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Prezista

CLINICAL PHARMACOLOGY

Mechanism Of Action

Darunavir is an HIV-1 antiviral drug.

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.

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 12 displays 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 12: 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-C229, 48-Week Analysis and Integrated Data from Studies TMC114-C213 and TMC114C202, Primary 24-Week Analysis)

Parameter  Study TMC114-C211 PREZISTA/ ritonavir 800/100 mg once daily
N = 335 
Study TMC114-C229 PREZISTA/ ritonavir 800/100 mg once daily
N = 280 
Study TMC114-C214 PREZISTA/ ritonavir 600/100 mg twice daily
N = 285 
Study TMC114-C229 PREZISTA/ ritonavir 600/100 mg twice daily
N = 278 
Studies TMC114-C213 and TMC114C202 (integrated data) PREZISTA/ ritonavir 600/100 mg twice daily
N =119 
AUC24h (ng•h/mL)* 
Mean ± Standard Deviation  93026 ± 27050  93334 ± 28626  116796 ± 33594  114302 ± 32681  124698 ± 32286 
Median (Range)  87854 (45000-219240)  87788 (45456-236920)  111632 (64874-355360)  109401 (48934-323820)  123336 (67714-212980) 
C0h (ng/mL) 
Mean ± Standard Deviation  2282 ± 1168  2160 ± 1201  3490 ± 1401  3386 ± 1372  3578 ± 1151 
Median (Range)  2041 (368-7242)  1896 (184-7881)  3307 (1517-13198)  3197 (250-11865)  3539 (1255-7368) 
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 suggest that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters.

Effects of Food on Oral Absorption

When PREZISTA tablets were 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 in healthy volunteers showed that after a single dose administration of 400 mg 14C-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-1.

Elimination

A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-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 and Use in Specific Populations].

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

Results from a mass balance study with 14C-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-1-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].

Gender

Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.

Race

Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.

Geriatric Patients

Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65) [see Use In Specific Populations].

Pediatric Patients

PREZISTA/ritonavir administered twice daily:

The pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment-experienced HIV-1infected 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 similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving PREZISTA/ritonavir 600/100 mg twice daily [see DOSAGE AND ADMINISTRATION].

PREZISTA/ritonavir administered once daily: The pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment-na´ve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving PREZISTA/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naive adults receiving PREZISTA/ritonavir 800/100 mg once daily. [see DOSAGE AND ADMINISTRATION]. Based on population pharmacokinetic modeling and simulation, the proposed PREZISTA/ritonavir once daily dosing regimens for pediatric patients 3 to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-na´ve adults receiving PREZISTA/ritonavir 800/100 mg once daily [see DOSAGE AND ADMINISTRATION]. The population pharmacokinetic parameters in pediatric subjects with PREZISTA/ritonavir administered once or twice daily are summarized in the table below.

Table 13: Population Pharmacokinetic Estimates of Darunavir Exposure (Study TMC114-C230, Study TMC114-C212 and Study TMC114-C228) Following Administration of Doses in Tables 2 and 3

Parameter  Study TMC114-C230 PREZISTA/ ritonavir once dailyβ
N = 12 
Study TMC114C212 PREZISTA/ ritonavir twice daily
N = 74 
Study TMC114-C228 PREZISTA/ ritonavir twice daily* 
10 to less than 15 kg‡
N = 10 
15 to less than 20 kg§
N = 13 
AUC24h (ng•h/mL) † 
Mean ± Standard Deviation  84390 ± 23587  126377 ± 34356  137896 ± 51420  157760 ± 54080 
Median (Range)  86741 (35527-123325)  127340 (67054-230720)  124044 (89688-261090)  132698 (112310 – 294840) 
C0h (ng/mL) 
Mean ± Standard Deviation  2141 ± 865  3948 ± 1363  4510 ± 2031  4848 ± 2143 
Median (Range)  2234 (542-3776)  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.
β Summary statistics for population pharmacokinetic parameter estimates for DRV after administration of DRV/rtv at 800/100 mg q.d. in treatment-na´ve HIV-1 infected subjects from 12 to < 18 years of age –Week-48 Analyses

Drug Interactions

[See also CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS]

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 14 (effect of other drugs on darunavir) and Table 15 (effect of darunavir on other drugs). For information regarding clinical recommendations, see DRUG INTERACTIONS.

