Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were administered supratheraputic doses of darunavir/ritonavir 1600/100 mg once daily and 800/100 mg twice daily for seven days.

At the mean maximum darunavir concentration of 6599 ng/mL observed in this study, the mean increase in QTcF was 2.2 ms with a 90% two-sided confidence interval (CI) of -2.0 to 6.3 ms. When evaluating the 2-sided 90% CI on the time-matched mean changes in QTcF versus placebo control, the upper bounds of both darunavir/ritonavir groups never exceeded the 10 ms boundary. In the setting of this trial, darunavir/ritonavir did not appear to prolong the QTc interval.

Pharmacokinetic Properties

11.3 Pharmacokinetics
Pharmacokinetics in Adults
General
Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of PREZISTA 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir.
Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.

The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 4displays the population pharmacokinetic estimates of darunavir after oral administration of PREZISTA/ritonavir 600/100 mg twice daily [based on sparse sampling in 285 patients in study TMC114-C214, 278 patients in Study TMC114-C229 and 119 patients (integrated data) from Studies TMC114-C202 and TMC114-C213] and PREZISTA/ritonavir 800/100 mg once daily [based on sparse sampling in 335 patients in Study TMC114-C211 and 280 patients in Study TMC114- C229] to HIV-1-infected patients.

Table 4: Population Pharmacokinetic Estimates of Darunavir at PREZISTA/ritonavir 800/100 mg once daily(Study TMC114-C211, 48 Week Analysis and Study TMC114-C229 48 week analysis) and PREZISTA/ritonavir 600/100 mg twice daily(Study TMC114-C214, 48 Week Analysis ,Study TMC114-229, 48 Week Analysis and Integrated data from Studies TMC114-C213 and TMC114-C202, Primary 24-Week
Analysis)
Parameter           StudyTMC114-           Study             Study          Study             Studies TMC114- C211                   TMC114-C229       TMC114-        TMC114-C229       C213 and TMC114- PREZISTA/ritonav       PREZISTA/         C214           PREZISTA/         C202 (integrated ir                     ritonavir         PREZISTA       ritonavir         data) 800/100 mg once        800/100 mg        /ritonavir     600/100 mg        PREZISTA/ritonavi daily                  once daily        600/100        twice daily       r N = 335                N = 280           mg twice       N = 278           600/100 mg twice daily                            daily
N = 285                          N =119
AUC24h
(ng·h/mL)*
Mean ± Standard     93026 ± 27050          93334±28626       116796 ±       114302±32681      124698 ± 32286 Deviation                                                    33594
Median (Range)      87854                  87788 (45456-     111632         109401            123336       (67714- (45000-219240)         236920)           (64874-        (48934±32382      212980) 355360)        0)
C0h (ng/mL)
Mean ± Standard     2282 ± 1168            2160±1201         3490       ±   3386±1372         3578 ± 1151 Deviation                                                    1401

Median (Range)        2041                 1896      (184-   3307          3197       (250-   3539 (1255-7368) (368-7242)           7881)             (1517-        11865)
13198)
N = number of subjects with data.
*AUC24h is calculated as AUC12h*2

Absorption and Bioavailability
Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5-4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters.

Effects of Food on Oral Absorption
When administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Therefore, PREZISTA tablets, co-administered with ritonavir, should always be taken with food. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).

Distribution
Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

Metabolism
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study 14 in healthy volunteers showed that after a single dose administration of 400 mg C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV.

Elimination
14
A mass balance study in healthy volunteers showed that after single dose administration of 400 mg C- darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14
C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

Special Populations

Hepatic Impairment
Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Dosage and Administration ( 2.2) and Use in Specific Populations (8.4)].
Hepatitis B or Hepatitis C Virus Co-infection
The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.

Renal Impairment
14
Results from a mass balance study with C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease [see Use in Specific Populations (8.5)].

Gender
Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-infected females compared to males. This difference is not clinically relevant.

