safety were evaluated. Prior to study entry, patients must have achieved stable suppression (HIV-1 RNA<50 copies/mL) for at least 3 months during their baseline treatment. Patients were randomized in a 1:1 ratio to switch to B/F/TAF treatment at baseline (N=282) or to continue on the baseline ARV regimen (N=281). The mean age of patients was 45 years (range 20 to 71 years), 89% were male, 73% were white, and 22% were black. 17% of patients identified as Hispanic/Latino. The incidence of different HIV-1 subtypes was comparable between treatment groups, with subtype B predominating in both groups; 5% were non-B subtypes. The mean baseline CD4+ cell count was 723 cells/mm3 (range 1242444).
In study GSUS3801878, conversion from abacavir/lamivudine or emtricitabine/tenofovir disoproxil fumarate (200/300 mg) + atazanavir or darunavir (boosted by cobicistat or ritonavir) to B/F/ was evaluated in a randomized, open-label study conducted in adults (n=577) with virologic features achieving suppression of HIV-1 infection. Efficacy and safety of TAF. Patients must have achieved at least 6 months of stable suppression at the time of the baseline regimen and must not have received any prior INSTI therapy. Patients were randomized in a 1:1 ratio to switch to B/F/ TAF treatment (N=290) or to continue on the baseline antiretroviral regimen (N=287). The mean age of patients was 46 years (range 20 to 79 years), 83% were male, 66% were white, and 26% were black. 19% of patients identified as Hispanic/Latino. The mean baseline CD4+ cell count was 663 cells/mm3 (range 622582). The incidence of different subtypes was comparable between treatment groups, with subtype B predominating in both groups; 11% were non-B subtypes. Patients were stratified by prior treatment regimen. At screening, 15% of patients were receiving abacavir/lamivudine + atazanavir or darunavir (boosted by cobicistat or ritonavir) and 85% were receiving emtricitabine/tenofovir disoproxil fumarate + atazanavir or darunavir (boosted by cobicistat or ritonavir).
Treatment results through week 48 for study GSUS3801844 and study GSUS3801878 are shown in Table 4.
Table 4: Virological results for study GSUS-3801844 and study GSUS3801878 at week 48a
Study GSUS3801844 Study GSUS3801878 B/F/TAF (n=282) ABC/DTG/3TC (n=281) B/F/TAF (n=290) Baseline ATV- or DRV-containing regimen (n=287) HIV-1 RNA<50 copies/mL 94% 95% 92% 89% Treatment difference ( 95% CI) -1.4% (-5.5% to 2.6%) 3.2% (-1.6% to 8.2%) HIV-1 RNA ≥50 copies/mLb1%<1%2%2% Treatment difference (95% CI) 0.7% (-1.0% to 2.8%) 0.0% (-2.5% to 2.5%) No virologic data at week 48 window5%5%6% 9% Discontinued study drug due to AE or death and last acquired HIV-1 RNA<50 copies/mL2%1%1%1% Discontinued study drug due to other reasons and last acquired HIV-1 RNA<50 copies/mLc2%3%3%7% Missing data during window period but still receiving study drug2%1%2%2%ABC=abacavir ATV=Atazanavir DRV=Darunavir DTG=Dotilavir 3TC=Lamivudine
a The 48th week window is defined as days 295 to 378 inclusive.
b Includes patients with a Week 48 window of ≥50 copies/mL; patients who discontinued early due to lack or loss of efficacy; and patients who discontinued for reasons other than lack or loss of efficacy and had a viral value ≥50 copies/mL at the time of discontinuation.
c Includes patients who discontinued treatment for reasons other than AE, death, or lack or loss of efficacy (e.g., withdrawal of consent, missed visits, etc.).
B/F/TAF was not inferior to the control regimen in either study. Treatment outcomes were similar between treatment groups in subgroups listed by age, sex, race, and region.
In GSUS3801844, the mean change in CD4+ count relative to baseline at week 48 was -31 cells/mm3 and 4 cells/mm3 for patients who switched to B/F/TAF and patients who continued their baseline abacavir/dotilaprevir/lamivudine treatment, respectively. The mean change in CD4+ count relative to baseline at week 48 was 25 cells/mm3 and 0 cells/mm3 for patients who switched to B/F/TAF therapy and those who continued to receive their baseline therapy, respectively.
