Immunodeficiency Clinic > Drug Information
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Other Names
GS-9137, JTK-303, EVG, Vitekta®
Combination formulation:
- Stribild® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate)
- Genvoya® (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide)
Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.
Molecular weight: 447.9
Activity
Preclinical pharmacokinetic studies have demonstrated potent anti-HIV activity in vitro with a serum free IC50 of 0.2 nM and an EC90 in peripheral blood mononuclear cells of 12 nM. It has shown additive to synergistic activity with all other antiretrovirals.
In vitro effects on HIV-1 clinical isolates: mean EC50 of 0.62 nM.
Elvitegravir displays antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 value of 0.53 nM). Elvitegravir does not show inhibition of replication of HBV or HCV in cell culture.
Vitekta®: 85 mg (DIN 02411172) and 150 mg (DIN 02411180) tablets.
Combination formulations:
- Stribild®: elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg, DIN 02397137. Green, capsule-shaped, film-coated, debossed with “GSI” on one side and the number “1” surrounded by a square box ( 1 ) on the other side.
- Genvoya®: elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg, DIN 02449498.
Commercial oral liquid available: No.
Stribild®:
Pharmacokinetics of crushed Stribild® tablets were studied in healthy volunteers. Whole tablets with breakfast were compared to:
- Crushed and suspended with breakfast
- Crushed and suspended with enteral nutrition (Nutrison®)
The groups were shown to be bioequivalent for elvitegravir, tenofovir and emtricitabine. Elvitegravir Cmax failed to fall within bioequivalence range (100-120%), but this difference is unlikely to be clinically significant. Cobicistat AUC was reduced by 10% for intervention 1 only.3067
Case report describing successful virological suppression with crushed Stribild in juice.3068
Genvoya®:
In 12 healthy volunteers who took E/C/F/TAF as a single whole dose and dissolved E/C/F/TAF in 120 mL tap water, bioequivalence was established for FTC. EVG Cmax and AUC were higher by 18% and 12%, respectively, and TAF and tenofovir AUC and Cmax were 5-8% lower with dissolved vs intact tablet. These differences are not considered clinically relevant. E/C/F/TAF dissolved rapidly in water and had no unpleasant taste. Dissolving E/C/F/TAF in water may be suitable for those with difficulty swallowing pills.3668
Case report describing a cancer patient who received Genvoya® via a percutaneous gastrostomy tube. The tablet was crushed (pulverized), mixed with 30 mL of tap water, and administered via a syringe followed by 2 x 250 mL cans of enteral feeds (Diabetisource AC). At week 14, the viral load was < 20 copies/mL. The patient died of metastatic cancer within 15 weeks of starting crushed Genvoya®.3251
Stribild®: 1 tablet daily with food.
Elvitegravir: 85 mg daily if taken with concomitant atazanavir/ritonavir or lopinavir/ritonavir; 150 mg daily if taken with concomitant darunavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir
Stribild (EVG/COBI/FTC/TDF)
Neonate/Infant: not approved for neonates/infants
Pediatric/Adolescent:
- Stribild is not approved in Canada for use in children or adolescents <18 years (Gilead CAN 2017)
- Stribild is not approved in the US for use in children/adolescents <12 years or weighing <35 kg (Gilead US Stribild 2019)
- Recommended dosing in US monograph for children >12 years and >35 kg
- 1 tab PO daily with food
Adults >18 years: 1 tab PO daily with food
Genvoya (EVG/COBI/FTC/TAF)
Neonate/Infant: not approved for neonates/infants
Pediatric/Adolescent:
- Genvoya is not approved in the US or in Canada for use in children / adolescents weighing less than 25 kg (Gilead CAN Genvoya 2019)(Gilead US Genvoya 2019)
- Recommended dosing in US and CAN monograph for children >25 kg without known associated resistant mutations
- 1 tab PO daily with food
Adults >18 years: 1 tab PO daily with food
Elvitegravir and cobicistat do not require dosage adjustment required for renal impairment. However, since elvitegravir/cobicistat are coformulated with emtricitabine and either tenofovir disoproxil fumarate (TDF) or tenofovir alafanamide (TAF) which are renally cleared, there are dosing considerations in renal insufficiency.