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 14: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs

Co-Administered Drug  Dose/Schedule  PK  LS Mean Ratio (90% CI) of Darunavir Pharmacokinetic Parameters With/Without Co-administered Drug No Effect =1.00 
Co-Administer ed Drug  Darunavir/ ritonavir  Cmax  AUC  Cmin 
Co-Administration With Other HIV Protease Inhibitors 
Atazanavir  300 mg q.d.*  400/100 mg b.i.d. †  13 1.02
(0.96-1.09) 
1.03
(0.94-1.12) 
1.01
(0.88-1.16) 
Indinavir  800 mg b.i.d.  400/100 mg b.i.d.  9 1.11
(0.98-1.26) 
1.24
(1.09-1.42) 
1.44
(1.13-1.82) 
Lopinavir/ Ritonavir  400/100 mg b.i.d. 1200/100 mg b.i.d.‡ 14 0.79
(0.67-0.92)
0.62
(0.53-0.73)
0.49
(0.39-0.63)
533/133.3 mg b.i.d.  1200 mg b.i.d.‡  15  0.79
(0.64-0.97) 
0.59
(0.50-0.70) 
0.45
(0.38-0.52) 
Saquinavir hard gel capsule  1000 mg b.i.d.  400/100 mg b.i.d.  14 0.83
(0.75-0.92) 
0.74
(0.63-0.86) 
0.58
(0.47-0.72) 
Co-Administration With Other HIV Antiretrovirals 
Didanosine  400 mg q.d.  600/100 mg b.i.d.  17 0.93
(0.86-1.00) 
1.01
(0.95-1.07) 
1.07
(0.95-1.21) 
Efavirenz  600 mg q.d.  300/100 mg b.i.d.  12 0.85
(0.72-1.00) 
0.87
(0.75-1.01) 
0.69
(0.54-0.87) 
Etravirine  200 mg b.i.d.  600/100 mg b.i.d.  15 1.11
(1.01-1.22) 
1.15
(1.05-1.26) 
1.02
(0.90-1.17) 
Nevirapine  200 mg b.i.d.  400/100 mg b.i.d.  8 1.40 §
(1.14-1.73) 
1.24 §
(0.97-1.57) 
1.02 §
(0.79-1.32) 
Rilpivirine  150 mg q.d.  800/100 mg q.d.  15 0.90
(0.81-1.00) 
0.89
(0.81-0.99) 
0.89
(0.68-1.16) 
Tenofovir Disoproxil Fumarate  300 mg q.d.  300/100 mg b.i.d.  12 1.16
(0.94-1.42) 
1.21
(0.95-1.54) 
1.24
(0.90-1.69) 
Co-Administration With HCV NS3-4A Protease Inhibitors 
Boceprevir^  800 mg three times daily  600/100 mg b.i.d.  11 0.64
(0.58-0.71) 
0.56
(0.51-0.61) 
0.41
(0.38-0.45) 
Telaprevir  750 mg every 8 hours 600/100 mg b.i.d. 11|| 0.60
(0.56-0.64)
0.60
(0.57-0.63)
0.58
(0.52-0.64)
1125 mg every 12 hours  600/100 mg b.i.d.  15  0.53
(0.47-0.59) 
0.49
(0.43-0.55) 
0.42
(0.35-0.51) 
Co-Administration With Other Drugs 
Artemether/ Lumefantrine  80/480 mg
(6 doses at 0, 8, 24, 36, 48, and 60 hours) 
600/100 mg b.i.d.  14 1.00
(0.93-1.07) 
0.96
(0.90-1.03) 
0.87
(0.77-0.98) 
Carbamazepine  200 mg b.i.d.  600/100 mg b.i.d.  16 1.04
(0.93-1.16) 
0.99
(0.90-1.08) 
0.85
(0.73-1.00) 
Clarithromycin  500 mg b.i.d.  400/100 mg b.i.d.  17 0.83
(0.72-0.96) 
0.87
(0.75-1.01) 
1.01
(0.81-1.26) 
Ketoconazole  200 mg b.i.d.  400/100 mg b.i.d.  14 1.21
(1.04-1.40) 
1.42
(1.23-1.65) 
1.73
(1.39-2.14) 
Omeprazole  20 mg q.d.  400/100 mg b.i.d.  16 1.02
(0.95-1.09) 
1.04
(0.96-1.13) 
1.08
(0.93-1.25) 
Paroxetine  20 mg q.d.  400/100 mg b.i.d.  16 0.97
(0.92-1.02) 
1.02
(0.95-1.10) 
1.07
(0.96-1.19) 
Ranitidine  150 mg b.i.d.  400/100 mg b.i.d.  16 0.96
(0.89-1.05) 
0.95
(0.90-1.01) 
0.94
(0.90-0.99) 
Rifabutin  150 mg q.o.d. ¶  600/100 mg b.i.d.  11 1.42
(1.21-1.67) 
1.57
(1.28-1.93) 
1.75
(1.28-2.37) 
Sertraline  50 mg q.d.  400/100 mg b.i.d.  13 1.01
(0.89-1.14) 
0.98
(0.84-1.14) 
0.94
(0.76-1.16) 
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 15: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir

Co-Admministered Drug  Dose/Schedule  PK  LS Mean Ratio (90% CI) of Co-Administered Drug Pharmacokinetic Parameters With/Without Darunavir No effect =1.00 
Co-Administered Drug  Darunavir/ ritonavir  Cmax  AUC  Cmin 
Co-Administration With Other HIV Protease Inhibitors 
Atazanavir  300 mg q.d.* /100 mg ritonavir q.d. when administered alone
300 mg q.d. when administered with darunavir/ ritonavir 
400/100 mg b.i.d. †  13 0.89
(0.78-1.01) 
1.08
(0.94-1.24) 
1.52
(0.99-2.34) 
Indinavir  800 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone
800 mg b.i.d. when administered with darunavir/ ritonavir 
400/100 mg b.i.d.  9 1.08
(0.95-1.22) 
1.23
(1.06-1.42) 
2.25
(1.63-3.10) 
Lopinavir/ Ritonavir  400/100 mg b.i.d.‡ 1200/100 m g b.i.d. 14 0.98
(0.78-1.22)
1.09
(0.86-1.37)
1.23
(0.90-1.69)
533/133.3 mg b.i.d.‡  1200 mg b.i.d.  15  1.11
(0.96-1.30) 
1.09
(0.96-1.24) 
1.13
(0.90-1.42) 
Saquinavir hard gel capsule  1000 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone
1000 mg b.i.d. when administered with darunavir/ ritonavir 
400/100 mg b.i.d.  12 0.94
(0.78-1.13) 
0.94
(0.76-1.17) 
0.82
(0.52-1.30) 
Co-Administration With Other HIV Antiretrovirals 
Didanosine  400 mg q.d.  600/100 mg b.i.d.  17 0.84
(0.59-1.20) 
0.91
(0.75-1.10) 
-
Dolutegravir  30 mg q.d  600/100 mg b.i.d.  15 0.89
(0.83-0.97) 
0.78
(0.72-0.85) 
0.62?
(0.56-0.69) 
Dolutegravir  50 mg q.d.  600/100 mg b.i.d. with 200 mg b.i.d. etravirine  9 0.88
(0.78-1.00) 
0.75
(0.69-0.81) 
0.63 ?
(0.52-0.76) 
Efavirenz  600 mg q.d.  300/100 mg b.i.d.  12 1.15
(0.97-1.35) 
1.21
(1.08-1.36) 
1.17
(1.01-1.36) 
Etravirine  100 mg b.i.d.  600/100 mg b.i.d.  14 0.68
(0.57-0.82) 
0.63
(0.54-0.73) 
0.51
(0.44-0.61) 
Nevirapine  200 mg b.i.d.  400/100 mg b.i.d.  8 1.18
(1.02-1.37) 
1.27
(1.12-1.44) 
1.47
(1.20-1.82) 
Rilpivirine  150 mg q.d.  800/100 mg q.d.  14 1.79
(1.56-2.06) 
2.30
(1.98-2.67) 
2.78
(2.39-3.24) 
Tenofovir Disoproxil Fumarate  300 mg q.d.  300/100 mg b.i.d.  12 1.24
(1.08-1.42) 
1.22
(1.10-1.35) 
1.37
(1.19-1.57) 
Maraviroc  150 mg b.i.d.  600/100 mg b.i.d.  12 2.29
(1.46-3.59) 
4.05
(2.94-5.59) 
8.00
(6.35-10.1) 
Maraviroc  150 mg b.i.d.  600/100 mg b.i.d. with 200 mg b.i.d. etravirine  10 1.77
(1.20-2.60) 
3.10
(2.57-3.74) 
5.27
(4.51-6.15) 
Co-Administration With HCV NS3-4A Protease Inhibitors 
Boceprevir  800 mg three times daily  600/100 mg b.i.d.  12^  0.75
(0.67-0.85) 
0.68
(0.65-0.72) 
0.65
(0.56-0.76) 
Telaprevir  750 mg every 8 hours  600/100 mg b.i.d.  11|| 0.64
(0.61-0.67) 
0.65
(0.61-0.69) 
0.68
(0.63-0.74) 
Co-Administration With Other Drugs 
Atorvastatin  40 mg q.d. when administered alone 10 mg q.d. when administered with darunavir/ ritonavir  300/100 mg b.i.d.  15 0.56
(0.48-0.67) 
0.85
(0.76-0.97) 
1.81
(1.37-2.40) 
Artemether Dihydroartemisinin  80 mg single dose  600/100 mg b.i.d.  15 0.85
