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 darunavir 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 darunavir /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 Pls in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS                         ODIN                       TITAN
Week 192                       Week 48                   Week 48
 darunavir /       darunavir /          darunavir /      darunavir / 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.
Clinical results
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 a
Week 48                                      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
< 50 copies/mlc
All patients                 83.7% (287) 78.3% (271)             5.3%          79.0% (271) 70.8% (245)                8.2% d
(-0.5; 11.2)                                         (1.7; 14.7)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 count          (112/141)        (104/148)          (-0.8; 19.2)d (111/141)          (96/148)            (3.5; 24.2)d < 200
With baseline            86.6%            84.3%              2.3%            79.2%            75.3%               4.0% CD4+ cell count          (175/202)        (167/198)          (-4.6; 9.2)d    (160/202)        (149/198)           (-4.3; 12.2)d ≥ 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
Outcomes                              darunavir /ritonavir           darunavir /ritonavir           Treatment difference 800/100 mg once                600/100 mg twice               (95% CI of daily + OBR                    daily + OBR                    difference) N=294                          N=296
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 count change                          108                            112                     -5d (-25; 16) 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.


Darunavir /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 metabolised 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 30% lower as compared to intake with food. Therefore, Darunavir Teva tablets should be taken with ritonavir 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 alpha 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 metabolised by the 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 metabolised and eliminated by the liver. In a multiple dose study with darunavir 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, Darunavir Teva 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 of     Second trimester of      Third trimester of       Postpartum (6-12 total darunavir          pregnancy (n=12)a        pregnancy (n=12)          weeks) (n=12) (mean ± SD)
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 of          Second trimester of      Third Trimester of      Postpartum (6-12 total darunavir                  pregnancy                pregnancy                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.