Immunodeficiency Clinic > Drug Information
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Other Names
GS-9883, BIC
Combination formulation:
- Biktarvy®: (bictegravir/emtricitabine/tenofovir alafenamide)
Integrase strand transfer inhibitor (INSTI)
- Bictegravir inhibits the strand transfer activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of linear HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the virus.2966
Bictegravir sodium has a molecular formula of C21H17F3N3NaO5 and a molecular weight of 471.4
Activity
The antiviral activity of bictegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes. 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 protein-adjusted EC95 value was 361 nM (0.162 micrograms per mL). Bictegravir displayed antiviral activity in activated PBMCs against clinical isolates of HIV-1 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 <0.05 to 1.71 nM). The EC50 value against a single HIV-2 isolate was 1.1 nM.2966
Bictegravir is available in a fixed dose oral combination tablet called Biktarvy®.
Each Biktarvy® tablet contains 50 mg of bictegravir (BIC) (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate).
The tablets are film-coated, purplish brown, capsule-shaped, and debossed with “GSI” on one side and “9883” on the other side.
Pharmacokinetic bioavailability study:
The bioequivalence of solid (swallowed whole tablet) vs. dissolved in water vs. crushed in applesauce was assessed in a crossover, randomized controlled trial in 18 HIV-negative volunteers. Dissolved B/F/TAF resulted in a very modest increase and decrease in bictegravir and TAF bioavailability, respectively, and met all criteria for bioequivalence, except for TAF Cmax where the lower bound of 90% CI was 74%. Crushed B/F/TAF did not meet criteria for bioequivalence, mainly due to reduced F/TAF bioavailability). If B/F/TAF cannot be swallowed whole, the authors recommend dissolving the tablet in water and taking immediately, rather than crushing it.3539
Case reports:
In a single-centre, retrospective review of 19 patients who received either crushed/dissolved B/F/TAF via enteral tube for at least 1 week (median 19 days), 17 (89%) remained/achieved viral suppression within 1 year of follow-up; 2 participants who did not meet the endpoint were either lost to care or deceased.3728
A 78 year old male with pancreatic cancer, virally suppressed on RPV/F/TDF was switched to B/F/TAF to avoid PPI interactions. Due to dysphagia, B/F/TAF was crushed, diluted in 30-60 mL water and administered via PEG tube. Viral suppression was maintained.3588
A 64 year-old male with HIV suppressed on dolutegravir/abacavir/ lamivudine was diagnosed with esophageal cancer and significant dysphagia. Therapy was changed to crushed Biktarvy® tablets for a smaller tablet size. The patient opted to crush the tablet and dilute in 30-60 mL of water, then administer via the PEG tube, immediately followed by 240 mL of enteral formula (Jevity 1.2). The viral load remained undetectable during 10 months of cancer therapy. The patient was able to resume oral therapy after. 3366
A 39 year-old woman who was antiretroviral experienced and lost to follow-up presented with cerebral toxoplasmosis and was undergoing treatment. Biktarvy® was started with an adequate 4-week virologic response (decreased from 1,023,292 to 1,084 copies/mL). After 2 months, the patient`s condition progressed with acute neurologic deterioration, right hemiparesis and dysphagia due to progressive multifocal leukoencephalopathy. The patient received nasogastric (NG) feeds and Biktarvy® was crushed and administered as a solution via the NG tube x 6 weeks. After 12 weeks of starting Biktarvy® therapy, the viral load was 10,232 copies/mL and resistance testing showed several mutations (M184V,L74I and R263K). Therapy was switched to tenofovir alafenamide, emtricitabine and darunavir/ritonavir with only partial response (viral load 204 copies/mL). It is unknown whether Biktarvy® failure was due to past exposure with possible failure to other ARVs (lopinavir/ritonavir, tenofovir DF, emtricitabine, abacavir, raltegravir) vs. NG administration of crushed tablets.3363
A virally suppressed, 52 year old female was switched to bictegravir/emtricitabine/tenofovir alafenamide. The patient self-administered by dissolving each Biktarvy® tablet in a tablespoon of orange juice for 10 minutes, then swallowing the mixture. At one year follow-up, viral load suppression was maintained. By visual inspection, when a Biktarvy tablet was submerged in orange juice (pH 4), the film coating disappeared after 4 minutes, and the tablet was easily disintegrated after 14 minutes without agitation.3426
Biktarvy® is a three-drug fixed dose combination product containing 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF).