(0.68-1.05) 
0.91
(0.78-1.06) 
-
15 1.06
(0.82-1.39) 
1.12
(0.96-1.30) 
-
Artemether Dihydroartemisinin Lumefantrine  Artemether/ lumefantrine 80/480 mg
(6 doses at 0, 8, 24, 36, 48, and 60 hours) 
600/100 mg b.i.d.  15 0.82
(0.61-1.11) 
0.84
(0.69-1.02) 
0.97
(0.90-1.05) 
15 0.82
(0.66-1.01) 
0.82
(0.74-0.91) 
1.00
(0.82-1.22) 
15 1.65
(1.49-1.83) 
2.75
(2.46-3.08) 
2.26
(1.92-2.67) 
Buprenorphine/ Naloxone Norbuprenorphine  8/2 mg to 16/4 mg q.d.  600/100 mg b.i.d.  17 0.92 §
(0.79-1.08)
0.89 §
(0.78-1.02)
0.98 §
(0.82-1.16)
17  1.36
(1.06-1.74) 
1.46
(1.15-1.85) 
1.71
(1.29-2.27) 
Carbamazepine  200 mg b.i.d.  600/100 mg b.i.d.  16 1.43
(1.34-1.53) 
1.45
(1.35-1.57) 
1.54
(1.41-1.68) 
Carbamazepine epoxide  16 0.46
(0.43-0.49) 
0.46
(0.44-0.49) 
0.48
(0.45-0.51) 
Clarithromycin  500 mg b.i.d.  400/100 mg b.i.d.  17 1.26
(1.03-1.54) 
1.57
(1.35-1.84) 
2.74
(2.30-3.26) 
Dextromethorphan Dextrorphan  30 mg  600/100 mg b.i.d.  12 2.27
(1.59-3.26)
2.70
(1.80-4.05)
0.87
(0.77-0.98) 
0.96
(0.90-1.03) 
--
Digoxin  0.4 mg  600/100 mg b.i.d.  8 1.15
(0.89-1.48) 
1.36
(0.81-2.27) 
-
Ethinyl estradiol (EE) Norethindrone (NE)  Ortho-Novum 1/35
(35 ?g EE / 1 mg NE) 
600/100 mg b.i.d.  11 0.68
(0.61-0.74)
0.56
(0.50-0.63)
0.38
(0.27-0.54)
11  0.90
(0.83-0.97) 
0.86
(0.75-0.98) 
0.70
(0.51-0.97) 
Ketoconazole  200 mg b.i.d.  400/100 mg b.i.d.  15 2.11
(1.81-2.44) 
3.12
(2.65-3.68) 
9.68
(6.4414.55) 
R-Methadone  55-150 mg q.d.  600/100 mg b.i.d.  16 0.76
(0.71-0.81) 
0.84
(0.78-0.91) 
0.85
(0.77-0.94) 
Omeprazole 40 mg single dose  600/100 mg b.i.d.  12 0.66
(0.48-0.90)
0.58
(0.50-0.66)
-
5-hydroxy omeprazole  0.93
(0.71-1.21) 
0.84
(0.77-0.92) 
-- 
Paroxetine  20 mg q.d.  400/100 mg b.i.d.  16 0.64
(0.59-0.71) 
0.61
(0.56-0.66) 
0.63
(0.55-0.73) 
Pravastatin  40 mg single dose  600/100 mg b.i.d.  14 1.63
(0.95-2.82) 
1.81
(1.23-2.66) 
-
Rifabutin 150 mg q.o.d. ¶ when administered with PREZISTA/ ritonavir 11 0.72
(0.55-0.93)
0.93
(0.80-1.09)
1.64
(1.48-1.81)
25-O-desacetylrifabutin  300 mg q.d. when administered alone  600/100 mg b.i.d. #  11  4.77
(4.04-5.63) 
9.81
(8.09-11.9) 
27.1
(22.2-33.2) 
Sertraline  50 mg q.d.  400/100 mg b.i.d.  13 0.56
(0.49-0.63) 
0.51
(0.46-0.58) 
0.51
(0.45-0.57) 
Sildenafil  100 mg
(single dose) administered alone 25 mg
(single dose) when administered with darunavir/ ritonavir 
400/100 mg b.i.d.  16 0.62
(0.55-0.70) 
0.97
(0.86-1.09) 
-
S-warfarin 7-OH-S-warfarin  10 mg single dose  600/100 mg b.i.d.  12 0.92
(0.86-0.97)
0.79
(0.73-0.85)
-
12  1.42
(1.24-1.63) 
1.23
(0.97-1.57) 
--
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 = 11 for the test arm
|| N = 14 for Cmax
Ω Noted as Cτ or C24 in the dolutegravir U.S. prescribing information
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 15.

