Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infection, combinations ATC code: J05AR14


Mechanism of action
Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (KD of 4.5 x 10-12M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.


Cobicistat is a 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 darunavir, where bioavailability is limited and half-life is shortened due to CYP3A-dependent metabolism.

Antiviral activity in vitro
Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM.
These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to > 100 µM.

Cobicistat has no detectable antiviral activity against HIV-1 and does not antagonise the antiviral effect of darunavir.

Resistance
In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM.
Viruses selected in these conditions and showing decreased susceptibility to darunavir (range:       23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. The decreased susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained by the emergence of these protease mutations.

The resistance profile of REZOLSTA is driven by darunavir. Cobicistat does not select any HIV resistance mutations, due to its lack of antiviral activity. The resistance profile of REZOLSTA is supported by two Phase III trials conducted with darunavir/ritonavir in treatment-naïve (ARTEMIS) and treatment-experienced (ODIN) patients and the analysis of 48 week data from trial GS-US-216-130 in treatment-naïve and treatment-experienced patients.

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treated for the first time with REZOLSTA or darunavir/ritonavir 800/100 mg once daily in combination with other ART, and in ART-experienced patients with no darunavir RAMs receiving REZOLSTA or darunavir/ritonavir 800/100 mg once daily in combination with other ART. The table below shows the development of HIV-1 protease mutations and loss of susceptibility to HIV PIs in virologic failures at endpoint in the GS-US-216-130, ARTEMIS and ODIN trials.

GS-US-216-130a                         ARTEMISb                                 ODINb Treatment-naïve       Treatment-experienced      Treatment-naïve      Treatment-experienced Treatment-experienced darunavir/cobicistat      darunavir/cobicistat    darunavir/ritonavir     darunavir/ritonavir        darunavir/ritonavir 800/150 mg                800/150 mg             800/100 mg               800/100 mg                600/100 mg once daily                once daily             once daily               once daily                twice daily N = 295                   N = 18                 N = 343                   N = 294                  N = 296 c
Number of subjects with virologic failure and genotype data that develop mutations at endpoint, n/N Primary              0/8                       1/7                    0/43                      1/60                     0/42 (major) PI mutations
PI RAMs              2/8                       1/7                    4/43                      7/60                     4/42 Number of subjects with virologic failure and phenotype data that show a loss of susceptibility to PIs at endpoint compared to baselined, n/N
HIV PI darunavir            0/8                       0/7                    0/39                      1/58                     0/41 amprenavir           0/8                       0/7                    0/39                      1/58                     0/40 atazanavir           0/8                       0/7                    0/39                      2/56                     0/40 indinavir            0/8                       0/7                    0/39                      2/57                     0/40 lopinavir            0/8                       0/7                    0/39                      1/58                     0/40 saquinavir           0/8                       0/7                    0/39                      0/56                     0/40 tipranavir           0/8                       0/7                    0/39                      0/58                     0/41 

a
Virologic failures selected for resistance testing were defined as: never suppressed: HIV-1 RNA < 1 log10 reduction from baseline and ≥ 50 copies/mL at week 8, confirmed at the following visit; rebound: HIV-1 RNA < 50 copies/mL followed by confirmed HIV-1 RNA to ≥ 400 copies/mL or confirmed > 1 log10 HIV-1 RNA increase from the nadir; discontinuations with HIV-1 RNA ≥ 400 copies/mL at last visit b
Virologic failures based on TLOVR non-VF censored algorithm (HIV-1 RNA > 50 copies/mL) c
IAS-USA lists d
In GS-US-216-130 baseline phenotype was not available


Cross-resistance
In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs was observed. Refer to the table above for information on ARTEMIS and ODIN.

Clinical results
The antiretroviral effect of REZOLSTA is due to the darunavir component. The activity of cobicistat as a pharmacokinetic enhancer to darunavir has been demonstrated in pharmacokinetic trials. In these pharmacokinetic trials, the exposure of darunavir 800 mg boosted with cobicistat 150 mg was consistent with that observed when boosted with ritonavir 100 mg. Darunavir as a component of REZOLSTA is bioequivalent to darunavir 800 mg once daily in combination with cobicistat 150 mg once daily co-administered as single medicinal products (see section 5.2).

The evidence of efficacy of REZOLSTA once daily is based on the analysis of 48 week data from trial GS-US-216-130 in ART-naïve and ART-experienced patients, trial TMC114FD2HTX3001 in ART-naïve patients, and two Phase III trials ARTEMIS and ODIN conducted with darunavir/ritonavir 800/100 mg q.d. in ART-naïve and ART-experienced patients, respectively.

Description of clinical studies of REZOLSTA in adults

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in ART-naïve and ART-experienced patients
GS-US-216-130 is a single-arm, open-label, Phase III trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients (295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg once daily in combination with cobicistat 150 mg once daily with an investigator selected optimised background regimen (OBR) consisting of 2 active NRTIs.

HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir RAMs and plasma HIV-1 RNA ≥ 1,000 copies/mL. The table below shows the efficacy data of the       48 week analyses from the GS-US-216-130 trial:

GS-US-216-130
Treatment-naïve               Treatment-experienced                 All subjects darunavir/cobicistat             darunavir/cobicistat             darunavir/cobicistat Outcomes at week 48                     800/150 mg once daily            800/150 mg once daily            800/150 mg once daily + OBR                            + OBR                            + OBR N = 295                          N = 18                           N = 313 HIV-1 RNA                                    245 (83.1%)                       8 (44.4%)                       253 (80.8%) < 50 copies/mLa mean HIV-1 RNA log                                 -3.01                            -2.39                            -2.97 change from baseline
(log10 copies/mL)
CD4+ cell count mean                               +174                             +102                             +170 change from baselineb a
Imputations according to the TLOVR algorithm b
Last Observation Carried Forward imputation

Efficacy of darunavir/cobicistat fixed-dose combination 800/150 mg once daily in ART-naïve patients TMC114FD2HTX3001 is a randomised, active-controlled, double blind, Phase III trial to evalate the efficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus darunavir/cobicistat fixed-dose combination + emtricitabine/tenofovir disoproxil fumarate. In the  darunavir/cobicistat fixed-dose combination treament arm, 363 HIV-1 infected, adult, treatment-naïve patients were treated.

HIV-1 infected patients who were eligible for this trial had a plasma HIV-1 RNA ≥ 1,000 copies/mL.
The table below shows the 48-week efficacy data of the darunavir/cobicistat arm of the TMC114FD2HTX3001 trial:

TMC114FD2HTX3001 (darunavir/cobicistat arm)
Treatment-naïve darunavir/cobicistat 800/150 mg once daily
Outcomes at week 48
+ emtricitabine/tenofovir disoproxil fumarate
N = 363
HIV-1 RNA < 50 copies/mLa                                         321 (88.4%) Virologic failurea                                                 12 (3.3%) No virologic data in 48-week                                       30 (8.3%) windowa
CD4+ cell count mean                                                      +173.8 change from baselineb a
Imputations according to the Snapshot algorithm.
b
Non completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0 


Description of clinical studies of darunavir/ritonavir in adults

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-naïve patients
The evidence of efficacy of darunavir/ritonavir 800/100 mg once daily is based on the analyses of 192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected patients comparing darunavir/ritonavir 800/100 mg once daily with lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and emtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS trial:

ARTEMIS
Week 48a                                           Week 96b
Outcomes              darunavir/       lopinavir/      Treatment       darunavir/       lopinavir/      Treatment ritonavir        ritonavir       difference      ritonavir        ritonavir       difference 800/100 mg       800/200 mg      (95% CI of      800/100 mg       800/200 mg      (95% CI of once daily       per day         difference)     once daily       per day         difference) N = 343          N = 346                         N = 343          N = 346 HIV-1 RNA                 83.7%            78.3%           5.3%            79.0%            70.8%            8.2% < 50 copies/mLc           (287)            (271)           (-0.5;          (271)            (245)         (1.7; 14.7)d All patients                                               11.2)d
With baseline         85.8%           84.5%            1.3%            80.5%           75.2%             5.3% HIV-RNA             (194/226)       (191/226)       (-5.2; 7.9)d     (182/226)       (170/226)       (-2.3; 13.0)d < 100,000
With baseline        79.5%            66.7%            12.8%          76.1%            62.5%             13.6% HIV-RNA             (93/117)         (80/120)       (1.6; 24.1)d     (89/117)         (75/120)        (1.9; 25.3)d ≥ 100,000
With baseline         79.4%           70.3%            9.2%            78.7%           64.9%             13.9% CD4+ cell           (112/141)       (104/148)          (-0.8;        (111/141)        (96/148)        (3.5; 24.2)d count < 200                                            19.2)d
With baseline         86.6%           84.3%            2.3%            79.2%           75.3%             4.0% CD4+ cell           (175/202)       (167/198)       (-4.6; 9.2)d     (160/202)       (149/198)       (-4.3; 12.2)d count ≥ 200
 median                        +137                +141                        +171           +188 CD4+ cell count change from baseline (x 106/l)e a
Data based on analyses at week 48 b
Data based on analyses at week 96 c
Imputations according to the TLOVR algorithm d
Based on normal approximation to the difference in % response e
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0 
Non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/mL, was demonstrated (at the pre-defined 12% non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the
ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-experienced patients
ODIN is a Phase III, randomised, open-label trial comparing darunavir/ritonavir 800/100 mg once daily versus darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patients with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/mL.
Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimised background regimen (OBR) of ≥ 2 NRTIs.