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil (Stribild®):
Stribild® should not be initiated in patients with estimated creatinine clearance < 70 mL/min. Stribild® should be discontinued if estimated creatinine clearance declines below 50 mL/ min during treatment as dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) cannot be achieved.
Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya®):
Genovoya is not recommended in patients with severe renal impairment (creatinine clearance of 15-30 mL/minute) or end stage renal disease (creatinine clearance <15 mL/minute) who are not receiving chronic hemodialysis. In adults with creatinine clearance <15 mL/minute who are receiving chronic hemodialysis, Genvoya should be administered after completion of hemodialysis treatment.2774
Data
The pharmacokinetics of elvitegravir 150 mg/cobicistat 150 mg QD for 7 days were compared in HIV-negative subjects with severe renal impairment (eGFR < 30 mL/min) vs. those with normal renal function (eGFR ≥ 90 mL/min). Elvitegravir AUC, Cmax and Ctau were 25% ↓, 33% ↓ and 31%↓¯ and cobicistat AUC, Cmax and Ctau were 25% ↑ , 22% ↑ and 13% ↑ , respectively, in subjects with renal impairment vs. normal renal function. Mean eGFR ↓ 11% in the renal impairment group and ↓ 9% in the normal renal function group at day 7 relative to day 1; mean eGFR returned to baseline by day 14; these decreases attributed to transient inhibition of proximal tubular secretion of creatinine by cobicistat.3058
The renal safety of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil or cobicistat (with darunavir 800 mg or atazanavir 300 mg) was assessed in subjects with mild- moderate renal impairment (eGFR 50-89 mL/min). At 24 weeks follow-up, no cases of proximal renal tubulopathy occurred.3059 At 48 weeks follow-up, no cases of proximal renal tubulopathy occurred in the Stribild®-treated subjects.3063
The safety and efficacy of E/C/F/TAF (Genvoya®) given once daily was studied in virologically suppressed HIV-infected adults on chronic hemodialysis. Patients had end stage renal disease (ESRD) (eGFR < 15 mL/min) and on chronic hemodialysis for ≥ 6 mos when they were swtiched to E/C/F/TAF. At week 48, 82% (45/55) maintained a viral load < 50 copies/mL; 4% had a VL > 50 copies/mL (1 resuppressed and 1 had prior resistance to FTC and elvitegravir and resuppressed on dolutegravir + darunavir/COBI); 15% had no virologic data. Exposures of EVG, COBI and TAF were consistent with ranges of historical data in HIV+ adults with normal renal function. Although exposures of tenofovir (renally eliminated metabolite of TAF) and FTC were higher than with TAF and FTC in normal renal function, the regimen maintained a favorable safety and tolerability profile. 78% of patients reported being "much more satisfied" with the STR regimen compared to baseline. Once daily E/C/F/TAF may be a useful option for patients with ESRD.3102
CrCl (mL/min) for men: 〈(140 - age) (weight kg) x 60〉 / 〈(serum creatinine umol/L) (50)〉 CrCl (mL/min) for women: as above multiplied by 0.85 |
The pharmacokinetics of elvitegravir 150 mg/cobicistat 150 mg QD for 10 days were compared in HIV-negative subjects with normal and moderately impaired hepatic function (Child-Pugh Class B). Elvitegravir AUC, Cmax and Ctau were 35% ↑ , 41%% ↑ and 80% ↑ and cobicistat AUC, Cmax were unaffected and Ctau was 108% ↑, respectively, in subjects with hepatic impairment vs. normal hepatic function. These changes are not considered clinically relevant, and dose adjustment is not required in patients with mild to moderate hepatic impairment.3052
No dose adjustment of Stribild® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of Stribild® in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Stribild® is not recommended for use in patients with severe hepatic impairment.
When administered as a fixed dose combination tablet with emtricitabine, tenofovir and cobicistat in healthy volunteers, elvitegravir AUCinf and Cmax ↑ by 34% and 22%, respectively, with a light meal (~373 kcal, 20% fat) and by 87% and 56% with a high-fat meal (~800 kcal, 50% fat).3056
Take fixed dose combination tablet with food.
