Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections, combinations. ATC code: J05AR09

Mechanism of action and pharmacodynamic effects

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is 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.

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 is a nucleoside analogue of cytidine. Tenofovir disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Both emtricitabine and tenofovir have activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain termination.


Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.

Antiviral activity in vitro

The dual-drug combinations and the triple combination of elvitegravir, emtricitabine and tenofovir demonstrated synergistic activity in cell culture. Antiviral synergy was maintained for elvitegravir, emtricitabine, and tenofovir when tested in the presence of cobicistat. No antagonism was observed for any of these combinations.

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the 50% effective concentration (EC50) values were in the range of 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 of 0.53 nM).

Cobicistat has no detectable anti-HIV activity and does not antagonise or enhance the antiviral effects of elvitegravir, emtricitabine, or tenofovir.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013 to 0.64 µM. 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 to 0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 µM).

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04 to 8.5 µM. 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 to 2.2 µM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 to 5.5 µM).

Resistance

In cell culture
Resistance to emtricitabine or tenofovir has been seen in vitro and in the HIV-1 from some patients due to the development of the M184V or M184I emtricitabine resistance substitution in reverse transcriptase or the K65R tenofovir resistance substitution in reverse transcriptase. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected clinically by tenofovir disoproxil and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir, and lamivudine.

Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and zidovudine. The K65R substitution can also be selected by abacavir, stavudine or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the K65R substitution.

In patients, HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil.

HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was most commonly associated with the integrase substitutions T66I, E92Q and Q148R. Additional integrase substitutions observed in cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q, and R263K. HIV-1 with the raltegravir-selected substitutions T66A/K, Q148H/K, and N155H showed cross-resistance to elvitegravir. Primary mutations for raltegravir/elvitegravir do not affect the in vitro susceptibility of dolutegravir as single mutations, and the additional presence of secondary mutations (except Q148) also does not result in relevant fold changes in experiments with site directed mutants.

No development of resistance to cobicistat can be demonstrated in HIV-1 in vitro due to its lack of antiviral activity.

Substantial cross-resistance was observed between most elvitegravir-resistant HIV-1 isolates and raltegravir, and between emtricitabine-resistant isolates and lamivudine. Patients who failed treatment with Stribild and who had HIV-1 with emergent Stribild resistance substitutions harboured virus that remained susceptible to all PIs, NNRTIs, and most other NRTIs.

In treatment-naïve patients
In a pooled analysis of antiretroviral-naïve patients receiving Stribild in Phase 3 studies GS-US-236-0102 and GS-US-236-0103 through Week 144, genotyping was performed on plasma HIV-1 isolates from all patients with confirmed virologic failure or who had HIV-1 RNA > 400 copies/mL at virologic failure, at Week 48, at Week 96, at Week 144 or at the time of early study drug discontinuation. As of Week 144, the development of one or more primary elvitegravir, emtricitabine, or tenofovir resistance-associated substitutions was observed in 18 of the 42 patients with evaluable genotypic data from paired baseline and Stribild treatment-failure isolates (2.6%, 18/701 patients). Of the 18 patients with viral resistance development, 13 occurred through Week 48, 3 occurred between Week 48 to Week 96, and 2 occurred between Week 96 to Week 144 of treatment.
The substitutions that emerged were M184V/I (n = 17) and K65R (n = 5) in reverse transcriptase and E92Q (n = 9), N155H (n = 5), Q148R (n = 3), T66I (n = 2), and T97A (n = 1) in integrase. Other substitutions in integrase that occurred in addition to a primary INSTI resistance substitution each in single cases were H51Y, L68V, G140C, S153A, E157Q, and G163R. Most patients who developed resistance substitutions to elvitegravir developed resistance substitutions to both emtricitabine and elvitegravir. In phenotypic analyses of isolates from patients in the resistance analysis population, 13 patients (31%) had HIV-1 isolates with reduced susceptibility to elvitegravir, 17 patients (40%) had reduced susceptibility to emtricitabine, and 2 patients (5%) had reduced susceptibility to tenofovir.

In Study GS-US-236-0103, 27 patients treated with Stribild had HIV-1 with the NNRTI-associated K103N substitution in reverse transcriptase at baseline and had virologic success (82% at Week 144) similar to the overall population (78%), and no emergent resistance to elvitegravir, emtricitabine, or tenofovir in their HIV-1.

In virologically-suppressed patients
No emergent resistance to Stribild was identified in clinical studies of virologically-suppressed patients who switched from a regimen containing a ritonavir-boosted protease inhibitor (PI+RTV) (Study GS-US-236-0115), an NNRTI (Study GS-US-236-0121) or raltegravir (RAL) (Study GS-US-236-0123).