Race
Population pharmacokinetic analysis of darunavir in HIV-infected subjects indicated that race had no apparent effect on the exposure to darunavir.

Geriatric Patients
Population pharmacokinetic analysis in HIV-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-infected subjects (n = 12, age ≥ 65) [see Use in Specific Populations (8.3)].

Pediatric Patients

The pharmacokinetics of darunavir in combination with ritonavir in 92 antiretroviral treatment-experienced HIV-1- infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in darunavir exposure that was comparable to the exposures achieved in treatment-experienced adults receiving PREZISTA/ritonavir 600/100 mg twice daily [see Dosage and Administration (2.2)].


Table 5: Population Pharmacokinetic Estimates of Darunavir Exposure (Study TMC114-C212 and Study TMC114-C228) Following Administration of Doses in Tables 1 and 2 
Parameter                Study TMC114-            Study TMC114-C228
C212                         PREZISTA/
PREZISTA/                      ritonavir ritonavir twice daily        twice daily*
N = 74
10 to less than 15       15 to less than 20 kg‡                      kg§
N = 10                   N = 12

AUC24h (ng·h/mL) †
Mean ± Standard          126377 ± 34356
Deviation                                         137896±51420             157760±54080 
Median (Range)           127340 (67054-           124044 (89688-
230720)                  261090)                 132698 (112310-
294840)

C0h (ng/mL)
Mean ± Standard          3948 ± 1363                                       4848± 2143 Deviation                                         4510±2031


Median (Range)             3888 (1836-7821)           4126 (2456-9361)           3927(3046-10292) 
N = number of subjects with data.
* Subjects may have contributed pharmacokinetic data to both the 10 kg to less than 15 kg weight group and the 15 kg to less than 20 kg weight group.
† AUC24h is calculated as AUC12h*2
‡
Calculated from individual pharmacokinetic parameters estimated for Week 2 and Week 4, based on the Week 48 analysis that evaluated a darunavir dose of 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily.

§ The 15 kg to less than 20 kg weight group received 380 mg (3.8 mL) PREZISTA oral suspension twice daily with 48 mg (0.6 mL) ritonavir oral solution twice daily in TMC114-C228..Calculated from individual pharmacokinetic parameters estimated for Week 2 post-dose adjustment visit; Week 24 and Week 48 based on the -Week 48 analysis that evaluated a darunavir dose of 380 mg twice daily.


Drug Interactions

[See also Contraindications (4), Warnings and Precautions (5.5), and Drug Interactions (7).] 
Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.

Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.

Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, Cmax, and Cmin values are summarized in Table 6 (effect of other drugs on darunavir) and Table 7 (effect of darunavir on other drugs). For information regarding clinical recommendations, see Drug Interactions (7).

Several interaction studies have been performed with a dose other than the recommended dose of the co- administered drug or darunavir; however, the results are applicable to the recommended dose of the co- administered drug and/or darunavir.


Table 6: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs 
LS Mean Ratio (90% CI) of
Darunavir
Pharmacokinetic Parameters
With/Without Co-administered Drug
Co-                 Dose/Schedule                                                   No Effect =1.00 Administered            Co-             Darunavir/
Drug                                                     N        PK
Administered         ritonavir
Drug                                              Cmax           AUC              Cmin 
Co-Administration With Other HIV Protease Inhibitors
↔
Atazanavir          300 mg q.d.*                         13
                                      400/100                         1.02         1.03       1.01 mg b.i.d. †                  (0.96-1.09)     (0.94-     (0.88-
1.12)      1.16)
↑
Indinavir          800 mg b.i.d.    400/100        9                 1.11         1.24       1.44 mg b.i.d.                    (0.98-1.26)     (1.09-     (1.13-
1.42)      1.82)