In GS-US-380-1961, a randomized, open study evaluated virologically suppressed HIV-1-infected women treated with atazanavir/ cobicistat/emtricitabine/propofol tenofovir (EVG/COBI/FTC/TAF), atazanavir/ cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF ) or atazanavir + ritonavir + emtricitabine/tenofovir disoproxil fumarate (ATV+RTV+FTC/TDF) to B/F/TAF for safety and efficacy. Patients had to have achieved suppression stably for at least 12 weeks on their baseline regimen and were randomly assigned to B/F/ TAF (n = 234), or maintain the original baseline regimen (n = 236). The mean age of patients was 40 years (range 21-63), 37% were black, 28% were white, and 22% were Asian. 16% of patients were identified as Hispanic/Latino. The mean baseline CD4+ cell count was 725 cells/mm3 (range 175-1703). At week 48, conversion to the B/F/TAF regimen was non-inferior compared to the maintenance baseline regimen; 1.7% of patients in each group presented with ≥50 copies/ mL, and the proportion of patients maintaining HIV-1 RNA <50 copies/mL after conversion to B/F/TAF was 96% compared to 95% of patients maintaining the baseline regimen. Efficacy was similar between treatment groups across subgroups of age, race, and region. CD4+ counts at week 48 compared to baseline had a mean variable of 29 cells/mm3 in patients who converted to B/F/TAF and 26 cells/mm3 in patients who maintained the baseline regimen.
Patients with HIV and HBV co-infection
The number of HIV and HBV co-infected patients treated with B/F/TAF is limited.
In study GSUS3801490, at week 48, 7/8 HIV/HBV co-infected patients randomized to B/F/TAF achieved HBV suppression (HBV DNA<29IU/mL) and HIV-1 RNA<50 copies/mL at baseline. one patient was missing HBV DNA data at week 48.
In study GSUS3801878, at week 48, 100% (8/8) of patients in the B/F/TAF group with baseline HIV/HBV co-infection maintained HBV DNA<29 IU/mL (missing=excluded from analysis) and HIV RNA<50 copies/mL.
In study GS-US-380-1961, at week 48, 100% (5/5) of patients in the B/F/TAF treatment arm who had HIV/HBV co-infection at baseline maintained HBV DNA <29 IU/mL (missing=excluded from analysis) and HIV RNA <50 copies/mL.
[Pharmacology and Toxicology].
Pharmacological action
Mechanism of action
Bictegravir (B/F/TAF) is a fixed-dose combination of the anti-retroviral agents bictegravir (BIC), emtricitabine (FTC) and propofol tenofovir (TAF).
Bictegravir: Bictegravir is an integrase strand transfer inhibitor (INSTI) that inhibits the strand transfer activity of HIV-1 integrase, an enzyme encoded by the HIV-1 virus and required for viral replication. Inhibition of integrase prevents the integration of linear DNA into host genomic DNA, blocking HIV-1 provirus formation and viral proliferation.
Emtricitabine: Emtricitabine is a synthetic cytidine nucleoside analogue that is phosphorylated by cytase to form emtricitabine 5′-triphosphate, which inhibits HIV-1 reverse transcriptase activity by competing with the natural substrate 5′-triphosphate deoxygenation for integration into nascent viral DNA to terminate DNA strand synthesis. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ and mitochondrial DNA polymerase γ.
Propofol tenofovir: Propofol tenofovir is a phosphoramidite precursor drug for tenofovir (2′-deoxyadenosine monophosphate analogue). Plasma-exposed propofol tenofovir penetrates into cells, and then propofol tenofovir is converted intracellularly by histone protease A hydrolysis to tenofovir, followed by tenofovir phosphorylation by cellular kinase to the active metabolite tenofovir diphosphate. Tenofovir diphosphate is embedded in viral DNA by HIV reverse transcriptase, resulting in DNA strand termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases, including mitochondrial DNA polymerase γ, but no evidence of toxicity to mitochondria has been seen in cell culture.
Antiviral activity in cell cultures
The antiviral activity of the tripartite combination of bictegravir, emtricitabine and propofol tenofovir was not antagonistic in cell culture systems.