Pharmacokinetic study in HIV-negative healthy Japanese subjects comparing the bioequiavalence of Stribild® when given with a nutirional protein-rich drink (Ensure- 250 kcal, 8.8 g protein, 8.8 g fat, 34.3 g carbs.) vs. a standard breakfast (413 kcal, 11.4 g protein, 9.6 g fat, 72.2 g carbs) vs. fasting state. Compared to a standard breakfast, administration via fasting state decreased EVG AUC by 50% and TDF by 28%. The AUCs of EVG and TDF were similar with Ensure and a standard breakfast. Cobicistat and FTC were bioequivalent under all conditions.3064
It should be noted that Ensure Regular contains per 235 mL- elemental calcium 300 mg, magnesium 64.9 mg and iron 3.8 mg. (Ensure Regular)
Pharmacokinetic study in HIV-negative healthy Japanese subjects comparing the bioequiavalence of Genvoya® when given with a nutirional protein-rich drink (Ensure- 250 kcal, 8.8 g protein, 8.8 g fat, 34.3 g carbs.) vs. a standard breakfast (413 kcal, 11.4 g protein, 9.6 g fat, 72.2 g carbs) vs. fasting state. Compared to a standard breakfast, administration via fasting state decreased EVG AUC by 50%. The AUC of EVG was similar with Ensure and a standard breakfast. The mean AUC and Cmax of cobi, FTC, TAF and TFV were comparable regardless of food intake or type of meal.3065
It should be noted that Ensure Regular contains per 235 mL- elemental calcium 300 mg, magnesium 64.9 mg and iron 3.8 mg. (Ensure Regular)
In a retrospective analysis of 9 HIV patients who underwent laparoscopic sleeve gastrectomy, all had undetectable viral loads at 1 year post-operatively, including 1 patient on elvitegravir/cobicistat/emtricitabine/TAF and darunavir/ritonavir.3646
Elvitegravir absorption is reduced 45% when administered simultaneously with antacids; separate dosing from antacids or vitamin or mineral supplements containing calcium, zinc or iron by at least 2 hours.
Elvitegravir may be administered simultaneously with proton-pump inhibitors and H2-blockers.
Stribild® can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of Stribild®.
Elvitegravir (in Stribild®) should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. Stribild® should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.
Coadministration of Stribild® is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
Elvitegravir (Stribild®) is also contraindicated with strong CYP3A inducers, which may lead to decreased exposure and possible loss of efficacy.
Protein Binding:
Approximately 98.8% protein bound. The mean blood-to-plasma ratio is 0.73.
Tmax:
4 hours (when administered as Stribild®).
Serum T½:
12.9 hours (when administered as Stribild®).
After single dose administration of [14C] elvitegravir coadministered with 100 mg ritonavir, 94.8 % and 6.7 % of the administered dose was excreted in feces and urine, respectively.
Metabolism:
The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.
Elvitegravir is a modest 2C9 inducer.
Excretion:
95% dose excreted via feces.
After single dose elvitegravir 50 mg/ritonavir 100 mg in 8 healthy male volunteers: elvitegravir Cmax 321 (30.2% CV) ng/mL, AUCinf 5430 ng.hr/mL (35.1% CV).
Steady-state administration in healthy subjects:
- EVG 150/rtv 100 mg QD: Ctrough 448 ng/mL
- EVG 300/rtv 100 mg QD: Ctrough 502 ng/mL
When administered as a fixed dose combination (elvitegravir 150 mg, emtricitabine 200 mg, tenofovir 300 mg, cobicistat 150 mg) in HIV-infected subjects, mean elvitegravir AUC 23.0 ± 7.5 ug.h/mL, Ctrough 0.45 ± 0.26 ug/mL, Cmax 1.7 ± 0.4 ug/mL.