Lopinavir/          400/100 mg      1200/100       14        ↓       0.79         0.62       0.49 Ri onavir              b.i.d.       mg b.i.d.‡                   (0.67-0.92)     (0.53-     (0.39- 533/133.3 mg     1200 mg        15        ↓       0.79        0.73)      0.63) b.i.d.        b.i.d.‡                     (0.64-0.97)      0.59       0.45 (0.50-     (0.38-
0.70)      0.52)
14        ↓
Saquinavir         1000 mg         400/100                           0.83         0.74       0.58 hard gel              b.i.d.       mg b.i.d.                     (0.75-0.92)     (0.63-     (0.47- capsule                                                                          0.86)      0.72) Co-Administration With Other HIV Antiretrovirals
↔
Didanosine         400 mg q.d.     600/100         17            0.93          1.01       1.07 mg b.i.d.                     (0.86-1.00)   (0.95-     (0.95-
1.07       1.21)
↓
Efaviren           600 mg q.d.     300/100         12            0.85          0.87       0.69 mg b.i.d.                     (0.72-1.00)   (0.75-     (0.54-
1.01)      0.87)
↔
Etravirine         200 mg b.i.d.   600/100         15            1.11          1.15       1.02 mg b.i.d.                     (1.01-1.22)   (1.05-     (0.90-
1.2 )      1.17)
↑
Nevir pin          200 mg b.i.d.   400/100         8             1.40 §        1.24 §     1.02 § e                                  mg b.i.d.                     (1.14-1.73)   (0.97-     (0.79- 1.57)      1.32)
↔
Rilpivirine        150 mg q.d.     800/100         15            0.90          0.89       0.89 mg q.d.                       (0.81-1.00)   ( .81-     (0.68-
0.99)      1.16)
↑
Tenofovir         300 mg q.d.    300/100         12               1.16         1.21       1.24 Disoproxil                       mg b.i.d.                        (0.94-       (0.95-     (0.90- Fumarate                                                          1.42)        1.54)      1.69) Co-Administration With HCV NS3-4A Protease Inhibitors
↓
Boceprevir     ^   800 mg three    600/100         11            0.64 (0.58-   0.56       0.41 (0.38- times daily     mg b.i.d.                     0.71)         (0.51-     0.45) 0.61)

Telaprevir         750 mg every    600/100         11║   ↓       0.60          0.60       0.58 8 hours         mg b.i.d.                     (0.56-0.64)   (0.57-     (0.52- 0.63)      0.64)
1125 mg         600/100         15    ↓       0.53 every 12        mg b.i.d.                     (0.47 0.5     0.49       0.42 hours                                         9)            (0.43-     (0.35- 0.55)               0.51)



Co-Administration With Other Drugs
Artemether/Lume 80/480mg (6       600/100 mg           14        ↔     1.00           0.96 (0.90-1.03)    0.87 (0.77- fantrine          doses at 0,     b.i.d.                               (0.93-1.07)                        0.98) 8,24,36,48 and
60 hours)
↔
Carbamazepine       200 mg b.i.d.      600/100          16             1.04           0.99                0.85 mg b.i.d.                       (0.93-1.16)    (0.90-              (0.73- 1.08)               1.00)
↔
Clarithromycin      500 mg b.i.d.      400/100                         0.83           0.87                1.01 mg b.i.d.        7              (0.72-0.96)    (0.75-              (0.81- 1.01)               1.26)
↑
Ketoconazole        200 mg b.i.d.      400/100          14             1.21           1.42                1.73 mg b.i.d.                       (1.04-1.40)    (1.23-              (1.39- 1.65)               2.14)
↔
Omeprazole          20 mg q.d.         400/100          16             1.02           1.04                1.08 mg b.i.d.
(0.95-1.09)    (0.96-              (0.93-
1.13)               1.25)
↔
Paroxetine          20 mg q.d.         400/100          16             0.97           1.02                1.07 mg b.i.d.                       (0.92-1.02)    (0.95-              (0.96- 1.10)               1.19)
↔
Ranitidine          150 mg b.i.d.      400/100          16             0.96           0.95                0.94 g b.i.d.                      (0.89-         (0.90-              (0.90- .05)         1.01)               0.99)
↑
Rifabutin           150 mg q.o.d.      600/100          11             1.42           1.57                1.75 ¶                  mg b.i.d.                       (1.21-1.67)    (1.28-              (1.28- 1.93)               2.37)
↔
Sertraline          50 mg q.d.         400/ 00          13             1.01           0.98                0.94 mg b.i.d.                       (0 89-         (0.84-              (0.76- 1.14)          1.14)               1.16)