The recommended dosage of Biktarvy® is one tablet taken orally once daily with or without food.2966
Canadian Monograph:
Biktarvy® has been approved for use in pediatric patients weighing > 25 kg.3226
Safety and efficacy of Biktarvy® in pediatric patients weighing less than 25 kg have not been established.
US Monograph:
Biktarvy® has been approved for use in children/adolesents at least 2 years of age and weighing at least 14 kg.3616
- >14 to 25 kg: 1 tab containing BIC 30 mg/FTC 120 mg/TAF 15 mg PO once daily
- < 25 kg: 1 tab containing BIC 50 mg/FTC 200 mg/TAF 25 mg PO once daily
Safety and efficacy data in pediatric patients < 6 years and weight less than 25 kg:
- Interim results have been reported from a prospective, 48-week, single-arm, open-label trial which evaluated safety, efficacy, and pharmacokinetics of a low-dose B/F/TAF (30/120/15mg) once daily tablet in virologically suppressed children > 2yrs weighing 14 to <25 kg. N=12 children were enrolled, median age 6 (range 3-9) years, median weight 20.1 (range 14.6-24.1) kg. Median duration of exposure to study drug was 20.1 (180, 27.1) weeks. Most commonly reported AEs included abdominal pain, diarrhea, upper respiratory tract infection (n=2 each); all were considered grade 1 or 2; no medication discontinuations. N=10/11 children had HIV VL<50 copies/ml at week 12. Bictegravir/FTC/TAF exposures were in the range of older populations.3323
- A prospective, 48-week, single-arm, open-label trial evaluated the safety, efficacy, and pharmacokinetics of a B/F/TAF (50/200/25mg) once daily regimen in virologically suppressed children/adolescents weighing > 25kg. A total of N=100 received bictegravir; N=50 were adolescents aged 12 to <18 years (median age 15 years, median weight 44.8 kg), N=50 were children aged 6 to < 12 years (median age 10, median weight 29.0 kg). Pharmacokinetic parameters were within predefined PK equivalence boundaries and within overall range of exposures observed in adults. Geometric least-squares mean ratio (GLSM): adolescents AUCtau 86.3% (90% CI, 80.0-93.0), Ctau 65.4% (90% CI, 58.3-73.3); children AUCtau 125% (90% CI, 117-134), Ctau 65.4% (90% CI, 88.9% (90% CI 80.6-98.0). B/F/TAF was well tolerated in both groups with no serious adverse events reported. Virological suppression was maintained in all participants.3536
- A clinical trial studied the relative bioavailability and food-effect of a low-dose B/F/TAF (30/120/15mg) once daily tablet in n=54 healthy volunteers n=12 virologically suppressed children >2 years, 14-<25kg. B/F/TAF low-dose tablet provided exposures equivalent to the B/F/TAF adult tablet with no clinically relevent food-effect and no clinically meaningful differences in PK between children taking the low-dose tablet compared to adults.3324 Longer term data at 24 weeks reported low tablet was well tolerated in n=22 children with N=2 transient neutropenia, N=3 abdominal pain.3617
B/F/TAF may be given with or without food.
B/F/TAF tablet may be split, with both halves swallowed separately but within a 10-15 minute window.
B/F/TAF tablet may be dissolved in water and taken immediately but should not be crushed.
The pharmacokinetics of BIC have not been fully evaluated in the elderly (65 years of age and older).
Population pharmacokinetics analysis of HIV- infected subjects in Phase 3 trials of Biktarvy® (BIC/FTC/TAF) showed that age did not have a clinically relevant effect on exposures of BIC and TAF up to 74 years of age.2966
HHS HIV Adult Guidelines recommendations:
- While the monograph does not recommend use in people with CrCl 15-29 ml/minute, there is insufficient evidence to recommend for or against the use of full-dose, daily FTC in people with CrCl <30 mL/min. To allow people to remain on the fixed dose product, some Panel members use full-dose, daily FTC in people with CrCl 15–29 mL/min.