Bictegravir: The antiviral activity of bictegravir was evaluated in lymphoblastoid cell lines, PBMC, primary monocytes/macrophages, and CD4+ T lymphocytes against laboratory and clinical isolates of HIV-1. In MT-4 cells (human lymphoblastoid T cell line) acutely infected with HIV-1 IIIB, the mean 50% effective concentration (EC50) was 2.4 ± 0.4 nM and the serum protein-corrected EC95 value was 361 nM (0.162 μg/ml). In activated PBMC, bictegravir showed antiviral activity against HIV-1 clinical isolates representing groups M, N and O (including subtypes A, B, C, D, E, F and G) with a median EC50 value of 0.55 nM (range <0.55 to 1.71 nM). The EC50 value for a single HIV-2 isolate was 1.1 nM.
Emtricitabine: The antiviral activity of emtricitabine against HIV-1 laboratory and clinical isolates was evaluated in T-like lymphoblastoid cell lines, MAGI-CCR5 cell lines, and PBMC, with a median EC50 value of 9.5 nM (range 1 to 30 nM) in PBMC acutely infected with HIV-1 subtypes A, B, C, D, E, F, and G, and a median EC50 value of 7 nM against HIV-2 The corresponding value for HIV-2 was 7 nM.
Propofol Tenofovir: The antiviral activity of propofol tenofovir was evaluated in lymphoblastoid cell lines, PBMC, primary monocytes/macrophages, and CD4-T lymphocytes against HIV-1 subtype B laboratory and clinical isolates. The EC50 values for propofol tenofovir ranged from 2.0 to 14.7 nM. In cell culture, propofol tenofovir showed antiviral activity against all HIV-1 groups (M, N, O groups, including subtypes A, B, C, D, E, F, and G) (EC50 values range from 0.1 to 12 nM), as well as against specific strains of HIV-2 (EC50 values range from 0.9 to 2.6 nM). 0.9 to 2.6 nM).
Drug resistance
In cell cultures
Bictegravir: HIV-1 isolates with reduced susceptibility to bictegravir have been selected in cell cultures. In a selective assay using bictegravir, HIV-1 integrase emerged as a pool of viral genes expressing the M50I and R263K amino acid substitution mutations, and when the M50I, R263K, and M50I+R263K substitution mutations were introduced into wild-type virus by site-directed mutagenesis, sensitivity to bictegravir was reduced by 1.3, 2.2, and 2.9-fold, respectively. In the second selective assay, T66I and S153F mutations were detected, and sensitivity to bictegravir was reduced by 0.4, 1.9, and 0.5-fold in the presence of T66I, S153F, and T66I+S153F mutations, respectively. In addition, S24G and E157K mutations were present during selection.
Emtricitabine: HIV-1 isolates with reduced susceptibility to emtricitabine were screened in cell cultures and subjects treated with emtricitabine. Reduced susceptibility to emtricitabine was associated with M184V or I mutations in HIV-1 reverse transcriptase.
Propofol tenofovir: HIV-1 isolates with reduced sensitivity to propofol tenofovir were screened in cell cultures. HIV-1 isolates expressing the K65R mutation in HIV-1 reverse transcriptase and sometimes the S68N or L429I mutations were selected for using propofol tenofovir. In addition, the K70E mutation has been observed in HIV-1 reverse transcriptase.
In clinical trials
In subjects without a history of retroviral treatment: treatment-phase HIV-1 isolates from subjects in clinical trials 1489 and 1490 who were treated with bicaprofloxacin tablets for 48 weeks and confirmed virologic failure (subjects with HIV-1 RNA ≥200 copies/ml at week 48 or earlier when study drug was discontinued due to virologic failure) as well as paired baseline isolates were Resistance genotype pooling analysis was performed and no specific amino acid mutations were present in the eight treatment-failed subjects with evaluable resistance genotype data to establish a correlation with bictegravir resistance genotype. No mutations associated with NRTI resistance emerging during the treatment period were detected in the eight isolates of treatment-naïve subjects evaluated. Resistance phenotypic analysis revealed exponential changes in susceptibility to bictegravir, emtricitabine and TFV in treatment-failed isolates compared to wild-type HIV-1, below biological or clinical thresholds.
In subjects with suppressed virological profiles: in 2 conversion trials (1844 and 1878) using HIV-1-infected subjects with suppressed virological profiles (n=572), only 1 subject with virological rebound in the resistance analysis population had integrase genotype and phenotype data, 2 subjects with virological rebound had reverse transcriptase whole genotype and phenotype data, and no subjects developed genotypes or phenotypes for resistance to bictegravir, emtricitabine, or propofol tenofovir during the treatment period.