N = number of subjects with data
* q.d. = once daily
† b.i.d. = twice daily
‡ The pharmacokinetic parameters of darunavir in this study were compared with the pharmacokinetic parameters following administration of darunavir/ritonavir 600/100 mg b.i.d.
§ Ratio based on between-study comparison.
¶ q.o.d. = every other day
^ AUC is AUC(0-last); N = 10 for Cmin in the reference arm
║ N = 14 for Cmax



Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir
Co-Administered      Dose/Schedule
Drug                                                                         LS Mean Ratio (90% CI) of Co-Administered Drug
Pharmacokinetic Parameters
With/Without Darunavir
No effect =1.00

Co-Administered        Darunavir                      Cmax        AUC          Cmin Drug                   / ritonavir
N       P
K

Co-Administration With Other HIV Protease Inhibitors
↔
Atazanavir          300 mg q.d.* /100      400/100        13              0.89        1.08         1.52 mg ritonavir q.d.      mg b.i.d. †                    (0.78-      (0.94-       (0.99- when administered                                     1.01)       1.24)        2.34) alone

300 mg q.d. when administered with darunavir/ ritonavir
↑
Indinavir           800 mg b.i.d. /100     400/100        9               1.08        1.23         2.25 mg ritonavir b.i.d.    mg b.i.d.                      (0.95-      (1.06-       (1.63- when administered                                     1.22)       1.42)        3.10) alone

800 mg b.i.d. when administered with darunavir/ ritonavir

Lopinavir/          400/100 mg             1200/100       14       ↔      0.98        1.09         1.23 Ritonavir           b.i.d.‡                mg b.i.d.                      (0.78-      (0.86-       (0.90- 1.22)       1.37)        1.69)

533/133.3 mg b.i.d.‡   1200 mg        15       ↔                  1.09         1.13 b.i.d.                         1.11        (0.96-       (0.90-
(0.96-      1.24)        1.42)
1.30)
↔
Saquinavir hard     1000 mg b.i.d. /100    400/100        12              0.94        0.94         0.82 gel capsule         mg ritonavir b.i.d.    mg b.i.d.                      (0.78-      (0.76-       (0.52- when administered                                     1.13)       1.17)        1.30) alone