Twenty patients from these studies who switched to Stribild had the NNRTI-associated K103N substitution in their historical genotype prior to starting initial antiretroviral therapy. Eighteen of these 20 patients maintained virologic suppression through 48 weeks. Due to protocol violation, two patients with historical K103N substitutions discontinued early with HIV-1 RNA < 50 copies/mL.

Clinical experience

The efficacy of Stribild in HIV-1 infected treatment-naïve adult patients is based on the analyses of 144-week data from 2 randomised, double-blinded, active-controlled, Phase 3 studies, GS-US-236-0102 and GS-US-236-0103 (n = 1,408). The efficacy of Stribild in HIV-1 infected virologically-suppressed adult patients is based on the analyses of 48-week data from two randomised, open-label studies (Studies GS-US-236-0115 and GS-US-236-0121) and a single group open-label study (Study GS-US-236-0123) (n = 910; 628 receiving Stribild).


Treatment-naïve HIV-1 infected adult patients
In Study GS-US-236-0102 HIV-1 infected antiretroviral treatment-naïve adult patients received once- daily treatment of Stribild or once-daily treatment of fixed-dose combination of EFV/FTC/tenofovir disoproxil. In Study GS-US-236-0103 HIV-1 infected antiretroviral treatment-naïve adult patients received once daily treatment of Stribild or ritonavir-boosted atazanavir (ATV/r) plus fixed-dose combination of emtricitabine(FTC)/tenofovir disoproxil. For both studies at 48 weeks, the virologic response rate was evaluated in both treatment arms. Virologic response was defined as achieving an undetectable viral load (< 50 HIV-1 RNA copies/mL, snapshot analysis).

Baseline characteristics and treatment outcomes for both Studies GS-US-236-0102 and GS-US-236-0103 are presented in Tables 3 and 4, respectively.

Table 3: Demographic and baseline characteristics of antiretroviral treatment-naïve HIV-1 infected adult subjects in studies GS-US-236-0102 and GS-US-236-0103

Study GS-US-236-0102             Study GS-US-236-0103
Stribild    EFV/FTC/tenofovir       Stribild      ATV/r + disoproxil                         FTC/ n = 348          n = 352            n = 353      tenofovir disoproxil n = 355
Demographic characteristics
Mean age, years (range)                          38.0                              38.0 (18-67)                           (19-72)
Sex
Male                                              89%                           90% Female                                            11%                           10% Ethnicity
White                                             63%                           74% Black/African                                     28%                           17% American
Asian                                           2%                              5% Other                                           7%                              4% Baseline disease characteristicsa
Mean baseline plasma                               4.8                              4.8 HIV-1 RNA (range)                               (2.6-6.5)                        (1.7-6.6) log10 copies/mL
Percentage of subjects                                 33                           40 with viral load
> 100,000 copies/mL
Mean baseline CD4+ cell                              386                           370 count (range), x                                  (3-1,348)                     (5-1,132) 106 cells/L
Percentage of subjects                                 13                           13 with CD4+ cell counts
≤ 200 cells/mm3 a    Patients were stratified by baseline HIV-1 RNA in both studies.


Table 4: Virologic outcome of randomised treatment of studies GS-US-236-0102 and GS-US-236-0103 at Week 48 (snapshot analysis)a and Week 144b

Week 48                                                 Week 144
Study GS-US-236-0102                   Study                    Study                 Study GS-US-236-0103             GS-US-236-0102      GS-US-236-0103
EFV/                       ATV/r +                  EFV/                 ATV/r + Stribild         FTC/         Stribild       FTC/         Strib     FTC/     Stribild      FTC/ n = 348      tenofovir        n = 353     tenofovir        ild    tenofovir n = 353 tenofovir disoproxil                   disoproxil      n = 3 disoproxil              disoproxil n = 352                      n = 355        48      n = 352                n = 355 Virologic success       88%           84%             90%          87%          80%        75%       78%         75% HIV-1 RNA
< 50 copies/mL
Treatment             3.6% (95% CI = -1.6%,            3.0% (95% CI                4.9% (95% CI              3.1% (95% CI difference                    8.8%)                    = -1.9%, 7.8%)             = -1.3%, 11.1%)            = -3.2%, 9.4%) Virologic                7%          7%               5%          5%             7%         10%             8%          7% failurec
No virologic data at Week 48 or 144 window
Discontinued            3%            5%            3%             5%          6%           8%            6%            8% study drug due to AE or deathd
Discontinued            2%            3%            2%             3%          5%           7%            8%            9% study drug due to other reasons and last available
HIV-1 RNA
< 50 copies/mLe
Missing data            0%            0%            0%             0%          1%           0%            1%            1% during window but on study drug a     Week 48 window is between Day 309 and 378 (inclusive).
b     Week 144 window is between Day 967 and 1,050 (inclusive).
c     Includes subjects who had ≥ 50 copies/mL in the Week 48 or Week 144 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
d     Includes patients who discontinued due to adverse event or death at any time point from day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
e     Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.