Cross-resistance
Bictegravir: Cross-resistance has been observed in INSTIs. Bictegravir was tested for sensitivity to 64 clinical isolates (20 with a single mutation and 44 with 2 or more mutations) expressing mutations known to be associated with INSTI resistance as listed by IAS-USA. Isolates with a single INSTI resistance mutation (including E92Q, T97A, Y143C/R, Q148R and N155H) showed less than a 2-fold reduction in sensitivity to ciclopirovir. All clinical isolates (n=14) with >2.5-fold reduction in sensitivity to bictegravir (above the biological threshold for bictegravir) contained G140A/C/S and Q148H/R/K mutations, and the majority (64.3%, 9/14) had complex INSTI resistance patterns (containing other INSTI resistance mutations). Among the isolates evaluated containing G140A/C/S and Q148H/R/K mutations without other INSTI resistance mutations, 38.5% (5/13) had a >2.5-fold reduction in susceptibility. In addition, viruses with site-directed mutations in G118R (a mutation that occurs during dolutegravir and everolimus treatment) and G118R+T97A had 3.4-fold and 2.8-fold reduced susceptibility to bictegravir, respectively.
Bictegravir showed comparable antiviral activity (less than 2-fold reduction in susceptibility) against HIV-1 variants expressing NNRTI, NRTI and PI resistance-associated mutations compared to wild viruses.
Emtricitabine: cross-resistance has been observed in NRTIs. Emtricitabine-resistant viruses with HIV-1 reverse transcriptase M184V/I mutations have cross-resistance to lamivudine. HIV-1 isolates containing the K65R RT mutation selected in vivo for abacavir, dehydroinositide, and tenofovir have reduced susceptibility to emtricitabine.
Propofol tenofovir: cross-resistance has been observed in NRTIs. Tenofovir resistance mutations K65R and K70E result in reduced susceptibility to abacavir, desoxymyxin, lamivudine, emtricitabine, and tenofovir. In cell cultures, HIV-1 containing multiple thymidine analogue mutations (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) or multinucleoside resistant HIV-1 containing T69S double insertion mutations or Q151M complex mutations (including K65R) have reduced susceptibility to propofol tenofovir.
Toxicology studies
Bictegravir
Bictegravir was not found to be genotoxic in bacterial revertant mutation assays (Ames test), mouse lymphoma or rat micronucleus assays.
Bictegravir had no effect on fertility, reproductive capacity or embryonic viability in male and female rats at an exposure level (AUC) 29 times the recommended daily human dose of Bictegravir tablets. Bictegravir was given orally to pregnant rats (5, 30, or 300 mg/kg/day) and pregnant rabbits (100, 300, or 1000 mg/kg/day) on days 7-17 and 7-19 of gestation, respectively, and no effects were seen at doses up to approximately 36 times (rats) and 0.6 times (rabbits) the recommended human dose of bictegravir for bictepiranos tablets. adverse embryo-fetal effects. Spontaneous abortions, increased clinical signs (fecal changes, wasting and coldness to touch) and decreased body weight were seen in rabbits at maternal toxicity doses (1000 mg/kg/day, approximately 1.4 times the recommended human exposure). In a perinatal developmental toxicity test, pregnant rats were given bictegravir orally (up to 300 mg/kg/day) from gestation day 6 to lactation/postnatal day 24, and maternal and pups were exposed to bictegravir daily from prenatal to lactation [exposure (AUC) approximately 30 and 11 times the human exposure], with no significant adverse effects seen in the offspring. In a perinatal developmental toxicity assay, bictegravir was detected in nursing rat pups (at postnatal day 10), possibly due to the presence of bictegravir in the milk.
In a 6-month study in rasH2 transgenic mice administered at doses up to 100 and 300 mg/kg/day in males and females, respectively (approximately 15 and 23 times the human exposure at the recommended human dose, respectively), no carcinogenicity of bictegravir was observed. In a 2-year rat trial in which rats were dosed orally at doses up to 300 mg/kg (exposure approximately 31 times the recommended human exposure for bictegravir), no carcinogenicity was observed for bictegravir.
Emtricitabine
Emtricitabine was not found to be genotoxic in bacterial revertant mutation assays (Ames test), mouse lymphoma or mouse micronucleus assays.