In a randomized study comparing the relative bioavailability and kinetics of elvitegravir 150/emtricitabine 200/tenofovir 300/cobicistat 150 mg fixed-dose tablet versus elvitegravir 150/ritonavir 100 mg plus tenofovir/emtricitabine in 42 healthy subjects, high EVG Ctrough and clinically equivalent tenofovir and FTC exposures were achieved with the fixed-dose tablet relative to ritonavir-boosted EVG.3057
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF.
In adolescents (ages 12-17): Administration of fixed-dose elvitegravir/cobicistat/tenofovir/FTC yielded plasma concentrations within the range of historical adult exposures: elvitegravir AUC ↑ 30%, Cmax ↑ 42%, emtrictabine AUC ↑ 20%, tenofovir AUC ↑ 37% compared to adults. These differences not expected to result in different safety or efficacy profile.3055
Elvitegravir pediatric tablets & suspension: Elvitegravir pediatric tablets and suspension are bioequivalent to adult elvitegravir tablet (all boosted with ritonavir) in healthy adult subjects.3053
Protein-adjusted, in vitro IC50: 7.17 ng/mL
Protein-adjusted, in vitro IC95: 44.9 ng/mL
Estimated IQ of elvitegravir 50/rtv 100 mg dose: 18.8 based on IC50.
Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Guidelines. DHHS Perinatal Guidelines
Genvoya (Elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) and Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil) are not recommended for use in pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters. Genvoya and Stribild should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with Genvoya or Stribild. (Gilead Genvoya monograph)(Gilead Stribild monograph).
Analysis of Canadian data from 22 sites has been reported. Between 2007-2017 a total of 2423 live infants were born whom have data on congenital abnormalities and antiretroviral therapy (ART) in pregnancy. A total rate of 4% (n=98) congenital abnormalities were reported. There was a 10.7% rate (95% CI 2.3%-28.2%) of congenital abnormalities in 28 women on elvitegravir in the first trimester, there were no cases of NTDs reported.3249
A retrospective, multi-centre case series in the US has reported data in 134 pregnant women (140 infant born) who used EVG-containing ART during pregnancy. The rate of viral suppression at delivery was 88.2%. Among the 82 women who received EVG before conception or during the first trimester, there were 2 birth defects reports (1.5%) and no cases of NTDs reported.3456
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 630 pregnancies were identified with elvitegravir exposure. There were no prospective NTD cases reported among 155 pregnancies. There was a total of 2 retrospective NTD cases reported (one with Genvoya, one with Stribild). Authors concluded that the rate of neural tube defects could not be distinguished from the background rate of neural tube defects in the general population.3223
Case Report:
The exposure to elvitegravir (AUC0–24 ) during pregnancy was similar to postpartum. Postpartum elvitegravir AUC and Cmax were relatively low compared with the previously reported values (mean ± SD) of 23 ± 8 mg*h/l and 1.7 ± 0.4 mg/l, respectively. The Cmin (0.06 mg/l) after observed medication intake in the third trimester was approximately 60% lower than postpartum and was below the suggested target concentration of 0.13 mg/l [5]. However, substantial intra-subject variability was observed during pregnancy for Ctrough after unobserved intake: predose concentration of 0.48 mg/l (~C22 h; PK curve) and 0.30 mg/l (~C24h) at delivery.
