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Trademark of Tibotec Pharmaceuticals, Ltd.
DESCRIPTION
PREZISTA™ (darunavir) is an inhibitor of the human immunodeficiency virus (HIV) protease.
PREZISTA™ (darunavir), in the form of darunavir ethanolate, has the following chemical name: [(1 S,2 R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3 R,3a S,6a R)-hexahydrofuro[2,3- b ]furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S • C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:
Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.
PREZISTA is available as an orange, oval-shaped, film-coated tablet for oral administration. Each tablet contains darunavir ethanolate equivalent to 300 mg of darunavir. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The tablet film coating, OPADRY® Orange, contains FD&C Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
All dosages for PREZISTA are expressed in terms of the free form of darunavir.
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 protease inhibitors 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, efavirenz, 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 6- to 21-fold decreased susceptibility to darunavir and harbored 3 to 6 of the following amino acid substitutions S37N/D, R41E/S/T, K55Q, K70E, A71T, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple protease inhibitor resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, including 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 mutations and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.
Clinical studies of darunavir/ritonavir in treatment-experienced subjects
In the Phase 2b Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, multiple protease inhibitor-resistant HIV-1 isolates from highly treatment-experienced subjects who received PREZISTA/rtv 600/100 mg b.i.d. and experienced virologic failure, either by rebound, or by never being suppressed, developed amino acid substitutions that were associated with a decrease in susceptibility to darunavir. The amino acid substitution V32I developed on PREZISTA/rtv 600/100 mg b.i.d. in greater than 30% of virologic failure isolates and substitutions at amino acid position I54 developed in greater than 20% of virologic failure isolates. Other substitutions that developed in 10% to 20% of PREZISTA/rtv virologic failure isolates occurred at amino acid positions I15, L33, I47, G73 and L89. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 21-fold at baseline and 94-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites of some darunavir virologic failure isolates. The resistance profile in treatment-naïve subjects has not been characterized.
Cross-resistance
Cross-resistance among protease inhibitors 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 protease inhibitors remain susceptible to darunavir. In Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, 60% (88/147) of subjects on darunavir/rtv whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change > 3) demonstrated a decrease of ≥ 1 log10 in viral load at week 24, and 36% (53/147) achieved < 50 copies/mL plasma HIV RNA levels.
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 protease inhibitor-resistant viruses showed a fold change in EC50 values < 3 for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg b.i.d., greater than 50% were still susceptible to tipranavir while less than 5% were susceptible to other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir).
Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors or the fusion inhibitor 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/rtv 600/100 mg b.i.d. therapy. Analyses were conducted to evaluate the impact of specific baseline protease inhibitor resistance-associated mutations and the number of protease inhibitor resistance-associated mutations at baseline on virologic response. Both specific mutations and the number of baseline mutations, as well as susceptible drugs in the optimized background regimen and enfuvirtide use, affected PREZISTA/rtv response rates in Phase 2b Studies TMC114-C213 and TMC114-C202.
The presence at baseline of the mutations V32I, I47V, or I54L or M, was associated with a decreased virologic response to darunavir and decreased susceptibility to darunavir. In addition, a diminished virologic response was observed in subjects with ≥ 7 protease inhibitor resistance-associated mutations (any change at amino acid positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88, or 90) at baseline (see Table 1). In a supportive analysis of Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, the presence at baseline of three or more of the mutations V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA/rtv (the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at week 24 was 50%, 22% and 10% when the baseline genotype had 0-2, 3 and ≥4 of these mutations, respectively). Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.
Table 1: Response to PREZISTA/rtv 600/100 mg b.i.d. by Baseline Number of Protease Inhibitor Resistance-Associated Mutations: As-Treated Analysis of Studies TMC114-C213 and TMC114-C202 | | Prezista/rtv 600/100 mg
(n = 125) | | Comparative Arm
(n = 120) |
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| PI Mutations^ | | n | Proportion of subjects with ≥ 1 log10 decrease at Week 24 | Proportion of subjects with < 50 copies/mL at Week 24 | Median DAVG24 | | n | Proportion of subjects with ≥ 1 log10 decrease at Week 24 | Proportion of subjects with < 50 copies/mL at Week 24 | Median DAVG24 |
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| ^ Any change at protease amino acid positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88 and 90 |
| 0 - 4 | | 57 | 81% | 46% | -2.16 | | 52 | 23% | 13% | -0.57
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| 5 - 6 | | 54 | 67% | 52% | -2.13 | | 51 | 24% | 16% | -0.43
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| ≥ 7 | | 14 | 21% | 14% | -0.87 | | 17 | 6% | 0% | -0.13
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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 2. These baseline phenotype groups are based on the select subject populations in the Studies TMC114-C213 and TMC114-C202 and the TMC114-C215/C208 analysis, and are not meant to represent definitive clinical susceptibility breakpoints for PREZISTA/rtv. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir in protease inhibitor-experienced patients.
Table 2: Response to PREZISTA/rtv 600/100 mg b.i.d. by Baseline Darunavir Phenotype: As-Treated Analysis of Studies TMC114-C213, TMC114-C202, and TMC114-C215/C208 Baseline Darunavir Phenotype
N = 340
(fold change ranges) | Proportion of subjects with ≥ 1 log10 decrease at Week 24 | Proportion of subjects with < 50 copies/mL at Week 24 | Clinical Response Range |
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| All ranges | 70%
238/340 | 43%
147/340 | Overall Response |
| 0 - 2 | 88%
119/136 | 60%
82/136 | Higher than Overall Response |
| > 2 - 7 | 73%
62/85 | 47%
40/85 | Similar to Overall Response |
| > 7 - 30 | 52%
33/63 | 24%
15/63 | Lower than Overall Response |
| > 30 | 43%
24/56 | 18%
10/56 | Lower than Overall Response |
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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 |
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| 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 |
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| Co-Administered Drug | Darunavir/rtv | Cmax | AUC | Cmin |
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| 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 |
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| Co-Administered Drug | Darunavir/rtv | Cmax | AUC | Cmin |
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| 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) | - |
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