- It is currently not recommended in people with CrCl<15 mL/min who are not on hemodialysis as safety hass not been established in this population.
- In people on chronic hemodialysis, no dose adjustment is necessary; on hemodialysis days, administer after hemodialysis.
Monograph recommendations:
- No dosage adjustment of BIKTARVY is recommended in patients with creatinine clearance ≥ 30 mL per minute or in adult patients with end stage renal disease (Clcr<15 mL/minute) who are receiving chronic hemodialysis. On days of hemodialysis, administer Biktarvy after completion of hemodialysis treatment.3226
- BIKTARVY is not recommended in patients with estimated CrCl ≥ 15 and < 30 mL per minute, or < 15 mL/minute who are not receiving chronic hemodialysis, as the safety of BIKTARVY has not been established in these populations.
Pharmacokinetics in severe renal impairment (Clcr 15-29 mL/min):
The pharmacokinetics of single-dose bictegravir 75 mg was assessed in 10 HIV-uninfected subjects with severe renal impairment (baseline creatinine clearance of 15-29 mL/minute) versus normal matched controls. In the subjects with severe renal impairment, total bictegravir AUC was 27% lower compared to controls, but free bictegravir AUC comparable between groups due to a higher mean bictegravir free fraction in the renal impairment subjects versus controls. These changes are not considered clinically relevant and dose adjustment of bictegravir is not required in patients with mild to severe renal impairment.2874
No clinically relevant differences in the pharmacokinetics of BIC, TAF, or its metabolite tenofovir were observed between subjects with severe renal impairment (CLcr 15 to 29 mL per minute) and healthy subjects.2966 Discontinue BIKTARVY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.2966
B/F/TAF in chronic hemodialysis:
In virologically suppressed adults with HIV with end-stage renal disease on chronic hemodialysis who completed Week 96 on elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, 10 transitioned to bictegravir/emtricitabine/tenofovir alafenamide for 48 weeks. Viral suppression was maintained in all subjects and was well tolerated. Mean bictegravir Ctrough were lower compared to PLWH not on hemodialysis but remained 4- to 7-fold higher than the EC95 for wild-type virus.3421
B/F/TAF in CAPD:
A 75 year old Black woman with ESRD was virally suppressed on dolutegravir, abacavir and lamivudine when initiated on CAPD. She was later switched to B/F/TAF to reduce pill burden, and remained virally suppressed with no adverse drug reactions or relevant changes in laboratory parameters.3740
The pharmacokinetics of single dose bictegravir 75 mg was assessed in 10 HIV-uninfected subjects with moderate hepatic impairment (Child-Pugh-Turcotte score of 7-9) versus normal matched controls. In the subjects with moderate hepatic impairment, total bictegravir AUC was 41% lower compared to controls, but free bictegravir AUC was only 23% lower in hepatic impairment versus controls. These changes are not considered clinically relevant and dose adjustment of bictegravir is not required in patients with mild to moderate hepatic impairment.2874
No dosage adjustment of Biktarvy® is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.2966
Biktarvy® has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and use is not recommended.2966
Biktarvy® can be taken with or without food. 2966
Effect of a high-fat meal (~800kcal, 50% fat) on Biktarvy® components:
- Bictegravir AUC ratio (high-fat meal/fasting): 1.24 ±0.08
- Bictegravir Cmax ratio (high-fat meal/fasting): 1.13 ±0.07 2966
A 64 year old female patient, virally suppressed on raltegravir 400 mg BID, abacavir 600 mg and lamivudine 300 mg once daily, was changed to once daily bictegravir/emtricitabine/tenofovir alafenamide 2 weeks after a Roux-en-Y gastrectomy for gastric cancer. Other comedications included pantoprazole and methadone. Two months after switching to B/F/TAF (i.e., 2.5 months after gastric surgery), a 24-hour pharmacokinetic measurement showed a modest (44%) decrease in bictegravir exposures and increases in F/TAF exposures compared to historical controls. HIV viral RNA remained suppressed out to 6 months follow-up.3540
A 56 year old female who had a sleeve gastrectomy 3 years prior to her HIV diagnosis, initiated bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) wiith calcium citrate and food. Other comedications included lovastatin, lisinopril/hydrochlorothiazide, and vitamin D3. Within 3 weeks, the viral load decreased from 139,790 copies/mL at baseline to 67 copies/mL and 8 weeks after increasing her nutritional supplements to twice-daily calcium and twice-daily multivitamins with minerals, all spaced apart except the morning dose of calcium taken with B/F/TAF and food, the viral load was <40 copies/mL and remained suppressed 3 months at a follow-up visit.3683
Bictegravir is primarily eliminated via hepatic metabolism, with similar contribution by CYP3A4 and UGT1A1. Drugs which are strong CYP3A4 and UGT1A1 inducers can substantially decrease plasma concentrations of bictegravir. Drugs which are strong CYP3A4 and UGT1A1 inhibitors may significantly increase bictegravir plasma concentrations.