There was no effect on fertility in male rats at an exposure (AUC) of approximately 140 times the recommended daily human dose of emtricitabine in Biclofenox tablets and no effect on fertility in male and female mice at an exposure of approximately 60 times the recommended daily dose of emtricitabine in Biclofenox tablets. Mice exposed to emtricitabine daily from before birth (in utero) to throughout sexual maturity [daily exposure (AUC) was approximately 60 times the recommended daily dose of emtricitabine in humans for Biclopirox tablets] had normal fertility in offspring. Oral administration of emtricitabine to pregnant mice (250, 500, or 1000 mg/kg/day) and pregnant rabbits (100, 300, or 1000 mg/kg) during the organogenesis phase (days 6-15 and days 7-19 of gestation, respectively) did not show significant toxicity in mouse and rabbit embryo-fetal developmental toxicity tests (emtricitabine exposure was approximately 60 and 108 times the recommended human dose, respectively) no significant toxic effects were observed. In the perinatal developmental toxicity test with emtricitabine, mice were administered doses up to 1000 mg/kg/day and offspring were exposed to emtricitabine daily from prenatal (in utero) to sexual maturity [daily exposure (AUC) was approximately 60 times the recommended daily human exposure] and no significant adverse effects directly related to the drug were observed.
In long-term carcinogenicity studies with emtricitabine, no administration-related increases in tumor incidence were observed at doses up to 750 mg/kg/day in mice (25 times the systemic exposure of the recommended human dose of emtricitabine with Biclopirox) or up to 600 mg/kg/day in rats (30 times the systemic exposure of the recommended human dose of emtricitabine with Biclopirox).
Propofol Tenofovir
Propofol tenofovir was not found to be genotoxic in the bacterial reversion mutation test (Ames test), mouse lymphoma, or rat micronucleus test.
There was no effect on fertility, mating behavior or early embryonic development in male rats given propofol tenofovir (approximately 155 times the human dose of propofol tenofovir in Biclofenac tablets, based on body surface area) from 28 days prior to mating through the mating period and in female rats given propofol tenofovir from 14 days prior to mating through day 7 of gestation. In pregnant rats (25, 100 or 250 mg/kg/day) and pregnant rabbits (10, 30 or 100 mg/kg/day) given orally during the organogenesis period (divided into gestation days 6-17 and gestation days 7-20), exposure to propofol tenofovir was approximately 2 times (rats) and 78 times (rabbits) the recommended daily human dose of emtricitabine in Biclopirox tablets. ) when no adverse embryo-fetal effects were seen. Propofol tenofovir was rapidly converted to tenofovir, and tenofovir exposure in rats and rabbits was 55 (rats) and 86 (rabbits) times the recommended human exposure to tenofovir, respectively. Because propofol tenofovir is rapidly converted to tenofovir in rats and mice, and because tenofovir exposure after propofol tenofovir administration in rats and mice was lower than that after tenofovir dipivoxil fumarate administration, only tenofovir dipivoxil fumarate was used for perinatal developmental toxicity testing, with doses of up to 600 mg/kg/day administered during lactation and tenofovir at day 7 of gestation (day 20 of lactation). Tenofovir exposure at day 7 of gestation (day 20 of lactation) was approximately 12 (19) times the human exposure at the recommended dose of Biclopirox tablets, and no adverse effects were observed in the offspring. Studies in rats and monkeys have demonstrated that tenofovir can be secreted into breast milk. Tenofovir dipivoxil fumarate (up to 600 mg/kg/day) was administered orally to lactating rats and tenofovir was secreted into breast milk up to approximately 24% of the median plasma concentration on day 11 of lactation in the high-dose group of animals. Tenofovir given as a single subcutaneous injection (30 mg/kg) in lactating monkeys was secreted into the milk, with the maximum tenofovir concentration in the milk being approximately 4% of the plasma concentration, yielding an exposure (AUC) of approximately 20% of the exposure in the plasma.
Because propofol tenofovir is rapidly converted to tenofovir in rats and mice, and because tenofovir exposure after propofol tenofovir administration in rats and mice is lower than exposure after tenofovir dipivoxil fumarate administration, carcinogenicity studies were conducted using only tenofovir dipivoxil fumarate. Long-term oral administration of tenofovir disoproxil fumarate was studied for carcinogenicity in mice and rats at exposures up to 10 times (mice) and 4 times (rats) the human exposure at the recommended dose of 300 mg tenofovir disoproxil fumarate, respectively. Tenofovir exposure in these studies was approximately 151 times (mice) and 51 times (rats) the exposure in humans following daily recommended dosing of Biclofenoxol tablets. In the high-dose group of female mice, tenofovir exposure was increased at approximately 151 times the recommended human dose of Biclopirox. Results of the carcinogenicity study in rats were negative.