1000 mg b.i.d.
when administered with darunavir/ ritonavir
 Co-Administration With Other HIV Antiretrovirals
↔                        -
Didanosine          400 mg q. .            600/100       17            0.84     0.91 mg b.i.d.                   (0.59-   (0.75-
1.20)    1.10)
↑
Efavirenz           600 mg q.d.            300/100       12            1.15     1.21     1.17 mg b.i.d.                   (0.97-   (1.08-   (1.01-
1.35)    1.36)    1.36)
↓
Etravirine          100 mg b.i.d.          600/100       14            0.68     0.63     0.51 mg b.i.d.                   (0.57-   (0.54-   (0.44-
0.82)    0.73)    0.61)
↑
Nevirapine          200 mg b.i.d.          400/100       8             1.18     1.27     1.47 mg b.i.d.                       (1.02    (1.12    (1.20
-        -        -
1.37)    1.44)    1.82)
↑
Rilpivirine         150 mg q d.            800/100       14            1.79     2.30     2.78 mg q.d.                     (1.56-   (1.98-   (2.39-
2.06)    2.67)    3.24)
↑
Tenofovir           300 mg q.d.            300/100       12            1.24     1.22     1.37 Disoproxil                                 mg b.i.d.                   (1.08-   (1.10-   (1.19- Fumarate                                                               1.42)    1.35)    1.57) ↑
Maraviroc           150 mg b.i.d.          600/100       12            2.29     4.05     8.00 mg b.i.d.                   (1.46-   (2.94-   (6.35-
3.59)    5.59)    10.1)
↑
Maraviroc           150 mg b.i.d.       600/100          10            1.77     3.10     5.27 mg b.i.d.                      (1.20-   (2.57-   (4.51- with 200                       2.60)    3.7 )    6.15) mg b.i.d.
etravirine
Co-Administration With HCV NS3-4A Protease Inhibitors
↓
Boceprevir          800 mg three times     600/100       12            0.75     0.68     0.65 daily                  mg b.i.d.                   (0.67-   (0.65-   (0.56- 0.85)    0.72)    0.76)
↓
Telaprevir          750 mg every 8         600/100       11║           0.64     0.65     0.68 hours                  mg b.i.d.                   (0.61-   (0.61-   (0.63- 0.67)    0.69)    0.74)
Co-Administration With Other Drugs
↑
Atorvastatin        40 mg q.d. when        300/100       15            0.56     0.85     1.81 administered alone     mg b.i.d.                   (0.48-   (0.76-   (1.37- 0.67)    0.97)    2.40)
10 mg q.d. when administered with darunavir/ ri onavir
Artemether           80 mg                      600/100 mg   15    ↓   0.85 (0.68-   0.91 (0.78-          - single dose                b.i.d.                    1.05)         1.06) Dihydroartemisinin                                           15    ↑   1.06 (0.82-   1.12 (0.96-          - 1.39)         1.30)
Artemether           Artemether/                600/100 mg   15    ↓   0.82 (0.61-   0.84 (0.69-   0.97 (0.90- lumefantrine               b.i.d.                    1.11)         1.02)         1.05) Dihydroartemisinin   80/480 mg (                             15    ↓   0.82 (0.66-   0.82 (0.74-   1.00 (0.82- 6 doses at 0, 8, 24, 36,                             1.01)         0.91)         1.22) Lumefantrine         48, and 60 hours)                       15    ↑   1.65 (1.49-   2.75 (2.46-   2.26 (1.92- 1.83)         3.08)         2.67)


Buprenorphine/       8/2 mg to 16/4 mg          600/100     17    ↔    0.92 §        0.89 §           0.98 § Naloxone             q.d.                       mg b.i.d.              (0.79-        (0.78-           (0.82- 1.08)         1.02)            1.16)

Norbuprenorphine                                            17    ↑    1.36          1.46             1.71 (1.06-        (1.15-           (1.29-
1.74)         1.85)            2.27)

200 mg b.i.d.              600/100     16    ↑    1.43          1.45             1.54 Carbamazepine                                  mg b.i.d.              (1.34-        (1.35-           (1.41- 1.53)         1.57)            1.68)

0.46          0.46             0.48
Carbamazepine                                              16    ↓    (0.43-        (0. 4-           (0.45- epoxide                                                               0.49)         0.49)            0.51) 
↑
Clarithromycin       500 mg b.i.d.              400/100      17        1.26          1.57             2.74 mg b.i.d.              (1.03-        (1.35-           (2.30-
1.54)         1.84)            3.26)

Dextromethorpha      30 mg                      600/100      12   ↑    2.27          2.70         - n                                               mg b.i.d               (1.59-        (1.80- 3.26)         4.05)

↓    0.87          0.96         -
Dextrorphan                                                            (0.77-        (0.90- 0.98)         1.03)
↑                               -
Digoxin              0.4 mg                     600/100      8         1.15          1.36 mg b.i.d.              (0.89-        (0.81-
1.48)         2.27)