Microbiology

Mechanism of Action

Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 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 EC 50 values ranging from less than 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-1 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 641fold 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 (less than 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 greater than 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 greater than 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 (greater than 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 (greater than 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 (greater than 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 (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or 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 less than 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 less than 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 greater than 3) achieved less than 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 (greater than 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 TMC125-C216 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 16).

Table 16: Response to PREZISTA/ritonavir 600/100 mg 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

# IAS-Defined Primary PI Substitutions  Studies TMC114-C213, TMC114-C202, TMC114-C215
< 50 copies/mL at Week 96
N=439 
Overall  De Novo ENF  Re-Used/ No ENF 
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 less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, 2 and greater than or equal to 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 17. 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 17: 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

Baseline DRV Phenotype  Proportion of Subjects with < 50 copies/mL at Week 96
N=417 
All  De Novo ENF  Re-Used/ No ENF 
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%) 

Animal Toxicology And/Or Pharmacology

In juvenile rats single doses of darunavir (20 mg/kg to 160 mg/kg at ages 5-11 days) or multiple doses of darunavir (40 mg/kg to 1000 mg/kg at age 12 days) caused mortality. The mortalities were associated with convulsions in some of the animals. Within this age range exposures in plasma, liver and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. No treatment-related mortalities were noted in juvenile rats after a single dose of darunavir at 1000 mg/kg on day 26 of age or after repeat dosing at 500 mg/kg from day 23 to 50 of age. The exposures and toxicity profile in the older animals (day 23 or day 26) were comparable to those observed in adult rats. Due to uncertainties regarding the rate of development of the human blood-brain barrier and liver enzymes, do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age.

Clinical Studies

Description Of Adult Clinical Studies

The evidence of efficacy of PREZISTA/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-na´ve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.

Treatment-Na´ve Adult Subjects

Study TMC114-C211

Study TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-na´ve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm³or greater than or equal to 200 cells/mm³). Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in Study TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 18). Table 18 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in Study TMC114-C211.

Table 18: Demographic and Baseline Characteristics of Subjects in Study TMC114-C211

Randomized Study TMC114-C211
PREZISTA/ ritonavir 800/100 mg once daily + TDF/FTC
N = 343 
lopinavir/ ritonavir 800/200 mg per day + TDF/FTC
N = 346 
Demographic Characteristics 
Median Age (years) (range, years)  34 (18-70)  33 (19-68) 
Sex 
  Male  70% 70%
  Female  30% 30%
Race 
  White  40% 45%
  Black  23% 21%
  Hispanic  23% 22%
  Asian  13% 11%
Baseline Characteristics 
Mean Baseline Plasma HIV-1 RNA (log10 copies/mL)  4.86 4.84
Median Baseline CD4+ Cell Count (cells/mm³) (range, cells/mm³)  228 (4-750)  218 (2-714) 
Percentage of Patients with Baseline Viral Load ≥ 100,000 copies/mL  34% 35%
Percentage of Patients with Baseline CD4+ Cell Count < 200 cells/mm³  41% 43%

Week 192 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from Study TMC114-C211 are shown in Table 19.