ODIN
Week 48
Outcomes                                      darunvir/ritonavir          darunvir/ritonavir     Treatment difference 800/100 mg once daily         600/100 mg twice      (95% CI of difference) + OBR                    daily + OBR
N = 294                    N = 296
HIV-1 RNA < 50 copies/mLa                        72.1% (212)                70.9% (210)             1.2% (-6.1; 8.5)b With Baseline
HIV-1 RNA (copies/mL)
< 100,000                                 77.6% (198/255)            73.2% (194/265)          4.4% (-3.0; 11.9) ≥ 100,000                                   35.9% (14/39)              51.6% (16/31)          -15.7% (-39.2; 7.7) With Baseline CD4+ cell count (x 106/l)
≥ 100                                      75.1% (184/245)            72.5% (187/258)          2.6% (-5.1; 10.3) < 100                                       57.1% (28/49)              60.5% (23/38)          -3.4% (-24.5; 17.8) With HIV-1 clade
Type B                                     70.4% (126/179)            64.3% (128/199)          6.1% (-3.4; 15.6) Type AE                                     90.5% (38/42)              91.2% (31/34)          -0.7% (-14.0, 12.6) Type C                                      72.7% (32/44)              78.8% (26/33)           -6.1% (-2.6, 13.7) Otherc                                      55.2% (16/29)              83.3% (25/30)          -28.2% (-51.0, -5.3) mean CD4+ cell count                                +108                       +112                   -5d (-25; 16) change from baseline
(x 106/l)e a
Imputations according to the TLOVR algorithm b
Based on a normal approximation of the difference in % response c
Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX d
Difference in means e
Last Observation Carried Forward imputation


At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/mL, with darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to be non-inferior (at the pre-defined 12% non-inferiority margin) compared to darunavir/ritonavir 600/100 mg twice daily for both ITT and OP populations.


REZOLSTA should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 106/l (see sections 4.2 and 4.4). Limited data is available in patients with HIV-1 clades other than B.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Darunavir exposure was shown to be comparable in a bioavailability trial between REZOLSTA and darunavir/ritonavir 800/100 mg q.d. at steady-state and fed conditions in healthy subjects.
The bioequivalence between REZOLSTA and darunavir/cobicistat 800/150 mg co-administered as single agents was established under fed and fasted conditions in healthy subjects.

Absorption

Darunavir
The absolute oral bioavailability of a single 600 mg dose of darunavir alone is approximately 37%.
Darunavir was rapidly absorbed following oral administration of REZOLSTA in healthy volunteers.
Maximum plasma concentration of darunavir in the presence of cobicistat is generally achieved within 3 to 4.5 hours. Following oral administration of REZOLSTA in healthy volunteers, maximum plasma concentrations of cobicistat were observed 2 to 5 hours post-dose.

When administered with food, the relative exposure of darunavir is 1.7-fold higher as compared to intake without food. Therefore, REZOLSTA tablets should be taken with food. The type of food does not affect exposure to REZOLSTA.

Distribution

Darunavir
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.

Cobicistat
Cobicistat is 97 to 98% bound to human plasma proteins and the mean plasma to blood-drug concentration ratio was approximately 2.

Biotransformation

Darunavir
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.

Cobicistat
Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does not undergo glucuronidation. Following oral administration of 14C-cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of cobicistat.


Elimination
Darunavir
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.

Cobicistat
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 REZOLSTA is approximately 3-4 hours.

Special populations

Paediatric population
The pharmacokinetics of REZOLSTA in paediatric patients aged 3 to 11 years, or weighing < 40 kg, have not been established, no data are available. REZOLSTA is not indicated in paediatric patients aged 12 to 17 years.

Elderly
Darunavir
Limited information is available in this population. Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n = 12, age ≥ 65 years) (see section 4.4).
However, only limited data were available in patients above the age of 65 years.

Cobicistat
Pharmacokinetics of cobicistat have not been fully evaluated in older people (65 years of age and older).

Gender
Darunavir
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.

Cobicistat
No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat.

Renal impairment
REZOLSTA has not been investigated in patients with renal impairment.
Darunavir
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.

Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 mL/min, n = 20) (see sections 4.2 and 4.4).

Cobicistat
A trial of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No meaningful  differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects, consistent with low renal clearance of cobicistat.

Hepatic impairment
REZOLSTA has not been investigated in patients with hepatic impairment.

Darunavir
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose trial with darunavir/ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n = 8) and moderate (Child-Pugh Class B, n = 8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown, therefore, darunavir/ritonavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).

Cobicistat
Cobicistat is primarily metabolised and eliminated by the liver. A trial of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dosage adjustment of REZOLSTA is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

Hepatitis B and/or hepatitis C virus co-infection
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 darunavir and cobicistat (refer to sections 4.4 and 4.8).

Pregnancy and postpartum
Treatment with REZOLSTA during pregnancy results in low darunavir exposure. In women receiving REZOLSTA during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associated enzyme induction (see below).

Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of        Second trimester          Third trimester          Postpartum total darunavir              of pregnancy              of pregnancy           (6-12 weeks) (mean ± SD)                       N=7                       N=6                   N=6 Cmax, ng/mL                  4,340 ± 1,616              4,910 ± 970           7,918 ± 2,199 AUC24h, ng.h/mL             47,293 ± 19,058           47,991 ± 9,879         99,613 ± 34,862 Cmin, ng/mL                    168 ± 149                  184 ± 99            1,538 ± 1,344 
The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as compared with postpartum.