Ethinyl estradiol    Ortho-Novum 1/35           600/100     11    ↓    0.68          0.56             0.38 (EE)                 (35 μg EE /                mg b.i.d.              (0.61-        (0.50-           (0.27- 1 mg NE)                                          0.74)         0.63)            0.54) 
0.90          0.86             0.70
Norethindrone                                               11    ↓    (0.83-        (0.75-           (0.51- (NE                                                                    0.97)         0.98)            0.97) ↑
Ketoconazole         200 mg b.i.d.              40 /100      15        2.11          3.12             9.68 mg b.i.d.              (1.81-        (2.65-           (6.44-
2.44)         3.68)            14.55)
                                                            ↓
R-Methadone       55-150 mg q.d.        600/100       16       0.76     0.84         0.85 mg b.i.d.              (0.71-   (0.78-       (0.77-
0.81)    0.91)        0.94)


600/100       12   ↓   0.66     0.58     -
Omeprazole       40 mg single dose     mg b.i.d.              (0.48-   (0.50- 0.90)    0.66)

0.93     0.84     -
5-hydroxy                                                 ↓   (0.71-   (0.77- meprazole                                                   1.21)    0.92) 
↓
Paroxetine        20 mg q.d.            400/100       16       0.64     0.61      0.63 mg b.i.d.              (0.59-   (0.56-    (0.55-
0.71)    0.66)     0.73)
↑                     _
Pravastatin       40 mg                 600/100       14       1.63     1.81 single dose           mg b.i.d.              (0.95-   (1.23-
2.82)    2.66)

Rifabutin         150 mg q.o.d. ¶       600/100       11   ↑   0.72     0.93         1.64 when administered     mg b.i.d. #            (0.55-   (0.80-       (1.48- with                                         0.93)    1.09)        1.81) PREZISTA/ritonavi r
4.77     9.81         27.1
(4.04-   (8.09-       (22.2-
25-O-desacetyl-   300 mg q.d. when                    11   ↑   5.63)    11.9)        33.2) rifabutin         administered alone

Sertraline        50 mg q.d.            400/100       13   ↓   0.56     0.51      0.51 mg b.i.d.              (0.49-   (0.46-    (0.45-
0.63)    0.58)     0.57)
_
Sildenafil        100 mg (single        400/100       16   ↑   0.62     0.97 dose) administered    mg b.i.d.              (0.55-   (0.86- alone                                        0.70)    1.09)


25 mg (single dose) when administered with darunavir/ ritonavir
S-warfarin        10 mg single dose     600/100       12   ↓   0.92     0.79     _ mg b.i.d.              (0.86-   (0.73-
0.97)    0.85)


7-OH-S-warfarin                                       12   ↑   1.42     1.23     _ (1.24-   (0.97-
1.63)    1.57)


 N = number of subjects with data;- = no information available
* q.d. = once daily
† b.i.d. = twice daily
‡ The pharmacokinetic parameters of lopinavir in this study were compared with the pharmacokinetic parameters following administration of lopinavir/ritonavir 400/100 mg b.i.d.
§ ratio is for buprenorphine; mean Cmax and AUC24 for naloxone were comparable when buprenorphine/naloxone was administered with or without PREZISTA/ritonavir
¶ q.o.d. = every other day
# In comparison to rifabutin 300 mg q.d.
║ N = 14 for Cmax
A cocktail study was conducted in 12 healthy volunteers to evaluate the effect of steady state pharmacokinetics of darunavir/ritonavir on the activity of CYP2D6 (using dextromethorphan as probe substrate), CYP2C9 (using warfarin as probe substrate), and CYP2C19 (using omeprazole as probe substrate). The pharmacokinetic results are shown in Table 7.


11.4 Microbiology
Mechanism of Action
Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Antiviral Activity
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 cell culture 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. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.

Resistance
Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild- type HIV had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.