Stribild met the non-inferiority criteria in achieving HIV-1 RNA < 50 copies/mL when compared to efavirenz/emtricitabine/tenofovir disoproxil and when compared to atazanavir/ritonavir + emtricitabine/tenofovir disoproxil.

In Study GS-US-236-0102, the mean increase from baseline in CD4+ cell count at Week 48 was 239 cells/mm3 in the Stribild-treated patients and 206 cells/mm3 in the EFV/FTC/tenofovir disoproxil
-treated patients. At Week 144, the mean increase from baseline in CD4+ cell count was 321 cells/mm3 in the Stribild-treated patients and 300 cells/mm3 in the EFV/FTC/ tenofovir disoproxil -treated patients. In Study GS-US-236-0103, the mean increase from baseline in CD4+ cell count at Week 48 was 207 cells/mm3 in the Stribild-treated patients and 211 cells/mm3 in the ATV/r+FTC/ tenofovir disoproxil -treated patients. At Week 144, the mean increase from baseline in CD4+ cell count was 280 cells/mm3 in the Stribild-treated patients and 293 cells/mm3 in the ATV/r+FTC/ tenofovir disoproxil -treated patients.


Virologically-suppressed HIV-1 infected patients
In Study GS-US-236-0115 and Study GS-US-236-0121, patients had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to the antiretroviral components of Stribild and must have been suppressed on a PI+RTV or an NNRTI in combination with FTC/ tenofovir disoproxil (HIV-1 RNA < 50 copies/mL) for at least six months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Stribild or stay on their baseline antiretroviral regimen (SBR) for 48 weeks. In Study GS-US-236-0115, virologic success rates were: Stribild 93.8% (272 of 290 patients); SBR 87.1% (121 of 139 patients). The mean increase from baseline in CD4+ cell count at Week 48 was 40 cells/mm3 in the Stribild-treated patients and 32 cells/mm3 in the PI+RTV+FTC/ tenofovir disoproxil -treated patients. In Study GS-US-236-0121, virologic success rates were: Stribild 93.4% (271 of 290 patients) and SBR 88.1% (126 of 143 patients). The mean increase from baseline in CD4+ cell count at Week 48 was 56 cells/mm3 in the Stribild-treated patients and 58 cells/mm3 in the NNRTI+FTC/ tenofovir disoproxil -treated patients.

In Study GS-US-236-0123, patients had to have previously only received RAL in combination with FTC/ tenofovir disoproxil as their first antiretroviral regimen for at least six months. Patients had to be stably suppressed for at least six months prior to study entry, have no current or past history of resistance to the antiretroviral components of Stribild, and have HIV-1 RNA < 50 copies/mL at screening. All 48 patients who received at least one dose of Stribild remained suppressed (HIV-1 RNA < 50 copies/mL) through Week 48. The mean increase from baseline in CD4+ cell count at Week 48 was 23 cells/mm3.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
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 disoproxil. The steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) following multiple doses of Stribild in HIV-1 infected subjects, respectively, were 1.7 ± 0.39 µg/mL, 23 ± 7.5 µg•h/mL, and 0.45 ± 0.26 µg/mL for elvitegravir, which provides inhibitory quotient of ~ 10 (ratio of Ctrough: protein binding-adjusted IC95 for wild-type HIV-1 virus). Corresponding steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) were 1.1 ± 0.40 µg/mL, 8.3 ± 3.8 µg•h/mL, and 0.05 ± 0.13 µg/mL for cobicistat, 1.9 ± 0.5 µg/mL, 13 ± 4.5 µg•h/mL, and 0.14 ± 0.25 µg/mL for emtricitabine, and 0.45 ± 0.16 µg/mL, 4.4 ± 2.2 µg•h/mL, and 0.1 ± 0.08 µg/mL for tenofovir.

Relative to fasting conditions, the administration of Stribild with a light meal (~373 kcal, 20% fat) or high-fat meal (~800 kcal, 50% fat) resulted in increased exposures of elvitegravir and tenofovir. For elvitegravir, Cmax and AUC increased 22% and 36% with a light meal, while increasing 56% and 91% with a high-fat meal, respectively. The Cmax and AUC of tenofovir increased 20% and 25% respectively with a light meal, while the Cmax was unaffected and AUC increased 25% with a high fat meal. Cobicistat exposures were unaffected by a light meal and although there was a modest decrease of 24% and 18% in Cmax and AUC respectively with a high-fat meal, no difference was observed in its pharmacoenhancing effect on elvitegravir. Emtricitabine exposures were unaffected with light or high- fat meal.

Distribution

Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng/mL to 1,600 ng/mL. The mean plasma to blood drug concentration ratio was 1.37. Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2.