Table 19: Virologic Outcome of Randomized Treatment of Study TMC114-C211 at 192 Weeks

  PREZISTA/ ritonavir 800/100 mg once daily + TDF/FTC
N = 343 
lopinavir/ ritonavir 800/200 mg per day + TDF/FTC
N = 346 
Virologic success HIV-1 RNA < 50 copies/mL  70%*  61%
Virologic failure†  12% 15%
No virologic data at Week 192 window‡     
Reasons    
  Discontinued study due to adverse event or death§   5% 13%
  Discontinued study for other reasons¶  13% 12%
  Missing data during window‡ but on study  < 1%  0%
N = total number of subjects with data
* 95% CI: 1.9; 16.1
† Includes patients who discontinued prior to Week 192 for lack or loss of efficacy and patients who are ≥ 50 copies in the 192-week window and patients who had a change in their background regimen that was not permitted by the protocol
‡ Window 186-198 Weeks § Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window
¶ Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was < 50 copies/mL

In Study TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm³in the PREZISTA/ritonavir 800/100 mg once daily arm and 263 cells/mm³in the lopinavir/ritonavir 800/200 mg per day arm. Of the PREZISTA/ritonavir subjects with a confirmed virologic response of < 50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the PREZISTA/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.

Treatment-Experienced Adult Subjects

Study TMC114-C229

Study TMC114-C229 is a randomized, open-label trial comparing PREZISTA/ritonavir 800/100 mg once daily to PREZISTA/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.

HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.

Table 20 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm in Study TMC114-C229. No imbalances between the 2 arms were noted.

Table 20: Demographic and Baseline Characteristics of Subjects in Study TMC114-C229

  Randomized Study TMC114-C229 
PREZISTA/ ritonavir 800/100 mg once daily + OBR
N = 294 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR
N = 296 
Demographic Characteristics 
Median Age (years) (range, years)  40 (18-70)  40 (18-77) 
Sex 
  Male  61% 67%
  Female  39% 33%
Race 
  White  35% 37%
  Black  28% 24%
  Hispanic  16% 20%
  Asian  16% 14%
Baseline Characteristics 
Mean Baseline Plasma HIV-1 RNA (log10 copies/mL)  4.19 4.13
Median Baseline CD4+ Cell Count (cells/mm³) (range, cells/mm³)  219 (24-1306)  236 (44-864) 
Percentage of Patients with Baseline Viral Load ≥ 100,000 copies/mL  13% 11%
Percentage of Patients with Baseline CD4+ Cell Count < 200 cells/mm³  43% 39%
Median Darunavir Fold Change (range)*  0.50 (0.1-1.8)  0.50 (0.1-1.9) 
Median Number of Resistance-Associated† :
  PI mutations 3 4
  NNRTI mutations 2 1
  NRTI mutations  1
Percentage of Subjects Susceptible to All Available PIs at Baseline  88% 86%
Percentage of Subjects with Number of Baseline Primary Protease Inhibitor Mutations†
  0 84% 84%
  1 8% 9%
  2 5% 4%
   ≥ 3  3%  2% 
Median Number of ARVs Previously Used‡:
  NRTIs 3 3
  NNRTIs 1 1
  PIs (excluding low-dose ritonavir)  1 1
* Based on phenotype (Antivirogram®)
† Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: December 2008. Top HIV Med 2008; 16(5): 138-145
‡ Only counting ARVs, excluding low-dose ritonavir

Week 48 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from Study TMC114-C229 are shown in Table 21.

Table 21: Virologic Outcome of Randomized Treatment of Study TMC114-C229 at 48 Weeks

  Randomized Study TMC114-C229 
PREZISTA/ ritonavir 800/100 mg once daily + OBR
N = 294 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR
N = 296 
Virologic success HIV-1 RNA < 50 copies/mL  69% 69%
Virologic failure*  26% 23%
No virologic data at Week 48 window† 
Reasons
  Discontinued study due to adverse event or death‡  3% 4%
  Discontinued study for other reasons§  2% 3%
  Missing data during window† but on study  0% < 1% 
N = total number of subjects with data
* Includes patients who discontinued prior to Week 48 for lack or loss of efficacy, patients who are ≥ 50 copies in the 48-week window, patients who had a change in their background regimen that was not permitted in the protocol (provided the switch occurred before the earliest onset of an AE leading to permanent stop of study medication) and patients who discontinued for reasons other than AEs/death and lack or loss of efficacy (provided their last available viral load was detectable (HIV RNA ≥ 50 copies/mL).
† Window 42-54 Weeks
‡ Patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
§ Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was < 50 copies/mL.

