Mechanism of Action

STRIBILD is a fixed-dose combination of antiviral drugs elvitegravir boosted by the pharmacokinetic enhancer cobicistat, emtricitabine, and tenofovir DF [See Microbiology].

Pharmacodynamics

Effects on Electrocardiogram

Thorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known.

The effect of multiple doses of elvitegravir 125 and 250 mg (coadministered with 100 mg ritonavir) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 ms, the threshold for regulatory concern. The dose of 250 mg elvitegravir (with 100 mg ritonavir) is expected to cover the high exposure clinical scenario.

The effect of a single dose of cobicistat 250 mg and 400 mg on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was below 10 ms, the threshold for regulatory concern. The dose of 400 mg cobicistat is expected to cover the high exposure clinical scenario. Prolongation of the PR interval was noted in subjects receiving cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) ms for 250 mg dose and 20.2 (22.8) for 400 mg dose cobicistat. Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation.

Pharmacokinetics

Pharmacokinetics in Adults

Absorption and Bioavailability

STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours post-dose for emtricitabine, and 2 hours for tenofovir following the rapid conversion of tenofovir DF (see Table 6 for additional pharmacokinetic parameters).

Table 6 : Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected Subjects

Effect of Food on Oral Absorption

Relative to fasting conditions, the administration of single dose STRIBILD with a light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.

Relative to fasting conditions, the administration of single dose STRIBILD with a high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.

STRIBILD should be taken with food.

Distribution

Elvitegravir: Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73.

Cobicistat: Cobicistat is 97-98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.

Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02–200 micrograms per mL.

Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01–25 micrograms per mL.

Metabolism

Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.

Cobicistat: Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Emtricitabine and tenofovir are not significantly metabolized.

Elimination

Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. 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.

Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [¹⁴C] cobicistat after multiple dosing of cobicistat for six days, 86.2 % and 8.2 % of the administered dose was excreted in feces and urine, respectively.

Emtricitabine and tenofovir are primarily excreted in the urine by a combination of glomerular filtration and active tubular secretion.

Special Populations

Patients with Renal Impairment

Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis, [See WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Patients with Hepatic Impairment

Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [See Use in Specific Populations].

Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.

Hepatitis B and/or Hepatitis C Virus Co-infection

Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of cobicistat boosted elvitegravir.

Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

Race Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.

Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of race on the pharmacokinetics of cobicistat.

Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.

Gender

No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF. There was insufficient pharmacokinetic data in clinical trials to determine the effect of gender on the pharmacokinetics of cobicistat.

Pediatric Patients

Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [See Use in Specific Populations].

Geriatric Patients

Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [See Use In Specific Populations].

Assessment of Drug Interactions

[See also CONTRAINDICATIONSand DRUG INTERACTIONS]

The drug-drug interaction studies described in Tables 7 and 8 were conducted with STRIBILD, elvitegravir (coadministered with cobicistat or ritonavir), or cobicistat administered alone.

As STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided [See WARNINGS AND PRECAUTIONS].

The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 7. The effects of elvitegravir or cobicistat on the exposure of coadministered drugs are shown in Table 8. For information regarding clinical recommendations, see DRUG INTERACTIONS.

Table 7 : Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Drug^a

Table 8 : Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Elvitegravir, Elvitegravir plus Cobicistat, Cobicistat, or STRIBILD^a

Microbiology

Mechanism of Action

Elvitegravir: 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.

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir Disoproxil Fumarate: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity in Cell

Culture Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate: The triple combination of elvitegravir, emtricitabine, and tenofovir was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of cobicistat.

Elvitegravir: The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, monocyte/macrophage cells, and primary peripheral blood lymphocytes. The 50% effective concentrations (EC50) ranged from 0.02 to 1.7 nM. Elvitegravir displayed 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). The antiviral activity of elvitegravir with antiretroviral drugs in two-drug combination studies was not antagonistic when combined with the INSTI raltegravir, NNRTIs (efavirenz, etravirine, or nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine), PIs (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir), the fusion inhibitor enfuvirtide, or the CCR5 coreceptor antagonist maraviroc. Elvitegravir did not show inhibition of replication of HBV or HCV in cell culture.

Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV and does not antagonize the antiviral activity of elvitegravir, emtricitabine, or tenofovir.

Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013–0.64 micromolar. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007– 0.075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 micromolar). No antagonistic effects were observed in two-drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, tenofovir, or zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, or rilpivirine), PIs (amprenavir, nelfinavir, ritonavir, or saquinavir), or the INSTI elvitegravir.

Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 micromolar. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6–5.5 micromolar). No antagonistic effects were observed in two-drug combination studies of tenofovir with NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, or zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, or rilpivirine), PIs (amprenavir, indinavir, nelfinavir, ritonavir, or saquinavir), or the INSTI elvitegravir.

Resistance

In Cell Culture

Elvitegravir: HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M.

Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2–4 fold reduction in susceptibility to tenofovir.

In Treatment-Naïve HIV-1-Infected Subjects

Virus samples from STRIBILD-treatment failure subjects in Studies 102 and 103 who were viremic with HIV-1 RNA greater than 400 copies per mL at virologic failure, at Week 48, or at the time of early study drug discontinuation were evaluated for STRIBILD resistance (genotypic and phenotypic data available for 23 subjects [3%, 23/669]). The development of one or more primary substitutions associated with resistance to elvitegravir, emtricitabine, and/or tenofovir was observed in 57% (13/23) of the viremic subjects with evaluable genotypic data. The most common substitutions that emerged were M184V/I (N=12) in HIV-1 RT and the primary elvitegravir resistance-associated substitutions T66I (N=2), E92Q (N=8), Q148R (N=3), and N155H (N=3) in integrase; K65R in RT was also detected (N=4). In isolates with primary elvitegravir resistance substitutions, additional substitutions in integrase associated with resistance to elvitegravir were H51Y, L68I/V, G140C, S153A, E157Q, V165I, and H₁83P. 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 phenotypic analyses, 50% (11/22) of the viremic subjects with evaluable data had HIV-1 isolates with reduced susceptibility to elvitegravir, 57% (12/21) had reduced susceptibility to emtricitabine, and 10% (2/21) had reduced susceptibility to tenofovir.

Cross Resistance

STRIBILD-treatment failure subject isolates exhibited varying degrees of cross resistance within the INSTI and NRTI drug classes depending on the specific substitutions observed. These isolates remained susceptible to all NNRTIs and protease inhibitors.

Elvitegravir: 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).

Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabineresistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine.

Tenofovir Disoproxil Fumarate: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in HIV-1 RT, all of whom had a reduced response in clinical trials.

Clinical Studies

The efficacy of STRIBILD is based on the analyses of 48-week data from two randomized, double-blind, active-controlled trials, Study 102 and Study 103, in treatment-naive, HIV-1 infected subjects (N=1408, randomized and dosed) with baseline estimated creatinine clearance above 70 mL per min.

In Study 102, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg; N=352) once daily. The mean age was 38 years (range 18-67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀ copies per mL (range 2.6–6.5). The mean baseline CD4+ cell count was 386 cells per mm³ (range 3-1348) and 13% had CD4+ cell counts less than 200 cells per mm³ . Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In Study 103, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=353) once daily or atazanavir 300 mg + ritonavir 100 mg (ATV+RTV) + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) (N=355) once daily. The mean age was 38 years (range 19-72), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀ copies per mL (range 1.7-6.6). The mean baseline CD4+ cell count was 370 cells per mm³ (range 5-1132) and 13% had CD4+ cell count less than 200 cells per mm³ . Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).

Treatment outcomes of Study 102 and Study 103 through 48 weeks are presented in Table 9.

Table 9 : Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 48^a

In Study 102, the mean increase from baseline in CD4+ cell count at Week 48 was 230 cells per mm³ in the STRIBILD-treated subjects and 193 cells per mm³ in the ATRIPLA-treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 48 was 202 cells per mm³ in the STRIBILD-treated subjects and 201 cells per mm³ in the atazanavir + ritonavir + TRUVADA-treated subjects.

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.