Following intravenous administration the volume of distribution of emtricitabine and tenofovir was approximately 1,400 mL/kg and 800 mL/kg, respectively. After oral administration of emtricitabine or tenofovir disoproxil, emtricitabine and tenofovir are widely distributed throughout the body. In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 µg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~ 1.0 and the mean semen to plasma drug concentration ratio was ~ 4.0.
In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL.

Biotransformation

Elvitegravir undergoes oxidative metabolism by CYP3A (major route), and glucuronidation by UGT1A1/3 enzymes (minor route). Following oral administration of boosted [14C]elvitegravir, elvitegravir was the predominant species in plasma, representing ~94% of the circulating radioactivity.
Aromatic and aliphatic hydroxylation or glucuronidation metabolites are present in very low levels, display considerably lower anti-HIV activity and do not contribute to the overall antiviral activity of elvitegravir.

Cobicistat is metabolised via CYP3A and/or CYP2D6-mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat.

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of [14C]emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~ 86%) and faeces (~ 14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2’-O-glucuronide (~ 4% of dose). No other metabolites were identifiable.

In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of a CYP1A1/2 substrate was observed.

Elimination

Following oral administration of [14C]elvitegravir/ritonavir, 94.8% of the dose was recovered in faeces, consistent with the hepatobiliary elimination of elvitegravir; 6.7% of the administered dose was recovered in urine. The median terminal plasma half-life of elvitegravir following administration of Stribild is approximately 12.9 hours.

Following oral administration of [14C]cobicistat, 86% and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of Stribild is approximately 3.5 hours and the associated cobicistat exposures provide elvitegravir Ctrough approximately 10-fold above the protein-binding adjusted IC95 for wild-type HIV-1 virus.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system (human organic anion transporter [hOAT1]) with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. The apparent clearance of tenofovir averaged approximately 307 mL/min. Renal clearance has been estimated to be approximately 210 mL/min, which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.

Elderly

Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been evaluated in the elderly (over 65 years).

Gender

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat-boosted elvitegravir, emtricitabine and tenofovir disoproxil.

Ethnicity

No clinically relevant pharmacokinetic differences due to ethnicity have been identified for cobicistat-boosted elvitegravir, emtricitabine and tenofovir disoproxil.

Paediatric population

The pharmacokinetics of elvitegravir or cobicistat in paediatric subjects have not been fully established. In general, elvitegravir pharmacokinetics in paediatric patients (12 to < 18 years of age) and emtricitabine pharmacokinetics in children (aged 4 months to 18 years of age) are similar to those seen in adults. Tenofovir exposure achieved in 8 paediatric patients (12 to < 18 years of age) receiving oral daily doses of tenofovir disoproxil fumarate 300 mg (tablet) was similar to exposures achieved in adults receiving once-daily doses of 300 mg.

Renal impairment

A study of pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected subjects with severe renal impairment (creatinine clearance below 30 mL/min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. No dose adjustment of elvitegravir or cobicistat is necessary for patients with renal impairment. The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end stage renal disease requiring dialysis, Cmax, and AUC of emtricitabine and tenofovir were increased (see section 4.4).

Hepatic impairment

Both elvitegravir and cobicistat are primarily metabolised and eliminated by the liver. A study of pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dose adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of elvitegravir or cobicistat has not been studied. The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited. Clinically relevant changes in tenofovir pharmacokinetics in patients with hepatic impairment were not observed. Therefore, no tenofovir disoproxil dose adjustment is required in patients with hepatic impairment.

Hepatitis B and/or hepatitis C virus co-infection

Pharmacokinetics of emtricitabine and tenofovir disoproxil have not been fully evaluated in hepatitis B and/or C virus co-infected patients. 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 boosted elvitegravir.

Pregnancy and postpartum

The results reported from a prospective study (IMPAACT P1026s) showed that treatment with cobicistat and elvitegravir-containing regimens during pregnancy results in lower elvitegravir and cobicistat exposures (Table 5).

Table 5: Changes in pharmacokinetic parameters from the IMPAACT P1026s study for elvitegravir and cobicistat in women receiving cobicistat and elvitegravir-containing regimens during the second and third trimesters of pregnancy compared to paired postpartum data 
Comparison to paired             Mean % change of elvitegravir       Mean % change of cobicistat postpartum data, n              pharmacokinetic parametersa         pharmacokinetic parametersa AUC24       Cmax          C24      AUC24       Cmax          C24
2T/PP, n = 14               ↓ 24%b
↓ 8%        ↓ 81%b     ↓ 44% b
↓ 28%  b
↓ 60%b
3T/PP, n = 24               ↓ 44%b
↓ 28% b
↓ 89%b     ↓ 59% b
↓ 38%  b
↓ 76%b
2T = second trimester; 3T = third trimester; PP =postpartum a paired comparisons b P<0.10 compared with postpartum