Clinical studies of PREZISTA/ritonavir in treatment-experienced subjects: In a pooled analysis of the 600/100 mg PREZISTA/ritonavir twice daily arms of Studies TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine studies TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M developed most frequently on PREZISTA/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (< 50 copies/mL).
Other substitutions that developed frequently in PREZISTA/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had a > 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some PREZISTA/ritonavir virologic failure isolates. In Study 
TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on PREZISTA/ritonavir.
In the 96-week as-treated analysis of the Phase 3 Study TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving PREZISTA/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on PREZISTA/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes > 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V.
These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post- baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (> 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (> 10-fold) to lopinavir at baseline.

In the 48-week analysis of the Phase 3 Study TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving PREZISTA/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving PREZISTA/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on PREZISTA/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on PREZISTA/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the PREZISTA/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the PREZISTA/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60, 12%) and 4 (4/42, 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.


Clinical studies of PREZISTA/ritonavir in treatment-naive subjects: In the 192-week as-treated analysis censoring those who discontinued before Week 4 of the Phase 3 Study TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving PREZISTA/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the PREZISTA/ritonavir arm, emergent PI resistance-associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43) .

However, none of the darunavir virologic failures had a decrease in darunavir susceptibility (> 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (> 10-fold change) at failure. The reverse transcriptase M184V substitution and resistance to emtricitabine, which was included in the fixed background regimen, was identified in 4 virologic failures from the PREZISTA/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm.


Cross-resistance
Cross-resistance among PIs has been observed. Darunavir has a < 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.

Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed a fold change in EC50 values < 3 for tipranavir, indicative of limited cross-resistance 
between darunavir and tipranavir. In Studies TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change > 3) achieved < 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on PREZISTA/ritonavir 600/100 mg twice daily (> 7 fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).

In Study TMC114-C214, the 7 darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos) amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these 7 were resistant to saquinavir and 5 were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline. .


Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely because the viral targets are different.

Baseline Genotype/Phenotype and Virologic Outcome Analyses
Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of PREZISTA/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as-treated analyses using pooled data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine Studies TMC125-C206 and TMC125C-216 at Week 24 (n=591).

Diminished virologic responses were observed in subjects with 5 or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 8).

Table 8: Response to PREZISTA/ritonavir 600/100mg twice daily by Baseline Number of IAS-Defined Primary PI Resistance-Associated Substitutions: As-treated Analysis of Studies TMC114-C213, TMC114- C202, and TMC114-C215
Studies TMC114-C213, TMC114-C202, TMC114-C215
< 50 copies/mL at Week 96
N=439
# IAS-Defined Primary    Overall                    De Novo ENF                Re-Used/No ENF PI Substitutions
All                 44% (192/439)              54% (61/112)             40% (131/327) 0-4                  50% (162/322)               58% (49/85)             48% (113/237) 5                   22% (16/74)                47% (9/19)                13% (7/55) ≥6                    9% (3/32)                  17% (1/6)                 8% (2/26) 
IAS Primary PI Substitutions (2008): D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M

The presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, 2 and ≥ 3 of these substitutions, respectively.

Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 9. These baseline phenotype groups are based on the select patient populations in the Studies TMC114-C213, TMC114- C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for 
PREZISTA/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir.

Table 9: Response (HIV-1 RNA < 50 copies/mL at Week 96) to PREZISTA/ritonavir 600/100 mg twice daily by Baseline Darunavir Phenotype and by Use of Enfuvirtide (ENF): As-treated Analysis of Studies TMC114-C213, TMC114-C202, and TMC114-C215
Proportion of Subjects with < 50 copies/mL at Week 96
N=417
Baseline           DRV All                          De Novo ENF               Re-Used/ No ENF Phenotype
Overall                  175/417 (42%)              61/112 (54%)              131/327 (40%) 0-7                      148/270 (55%)              44/65 (68%)               104/205 (51%) > 7 - 20                 16/53 (30%)                7/17 (41%)                9/36 (25%) > 20                     11/94 (12%)                6/23 (26%)                5/71 (7%)