Bictegravir inhibits OCT2 and MATE1. Coadministration of bictegravir with substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations.
At clinically relevant concenentrations, bictegravir is not an inhibitor of OATP1B1, OATP1B3, OCT1, BSEP, OAT1, OAT3, CYP or UGT1A1 enzymes.2966
Protein Binding:
- >99% bound to human plasma proteins 2966
- Mean blood-to-plasma ratio is 0.64 2966
Tmax:
2.0 - 4.0 hours 2966
Serum T½:
17.3 hours [Range: 14.8 - 20.7 hours] 2966
Metabolism:
Hepatic metabolism via: CYP3A and UGT1A1 2966
Excretion:
The major route of elimination is through hepatic metabolism of the parent drug.2966
- 35% excreted in urine (single dose)
- 60.3% excreted in feces (single dose)
Multiple dose PK parameters following oral administration of Biktarvy® in adults living with HIV: 2966
- Bictegravir Cmax 6.15 ug/mL
- Bictegravir AUCtau 102 ug⋅h/mL
- Bictegravir Ctrough 2.61 ug/mL
In obese adults:
In a PBPK model, bictegravir Cmax and AUC were predicted to be reduced by 15% and 11%, respectively, in obese (BMI 30-40 kg/m2) vs. non-obese (BM 18.5-30 kg/m2) individuals. Dose adjustment of bictegravir is not required in this population.3578
Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Perinatal Guidelines.
There are insufficient human data on the use of bictegravir in pregnancy to inform a drug-associated risk determination for birth defects and miscarriage.
- Limited human data are available on placental transfer of bictegravir
- Transplacental transfer of bictegravir has been reported in 2 pregnant women treated with bictegravir in PANNA study (cord-blood:maternal-blood plasma ratios 1.49 and 1.42)3534 and in 29 mother-infant pairs (mean cord-blood:maternal blood plasma ratio 1.4)3694
- No evidence of teratogenicity/carcinogenicity in rats or rabbits.
- Insufficient data to assess for teratogenicity in humans
- In a product manufacturer global safety database search of clinical trials, antiretroviral pregnancy registry data, post-marketing and solicited cases and published literature, a total of 25 pregnancies were identified with bictegravir exposure. There were no cases of neural tube defects reports.3223
- In an open-label, single-arm prospective study in n=33 pregnant women with HIV, there were no cases of neural tube defect reports.3694
- In a product manufacturer global safety database search of clinical trials, antiretroviral pregnancy registry data, post-marketing and solicited cases and published literature, a total of 25 pregnancies were identified with bictegravir exposure. There were no cases of neural tube defects reports.3223
- In open-label, single-arm prospective study in n=33 pregnant women with HIV (baseline HIV VL<50), all women (32/32) had HIV VL<50 at delivery and through 18-weeks postpartum. All enrolled neonates (29/29) were HIV PCR negative, and there were no drug-related adverse events reported in women or neonates.3694
- Limited pharmacokinetic data have been reported in human pregnancy.