Very minimal to mild postocular uveal mononuclear cell infiltration of similar severity was observed in dogs receiving propofol tenofovir administration at 3 and 9 months, with reversibility seen after a 3-month recovery period. The systemic exposure in dogs when no ocular toxicity was seen was approximately 7 times (propofol tenofovir) and 14 times (tenofovir) the human exposure at the recommended daily dose of Biclofenac tablets.
Pharmacokinetics]
Absorption
Bictegravir is absorbed after oral administration, reaching peak plasma concentrations 2.0-4.0 hours after B/F/TAF administration. Relative to the fasted state, B/F/TAF administration with a moderate fat meal (~600kcal, 27% fat) or a high fat meal (~800kcal, 50% fat) resulted in an increase in Bictegravir AUC (24%). This moderate change was not considered clinically significant and B/F/TAF may or may not be administered with or without food.
After oral administration of B/F/TAF with or without food in HIV-1-infected adults, the mean (CV%) pharmacokinetic parameters for multiple doses of bictegravir were: Cmax=6.15mcg/mL (22.9%), AUCtau=102mcg-h/mL (26.9%), Ctrough= 2.61mcg/mL (35.2%).
Following oral administration emtricitabine was rapidly and extensively absorbed, reaching peak plasma concentrations 1.5-2.0 h after B/F/TAF administration. the mean absolute bioavailability of emtricitabine in 200 mg hard capsules was 93%. Systemic exposure to emtricitabine was not affected when administered with food, and B/F/TAF could be administered with or without food.
After oral administration of B/F/TAF with or without food in HIV-1-infected adults, the mean (CV%) pharmacokinetic parameters for multiple dosing of emtricitabine were Cmax=2.13mcg/mL (34.7%), AUCtau=12.3mcg-h/mL (29.2%), Ctrough= 0.096mcg/mL (37.4%).
Propofol tenofovir was rapidly and extensively absorbed after oral administration, reaching peak plasma concentrations 0.5-2.0 hours after B/F/TAF administration. Relative to the fasted state, propofol tenofovir administration with a moderate fat meal (~600kcal, 27% fat) and a high fat meal (~800kcal, 50% fat) resulted in a 48% and 63% increase in AUClast, respectively. These moderate changes were not considered clinically significant, and B/F/TAF could be administered with or without food.
After oral administration of B/F/TAF with or without food in HIV-1-infected adults, the mean (CV%) pharmacokinetic parameters of propofol tenofovir administered multiple times were Cmax=0.121 mcg/mL (15.4%) and AUCtau=0.142 mcg-h/mL (17.3%).
Distribution
Bictegravir was bound to human plasma proteins in vitro >99% (free fraction ~0.25%). The in vitro human blood to plasma bictegravir concentration ratio was 0.64.
The in vitro binding of emtricitabine to human plasma proteins<4% and this binding was independent of drug concentration in the range of 0.02 to 200 mcg/mL drug concentration. At peak plasma concentrations, the mean value of the plasma to blood drug concentration ratio was approximately 1.0 and the mean value of the semen to plasma drug concentration ratio was approximately 4.0.
The in vitro binding of tenofovir to human plasma proteins was less than 0.7% and was concentration independent in the range of 0.01-25 mcg/mL. The ex vivo binding of propofol tenofovir to human plasma proteins was approximately 80% in samples collected during the clinical study.
Biotransformation
Metabolism is the primary route of clearance of bictegravir in humans. In vitro phenotyping studies have shown that bictegravir is mainly metabolized via CYP3A and UGT1A1. After a single oral administration of [14C]-bictegravir, ~60% of the dose is eliminated via feces, including the unchanged parent drug, desfluride-hydroxy-bictegravir-cysteine -conjugates and other minor oxidative metabolites. 35% of the dose is recovered from the urine, consisting mainly of bictegravir glucosinolate and other minor oxidative metabolites and their phase II conjugates. The renal clearance of the unchanged parent drug was minimal.
The full dose of [14C]-emtricitabine was recovered in urine (~86%) and feces (~14%) after emtricitabine administration. Thirteen percent of the dose was recovered in urine as the three putative metabolites. Biotransformation of emtricitabine included partial oxidation of thiols to form 3′-sulfoxide diastereoisomers (~9% of the dose) and binding to glucuronide to form 2′-O-glucuronide (~4% of the dose). No other metabolites were identified.