Cobicistat exposure was 44% lower during pregnancy compared with postpartum. This decrease could hypothetically result in diminished boosting of elvitegravir. This is possibly reflected by the low Cmin of elvitegravir found in the third trimester. Postpartum AUC and Cmax for cobicistat were similar to previously reported values (mean ± SD) of 8.3 ± 3.8 mg*h/l and 1.1 ± 0.4 mg/l, respectively. Authors recommend the use of therapeutic drug monitoring until more data is available.3062
Pharmacokinetic Study:
A prospective study (IMPAACT P1026s) enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat based regimens in the second trimester (20-26 weeks gestation), third trimester (30-38 weeks gestation) and postpartum (6-12 weeks following delivery) to evaluate the pharmacokinetics of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. Compared to paired postpartum data, elvitegravir AUC(0-24) was 24% lower in the second trimester (n=14, p=0.06, 90%CI 0.57-1.0) and 44% lower in the third trimester (n=24, p=0.0001, 90% CI 0.42-0.73). The frequency of women meeting the target AUC(0-24) in the second and third trimesters was 47% and 38% respectively. Similarly, compared to paired postpartum data, cobicistat AUC(0-24h) was 44% lower in the second trimester (n=14, p=0.009, 90% CI 0.37-0.85) and 59% lower in the third trimester (n=24, p<0.0001, 90% CI 0.30-0.57). The proportion of pregnant women who were virologically suppressed was 76.5% in the second trimester, 92.3% in the third trimester, and 76% at both during delivery and postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.3368
In an open-label, multi-centre, observational, phase IV study, elvitegravir exposure was studied in the 3rd trimester of pregnancy and 5-7 weeks postpartum (PANNA Network). Seven patients were included in the study and one of these patients switched late in the 3rd trimester due to resistant virus and only had prenatal pharmacokinetic (PK) profiling done. Six paired PK curves were available. Compared to post-partum PK, 3rd trimester PK showed that the AUC was 33% lower, Cmax 21% lower and Cmin 65% lower (0.06 vs. 0.17 mg/L). Five (71%) vs. one (17%) of the 7 patients has a subtherapeutic trough (< 0.13 mg/L) in the 3rd trimester vs. postpartum, respectively. Near delivery, 6/7 patients had an undetectable viral load. No serious adverse events or birth defects were reported. The cord blood:maternal blood indicate substantial fetal exposure at delivery.3105
Lactation
Elvitegravir is excreted in human breast milk.
Mutations in the integrase gene associated with resistance to elvitegravir (IAS-USA Winter 2017 Resistance Mutations):
- Primary mutations: T66A/I/K, E92G/Q, F121Y, S147G, and Q148H/K/R, N155H.
- Additional integrase substitutions: T97A, R263K. T97A results in only a 2-fold change in elvitegravir susceptibility and may require additional mutations for resistance.
In treatment-naïve HIV-1 infected subjects:
- Failure isolates expressing primary elvitegravir resistance-associated substitutions (N=11) had median decreases in susceptibility to elvitegravir of 44-fold (range: 6- to greater than 198-fold) and 33-fold (range: 4- to greater than 122- fold) compared to wild-type reference HIV-1 and to the respective baseline isolates, respectively. Most subjects (N=10) who developed integrase substitutions associated with elvitegravir resistance also developed the M184I/V RT substitutions, conferring reduced susceptibility to both elvitegravir and emtricitabine.
In preclinical studies, this compound has been found to be fully active against nucleoside-, non-nucleoside- and PI-resistant isolates.
Cross-resistance has been observed among INSTIs.  Elvitegravir-resistant viruses showed varying degrees of cross- resistance in cell culture to raltegravir depending on the type and number of substitutions in HIV-1 integrase. Among the four primary elvitegravir resistance-associated substitutions detected in the STRIBILD-treatment virologic failure isolates, E92Q, Q148R, and N155H individually conferred reduced susceptibility both to elvitegravir (greater than 32-fold) and raltegravir (greater than 5-fold) when introduced into a wild-type virus by site- directed mutagenesis. The T66I substitution conferred greater than 14-fold reduced susceptibility to elvitegravir but less than 3- fold to raltegravir. Among the three primary raltegravir resistance-associated substitutions (Y143H/R, Q148H/K/R, and N155H), all but one (Y143H) conferred significant reductions in susceptibility to elvitegravir (greater than 5-fold).
Most common adverse drug reactions (to Stribild®) are nausea and diarrhea (incidence greater than or equal to 10%, all grades).
Effects reported with tenofovir or Stribild® include new onset or worsening renal impairment, and decreases in bone mineral density. Avoid administering Stribild® with concurrent or recent use of nephrotoxic drugs.
NB: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Stribild®.
Baseline Assessment
Assess creatinine clearance (CrCl), urine glucose and urine protein before initiating treatment with Stribild®.
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 emtricitabine or tenofovir DF, two of the components of Stribild®.
Routine Labs
Monitor CrCl, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment.
Cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.
Consider monitoring bone mineral density (BMD) in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss.
Store at 25C (or between 15°C - 30°C) in original container.
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