The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm³and 112 cells/mm³in the PREZISTA/ritonavir 800/100 mg once daily arm and the PREZISTA/ritonavir 600/100 mg twice daily arm, respectively).

Study TMC114-C214

Study TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-na´ve HIV-1-infected adult subjects. Both arms used an optimized background regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 400 copies/mL. Analyses included 595 subjects in Study TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 22). Table 22 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in Study TMC114-C214.

Table 22: Demographic and Baseline Characteristics of Subjects in Study TMC114-C214

  Randomized Study TMC114-C214 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR
N = 298 
lopinavir/ ritonavir 400/100 mg twice daily + OBR
N = 297 
Demographic Characteristics 
Median Age (years) (range, years)  40 (18-68)  41 (22-76) 
Sex 
  Male  77% 81%
  Female  23% 19%
Race 
  White  54% 57%
  Black  18% 17%
  Hispanic  15% 15%
  Asian  9% 9%
Baseline Characteristics 
Mean Baseline Plasma HIV-1 RNA (log10 copies/mL)  4.33 4.28
Median Baseline CD4+ Cell Count (cells/mm³) (range, cells/mm³)  235 (3-831)  230 (2-1096) 
Percentage of Patients with Baseline Viral Load ≥ 100,000 copies/mL  19% 17%
Percentage of Patients with Baseline CD4+ Cell Count < 200 cells/mm³  40% 40%
Median Darunavir Fold Change (range)  0.60 (0.10-37.40)  0.60 (0.1-43.8) 
Median Lopinavir Fold Change (range)  0.70 (0.40-74.40)  0.80 (0.30-74.50) 
Median Number of Resistance-Associated*:
  PI mutations 4 4
  NNRTI mutations 1 1
  NRTI mutations  2
Percentage of Subjects with Number of Baseline Primary Protease Inhibitor Mutations*:
   ≤ 1  78% 80%
  2 8% 9%
   ≥ 3  13%  11% 
Median Number of ARVs Previously Used†:
 NRTIs 4 4
  NNRTIs 1 1
  PIs (excluding low-dose ritonavir) 
Percentage of Subjects Resistant‡ to All Available§ PIs at Baseline, excluding Darunavir  2% 3%
* Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125-130
† Only counting ARVs, excluding low-dose ritonavir
‡ Based on phenotype (Antivirogram®)
§ Commercially available PIs at the time of study enrollment

Week 96 outcomes for subjects on PREZISTA/ritonavir 600/100 mg twice daily from Study TMC114-C214 are shown in Table 23.

Table 23: Virologic Outcome of Randomized Treatment of Study TMC114-C214 at 96 Weeks

  PREZISTA / ritonavir 600/100 mg twice daily + OBR
N = 298 
lopinavir/ ritonavir 400/100 mg twice daily + OBR
N = 297 
Virologic success HIV-1 RNA < 50 copies/mL  58% 52%
Virologic failure*  26% 33%
No virologic data at Week 96 window†
Reasons
  Discontinued study due to adverse event or death‡   7% 8%
  Discontinued study for other reasons§  8%  7% 
  Missing data during window† but on study  1% < 1% 
N = total number of subjects with data
* Includes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are ≥ 50 copies in the 96-week window and patients who had a change in their OBR that was not permitted by the protocol.
† Window 90-102 Weeks
‡ Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
§ Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was < 50 copies/mL.

In Study TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm³in the PREZISTA/ritonavir 600/100 mg twice daily arm and 93 cells/mm³in the lopinavir/ritonavir 400/100 mg twice daily arm.

Studies TMC114-C213 and TMC114-C202

Studies TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to PREZISTA/ritonavir received the recommended dose of 600/100 mg twice daily.

HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.

The virologic response rate was evaluated in subjects receiving PREZISTA/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-na´ve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log10 versus baseline.

In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the comparator PI arm (see Table 24). Table 24 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of Studies TMC114-C213 and TMC114-C202.