Metabolism is the primary route of elimination of propofol tenofovir in humans, accounting for >80% of the oral dose. In vitro studies have shown that propofol tenofovir is metabolized to tenofovir (the major metabolite) by histone protease A in PBMCs (including lymphocytes and other HIV target cells) and macrophages and by carboxylesterase-1 in hepatocytes. In vivo, propofol tenofovir is hydrolyzed intracellularly to produce tenofovir (the major metabolite), which is phosphorylated to form the active metabolite tenofovir diphosphate. In human clinical studies, a 25 mg oral dose of propofol tenofovir produced more than four times the concentration of tenofovir diphosphate in PBMC compared to a 300 mg oral dose of tenofovir dipivoxil fumarate, and plasma tenofovir concentrations were more than 90% lower than the former.
Elimination
Bictegravir is eliminated primarily by hepatic metabolism. Renal excretion of intact bictegravir is the secondary route of elimination (~1% of the dose). Plasma bictegravir has a half-life of 17.3 hours.
Emtricitabine is primarily excreted by the kidneys through glomerular filtration and active tubular secretion. Plasma emtricitabine has a half-life of approximately 10 hours.
Propofol tenofovir is cleared after metabolism to tenofovir. The median plasma half-lives of propofol tenofovir and tenofovir are 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body primarily by the kidneys through glomerular filtration and active tubular secretion. Renal excretion of complete propofol tenofovir is a secondary route, with less than 1% of the dose cleared in the urine.
Linearity
The multiple dosing pharmacokinetics of bictegravir are dose proportional over the dose range of 25 to 100 mg. The multiple-dose pharmacokinetics of emtricitabine are dose proportional over a dose range of 25 to 200 mg. Propofol tenofovir exposure is dose proportional when the dose range is 8 to 125 mg.
Other Special Populations
Renal Impairment
No clinically relevant differences in bictegravir, propofol tenofovir, or tenofovir pharmacokinetics were observed in healthy subjects and subjects with severe renal impairment (CrCl estimate <30 mL/min). No data are available on the pharmacokinetics of bictegravir or propofol tenofovir in patients with creatinine clearance less than 15 mL/min. Mean emtricitabine systemic exposure was greater in patients with severe renal impairment (CrCl<30mL/min) (33.7μg-h/ml) than in subjects with normal renal function (11.8μg-h/mL).
Hepatic impairment
No clinically relevant changes in bictegravir pharmacokinetics have been observed in subjects with moderate hepatic impairment. Emtricitabine pharmacokinetics have not been studied in subjects with hepatic impairment; however, since emtricitabine is not primarily metabolized by hepatic enzymes, the effect of hepatic impairment should be limited. No clinically relevant changes in the pharmacokinetics of propofol tenofovir or its metabolite tenofovir have been observed in patients with mild, moderate, or severe hepatic impairment.
Age, Gender, and Race
The pharmacokinetics of bictegravir, emtricitabine, and tenofovir in elderly (≥65 years) patients were not adequately evaluated. Population analyses using pooled pharmacokinetic data from adult trials did not identify any clinically relevant differences in exposure to bictegravir, emtricitabine, or propofol tenofovir by age, sex, and race.
[Storage].
Store under 30°C in an airtight container.
Packaging
High-density polyethylene (HDPE) vials with inductively activated aluminum foil-lined polypropylene continuous threaded child-resistant caps containing 30 film-coated tablets. Each bottle contains silica gel desiccant and polyester cotton stopper.
Expiration date
24 months
【Execution standard
Import registration standard: JX20190161
Manufacturer
Licensee’s name: Gilead Sciences International Ltd.
Licensee’s address: Cambridge, CB21 6GT, United Kingdom
Manufacturer’s name: Gilead Sciences Ireland UC
Address of manufacturer: IDA Business & Technology Park, Carrigtohill, County Cork, Ireland
Adverse Drug Reaction Report
Gilead (Shanghai) Pharmaceutical Technology Co.
Domestic Contact Name: Gilead (Shanghai) Pharmaceutical Technology Co.
Address: 31F, No. 1198, Century Avenue, China (Shanghai) Pilot Free Trade Zone
Domestic contact telephone number: 4008201135
cn–jul2019-eu-jun18