CLINICAL PHARMACOLOGY
Pharmacokinetics in Adults
The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg twice daily), have been evaluated in healthy adult volunteers and in HIV-1 infected subjects. Table 3 displays the population pharmacokinetic estimates of darunavir from an analysis of integrated data from Studies TMC114-C213 and TMC114-C202 of 119 subjects administered the darunavir/ritonavir 600/100 mg b.i.d. dose. Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of 600 mg darunavir was given orally in combination with 100 mg ritonavir b.i.d., 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.
Table 3: Population Pharmacokinetic Estimates of Darunavir at the Darunavir/Ritonavir 600/100 mg b.i.d. dose (Integrated data from TMC114-C213 and TMC114-C202, Primary 24-Week Analysis) | Parameter | Darunavir/Ritonavir 600/100 mg b.i.d.
N = 119 |
|---|
| N = number of subjects with data. |
| AUC12h (ng∙h/mL) | |
| Geometric Mean ± Standard Deviation | 62349 ± 16143 |
| Median (Range) | 61668 (33857-106490) |
| C0h (ng/mL) | |
| Geometric Mean ± Standard Deviation | 3578 ± 1151 |
| Median (Range) | 3539 (1255-7368) |
Figure 1 displays the mean plasma concentrations of darunavir and ritonavir at steady-state for the darunavir/ritonavir 600/100 mg b.i.d. dose.
Figure 1: Mean Steady-State Plasma Concentration-Time Profiles of Darunavir and Ritonavir at 600/100 mg b.i.d. at Week 4 (Integrated data from TMC114-C213 and TMC114-C202, Primary 24-Week Analysis)
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.
Effects of Food on Oral Absorption
When administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 30% 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.
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 combined 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 primarily undergoes hepatic metabolism. PREZISTA has not been studied in patients with varying degrees of hepatic impairment (see PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION).
Hepatitis B or Hepatitis C Virus Co-infection
The primary 24-week analysis of the data from Study TMC114-C213 in 31 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 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 PRECAUTIONS, Patients with co-existing conditions, Renal Impairment, and DOSAGE AND ADMINISTRATION).
Gender
Population pharmacokinetic analysis showed higher mean darunavir exposure (16.8%) in HIV infected females (n=68) 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 PRECAUTIONS, Geriatric Use).
Pediatric Patients
The pharmacokinetics of darunavir in combination with ritonavir in pediatric patients has not been established. There are insufficient data at this time to recommend a dose.
Drug Interactions
See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions.
Darunavir and ritonavir are both inhibitors of CYP3A. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see sections CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions).
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 4 (effect of other drugs on darunavir) and Table 5 (effect of darunavir on other drugs). For information regarding clinical recommendations, see PRECAUTIONS, Drug Interactions.
Table 4: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs | Co-Administered Drug | Dose/Schedule | N | PK | LS Mean Ratio (90% CI) of Darunavir
Pharmacokinetic Parameters With/Without Co-administered Drug
No Effect =1.00 |
|---|
| Co-Administered Drug | Darunavir/rtv | Cmax | AUC | Cmin |
|---|
| N = number of subjects with data; - = no information available. |
| ^ q.d. = daily |
| † b.i.d. = twice daily |
| ‡ Ratio based on between-study comparison. |
| Co-Administration With Other 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. | 300/100 mg b.i.d. | 9 | ↓ | 0.61
(0.51-0.74) | 0.47
(0.40-0.55) | 0.35
(0.29-0.42) |
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 Antiretrovirals |
| 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) |
| 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) |
| 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 Other Drugs |
| 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) |
| 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) |
Table 5: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir | Co-Administered Drug | Dose/Schedule | N | PK | LS Mean Ratio (90% CI) of Co-Administered Drug
Pharmacokinetic Parameters With/Without Darunavir
No Effect =1.00 |
|---|
| Co-Administered Drug | Darunavir/rtv | Cmax | AUC | Cmin |
|---|
| N = number of subjects with data;- = no information available. |
| ^ q.d. = daily |
| † b.i.d. = twice daily |
| Co-Administration With Other Protease Inhibitors |
| Atazanavir | 300 mg q.d.^/100 mg RTV 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 RTV 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. | 300/100 mg b.i.d. | 9 | ↑ | 1.22
(1.12-1.32) | 1.37
(1.27-1.49) | 1.72
(1.46-2.03) |
| Saquinavir hard gel capsule | 1000 mg b.i.d./100 mg RTV 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 Antiretrovirals |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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
(6.44-14.55) |
| 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) | - |
| 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) | - |
|