- Open-label, single-arm, prospective study in n=33 pregnant women with HIV, has reported bictegravir exposure (AUCtau) was decreased by 41% (total) and 59% (unbound) in the third trimester compared to 12 weeks postpartum. Bictegravir Ctrough values were 6.9- and 6.0-fold of IQ1 (0.162 mcg/mL) during the second and third trimesters respectively.3694 Despite lower bictegravir concentrations, the mean bictegravir Ctrough was >6x IQ during pregnancy and all mothers remained virally suppressed.3707
- PANNA study has reported bictegravir exposure (AUC0-24h) was decreased by 35% in the 3rd trimester (33 weeks) compared to postpartum in one pregnant woman. Bictegravir Ctrough (0.63 mg/L) remained above the protein-adjusted IC95 of 0.16 mg/L. Observed cord blood:maternal blood ratios (1.42 and 1.49 in two mother-infant pairs) indicate transplacental transfer of bictegravir. 3534
Lactation
- It is not known if bictegravir is secreted in human milk.
- Bictegravir was dectected in the plasma of nursing rat pups.2966
- It is recommended that HIV infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
In cell culture, HIV-1 isolates with reduced susceptibility to bictegravir were found to express the following amino acid substitutions:
Integrase Substitutions: M50I, R263K, T66I, S153F, S24G, E157K
- M50I, R263K, and M50I+R263K substitutions conferred 1.3-, 2.2-, and 2.9-fold reduced susceptibility to bictegravir, respectively.
- T66I, S153F, and T66I+S153F substitutions conferred 0.4-, 1.9-, and 0.5-fold reductions in bictegravir susceptibility respectively. 2966
In Subjects with No Antiretroviral Treatment History:
Phenotypic resistance analyses of failure isolates found fold-changes in drug susceptibility below the biological or clinical cutoffs for bictegravir, emtricitabine, and tenofovir alafenamide, compared to wild-type reference HIV-1.2966
In Virologically Suppressed Subjects:
In 2 switch trials of virologically suppressed HIV-1 infected subjects (n=572), only one subject with virologic rebound in the resistance analysis population had IN genotypic and phenotypic data, and 2 rebounders had RT genotypic and phenotypic data. No subjects had HIV-1 with treatment-emergent genotypic or phenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide.2966
Cross-resistance has been observed among INSTIs. The susceptibility of bictegravir was tested against 64 clinical isolates expressing known INSTI resistance- associated substitutions listed by IAS-USA (20 with single substitutions and 44 with 2 or more substitutions).
Isolates with a single INSTI-resistance substitution including E92Q, T97A, Y143C/R, Q148R, and N155H showed less than 2-fold reduced susceptibility to bictegravir.
All isolates (n=14) with more than 2.5-fold reduced susceptibility to bictegravir (above the biological cutoff for bictegravir) contained G140A/C/S and Q148H/R/K substitutions; the majority (64.3%, 9/14) had a complex INSTI resistance pattern with an additional INSTI-resistance substitution L74M, T97A, or E138A/K. Of those evaluated isolates containing G140A/C/S and Q148H/R/K substitutions in the absence of additional INSTI-resistance substitutions, 38.5% (5/13) showed more than 2.5-fold reduction.
Site-directed mutant viruses with G118R (dolutegravir and raltegravir treatment-emergent substitution) and G118R+T97A had 3.4- and 2.8-fold reduced susceptibility to bictegravir, respectively.
Bictegravir demonstrated equivalent antiviral activity with less than 2-fold reductions in susceptibility against HIV-1 variants expressing substitutions associated with resistance to NNRTIs, NRTIs, and PIs, compared with the wild-type virus.2966
Baseline Assessment
Test for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine (FTC) or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of Biktarvy®.2966
Prior to initiating 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. Discontinue Biktarvy® in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.2966
Routine Labs
Assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.
Serum Creatinine: Bictegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 48. In trials with healthy adults who recieved 75mg bictegravir (1.5x recommended dose) once daily with food for 14 days, median serum creatinine increased by 0.10 mg/dL.2966
Bilirubin: In trials with antiretroviral naive adults, total bilirubin increases were observed in 12% of subjects administered Biktarvy® through Week 48. Increases were primarily Grade 1 (1.0 to 1.5 x ULN) (9%) and Grade 2 (1.5 to 2.5 x ULN) (3%). 2966
- Store below 30 °C (86 °F).
- Keep container tightly closed.
- Dispense only in original container.