Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors, ATC code: J05AE10.


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.


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.


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 clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to PREZISTA co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these mutations developed during treatment.

Increasing baseline darunavir fold change in EC50 (FC) was associated with decreasing virologic response. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC ≤ 10 are susceptible; isolates with FC > 10 to 40 have decreased susceptibility; isolates with FC > 40 are resistant (see Clinical results).

Viruses isolated from patients on PREZISTA/ritonavir 600/100 mg twice daily experiencing virologic failure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavir after treatment in the vast majority of cases.


The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated for the first time with darunavir in combination with other ART.

The table below shows the development of HIV-1 protease mutations and loss of susceptibility to PIs in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.


ARTEMIS       ODIN                             TITAN

Week 192      Week 48                          Week 48

PREZISTA/     PREZISTA/        PREZISTA/       PREZISTA/ ritonavir     ritonavir        ritonavir       ritonavir
800/100 mg    800/100 mg       600/100 mg      600/100 mg
 once daily    once daily       twice daily     twice daily

N=343         N=294            N=296           N=298
Total number of        55 (16.0%)    65 (22.1%)       54 (18.2%)      31 (10.4%) virologic failuresa,
n (%)

Rebounders             39 (11.4%)    11 (3.7%)        11 (3.7%)       16 (5.4%) 
Never suppressed 16 (4.7%)           54 (18.4%)       43 (14.5%)      15 (5.0%) subjects

Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutationsb at endpoint, n/N

Primary (major) PI 0/43              1/60             0/42            6/28 mutations

PI RAMs                4/43          7/60             4/42            10/28 
Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss of susceptibility to PIs at endpoint compared to baseline, n/N 
PI
 darunavir              0/39          1/58             0/41            3/26  amprenavir             0/39          1/58             0/40            0/22  atazanavir             0/39          2/56             0/40            0/22  indinavir              0/39          2/57             0/40            1/24  lopinavir              0/39          1/58             0/40            0/23 

saquinavir              0/39           0/56                0/40           0/22  tipranavir              0/39           0/58                0/41           1/25 a     TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 copies/ml) b       IAS-USA lists


Cross-resistance

Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.

In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.


Efficacy of PREZISTA 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-naïve patients

The evidence of efficacy of PREZISTA/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 PREZISTA/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               PREZIST      Lopinavi     Treatmen     PREZIS      Lopinavi    Treatmen A/           r/           t            TA/         r/          t ritonavir    ritonavir    difference   ritonavir   ritonavir   difference (95% CI                              (95% CI
800/100      800/200      of           800/100     800/200     of mg once      mg per       difference   mg once     mg per      difference daily        day          )            daily       day         )
N=343        N=346                     N=343       N=346


HIV-1 RNA
< 50 copies/mlc

All patients
83.7%      78.3%      5.3%        79.0%      70.8%      8.2%

(287)      (271)      (-0.5;      (271)      (245)      (1.7;
11.2)d                            14.7)d
With baseline HIV-    85.8%      84.5%      1.3%        80.5%      75.2%      5.3% RNA < 100,000
(194/226) (191/226 (-5.2;         (182/226   (170/226 (-2.3;
)        7.9)d          )          )        13.0)d

With baseline HIV-    79.5%      66.7%      12.8%       76.1%      62.5%      13.6% RNA ≥ 100,000
(93/117)   (80/120)   (1.6;       (89/117)   (75/120)   (1.9;
24.1)d                            25.3)d

With baseline         79.4%      70.3%      9.2%        78.7%      64.9%      13.9% CD4+ cell count
< 200                 (112/141) (104/148 (-0.8;         (111/141   (96/148)   (3.5; )        19.2)d         )                     24.2)d

With baseline         86.6%      84.3%      2.3%        79.2%      75.3%      4.0% CD4+ cell count
≥ 200                 (175/202) (167/198 (-4.6;         (160/202   (149/198 (-4.3; )        9.2)d          )          )        12.2)d
 median CD4+ cell      137        141                    171        188 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 PREZISTA/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 PREZISTA 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 PREZISTA/ritonavir 800/100 mg once daily versus PREZISTA/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

Outcomes              PREZISTA/ritonavir PREZISTA/ritonavir Treatment 800/100 mg once    600/100 mg twice   difference daily + OBR        daily + OBR
(95% CI of
N=294              N=296              difference)

HIV-1 RNA             72.1% (212)         70.9% (210)           1.2% (-6.1; 8.5)b < 50 copies/mla

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        108                  112                   -5d (-25; 16) count 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 PREZISTA/ritonavir 800/100 mg once daily treatment was demonstrated to be non-inferior (at the pre-defined 12% non-inferiority margin) compared to PREZISTA/ritonavir 600/100 mg twice daily for both ITT and OP populations.

PREZISTA/ritonavir 800/100 mg once daily in ART-experienced patients 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 section 4.2 and 4.4).
Limited data is available in patients with HIV-1 clades other than B.


Pregnancy and postpartum

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) during the second and third trimesters, and postpartum. Virologic response was preserved throughout the study period in both arms. No mother to child transmission occurred in the infants born to the 31 subjects who stayed on the antiretroviral treatment through delivery.
There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 infected adults (see sections 4.2, 4.4 and 5.2).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of α1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.

Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.


Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is lower as compared to intake with food. Therefore, PREZISTA tablets should be taken with biciritonavir and with food. The type of food does not affect exposure to darunavir.

Distribution
Darunavir is approximately 95% bound to plasma proteins. 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.

Biotransformation

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized 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.

Elimination
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.


Special Populations
Elderly
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) (see section 4.4). However, only limited data were available in patients above the age of 65 year.

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

Renal impairment
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).

Hepatic Impairment
Darunavir is primarily metabolized and eliminated by the liver.
In a multiple dose study with PREZISTA co-administered with 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, PREZISTA 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).

Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e.
active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.



Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum 
Pharmacokinetics        Second trimester     Third trimester of       Postpartum of total darunavir       of pregnancy           pregnancy            (6-12 weeks) 
(mean ± SD)                     (n=12)a           (n=12)                 (n=12) 
Cmax, ng/ml                 4,668 ± 1,097      5,328 ± 1,631         6,659 ± 2,364 
AUC12h, ng.h/ml           39,370 ± 9,597      45,880 ± 17,360       56,890 ± 26,340 
Cmin, ng/ml                   1,922 ± 825      2,661 ± 1,269         2,851 ± 2,216 a n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum 
Pharmacokinetics        Second trimester    Third Trimester of        Postpartum of total darunavir        of pregnancy          pregnancy            (6-12 weeks) 
(mean ± SD)                     (n=17)            (n=15)                 (n=16) 
Cmax, ng/ml                 4,964 ± 1,505      5,132 ± 1,198         7,310 ± 1,704 
AUC24h, ng.h/ml          62,289 ± 16,234      61,112 ± 13,790       92,116 ± 29,241 
Cmin, ng/ml                   1,248 ± 542       1,075 ± 594          1,473 ± 1,141 

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.