Table 24: Demographic and Baseline Characteristics of Subjects in the Studies TMC114-C213 and TMC114-C202 (Pooled Analysis)

  Randomized Studies TMC114-C213 and TMC114-C202 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR
N = 131 
Comparator PI(s) + OBR
N = 124 
Demographic Characteristics 
Median Age (years) (range, years)  43 (27-73)  44 (25-65) 
Sex 
  Male  89% 88%
  Female  11% 12%
Race 
  White  81% 73%
  Black  10% 15%
  Hispanic  7% 8%
Baseline Characteristics 
Mean Baseline Plasma HIV-1 RNA (log10 copies/mL)  4.61 4.49
Median Baseline CD4+ Cell Count (cells/mm³) (range, cells/mm³)  153 (3-776)  163 (3-1274) 
Percentage of Patients with Baseline Viral Load > 100,000 copies/mL  24% 29%
Percentage of Patients with Baseline CD4+ Cell Count < 200 cells/mm³  67% 58%
Median Darunavir Fold Change  4.3 3.3
Median Number of Resistance-Associated*:
  PI mutations 12 12
  NNRTI mutations 1 1
  NRTI mutations 
Percentage of Subjects with Number of Baseline Primary Protease Inhibitor Mutations*:
   ≤ 1 8% 9%
  2 22% 21%
   ≥ 3  70%  70% 
Median Number of ARVs Previously Used†:
  NRTIs 6 6
  NNRTIs 1 1
  PIs (excluding low-dose ritonavir) 
Percentage of Subjects Resistant† to All Available‡ PIs at Baseline, excluding Tipranavir and Darunavir  63% 61%
Percentage of Subjects with Prior Use of Enfuvirtide  20% 17%
* Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125-130
† Based on phenotype (Antivirogram®)
‡ Commercially available PIs at the time of study enrollment

Week 96 outcomes for subjects on the recommended dose PREZISTA/ritonavir 600/100 mg twice daily from the pooled Studies TMC114-C213 and TMC114-C202 are shown in Table 25.

Table 25: Outcomes of Randomized Treatment Through Week 96 of the Studies TMC114-C213 and TMC114-C202 (Pooled Analysis)

  Randomized Studies TMC114-C213 and TMC114-C202 
PREZISTA/ ritonavir 600/100 mg twice daily + OBR
N=131 
Comparator PI(s) + OBR
N=124 
Virologic Responders confirmed at least 1 log10 HIV-1 RNA below baseline through Week 96 ( < 50 copies/mL at Week 96)  57% (39%)  10% (9%) 
Virologic failures  29% 80%
  Lack of initial response*  8% 53%
  Rebounder†  17% 19%
  Never Suppressed‡  4% 8%
Death or discontinuation due to adverse events  9% 3%
Discontinuation due to other reasons  5% 7%
* Subjects who did not achieve at least a confirmed 0.5 log10 HIV-1 RNA drop from baseline at Week 12
† Subjects with an initial response (confirmed 1 log10 drop in viral load), but without a confirmed 1 log10 drop in viral load at Week 96
‡ Subjects who never reached a confirmed 1 log10 drop in viral load before Week 96

In the pooled Studies TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log10 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily and –0.37 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily (103 cells/mm³) than in the comparator PI arm (17 cells/mm³).

Pediatric Patients

The pharmacokinetic profile, safety and antiviral activity of PREZISTA/ritonavir were evaluated in 3 randomized, open-label, multicenter studies.

Study TMC114-C212

Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received PREZISTA tablets with either ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of PREZISTA/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

The 80 randomized pediatric subjects had a median age of 14 (range 6 to less than 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm³(range: 6 to 1505 cells/mm³). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.

Seventy-seven pediatric subjects (96%) completed the 24-week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation. The proportion of pediatric subjects with HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL was 64% and 50%, respectively. The mean increase in CD4+ cell count from baseline was 117 cells/mm³.

Study TMC114-C228

Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received PREZISTA oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of PREZISTA/ritonavir.

The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 x 106 cells/l (range: 209 to 2,429 x 106 cells/l) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 NRTIs, 62% of subjects had used greater than or equal to 1 NNRTI and 76% had previously used at least one HIV PI.

Twenty subjects (95%) completed the 48 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%.. The mean increase in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 187 x 106 cells/L.

Study TMC114-C230

Treatment-na´ve pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of PREZISTA/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.

The 12 randomized pediatric subjects had a median age of 14.4 years (range 12.6 to 17.3 years), and were 33.3% male, 58.3% Caucasian and 41.7% Black. The mean baseline plasma HIV-1 RNA was 4.72 log10 copies/mL, and the median baseline CD4+ cell count was 282 cells/mm³(range: 204 to 515 cells/mm³). Overall, 41.7% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL.

All subjects completed the 48 week treatment period.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 83.3% and 91.7%, respectively. The mean increase in CD4+ cell count from baseline was 221 x 106 cells/L.

Last reviewed on RxList: 4/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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