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Edurant

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Edurant

CLINICAL PHARMACOLOGY

Mechanism of Action

Rilpivirine is an antiviral drug [see Microbiology].

Pharmacodynamics

Effects on Electrocardiogram

The effect of EDURANT at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of EDURANT were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of EDURANT [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-na´ve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.

Table 5: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Na´ve HIV-1-Infected Subjects (Pooled Data from Phase 3 Trials through Week 96)

Parameter Rilpivirine 25 mg once daily
N = 679
AUC24h (ng•h/mL)
  Mean ± Standard Deviation 2235 ± 851
  Median (Range) 2096 (198 -7307)
C0h (ng/mL)
  Mean ± Standard Deviation 79 ± 35
  Median (Range) 73 (2 -288)

Absorption and Bioavailability

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hours. The absolute bioavailability of EDURANT is unknown.

Effects of Food on Oral Absorption

The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.

Distribution

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.

Elimination

The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine ( < 1% of dose) were detected in urine.

Special Populations

Hepatic Impairment

Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use In Specific Populations].

Hepatitis B and/or Hepatitis C Virus Co-infection

Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.

Renal Impairment

Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations].

Gender

No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.

Race

Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.

Pediatric Patients

The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established [see Use in Specific Populations].

Drug Interactions

[See also CONTRAINDICATIONS and DRUG INTERACTIONS.]

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Co-administration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.

EDURANT at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

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

Table 6: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Co-administered Drugs

Co-administered Drug Dose/Schedule N Mean Ratio of Rilpivirine Pharmacokinetic Parameters With/Without Co-administered Drug (90% CI); No Effect = 1.00
Co-administered Drug Rilpivirine Cmax AUC Cmin
Co-Administration With HIV Protease Inhibitors (PIs)
Darunavir/ ritonavir 800/100 mg q.d. 150 mg q.d.† 14 1.79
(1.56-2.06)
2.30
(1.98-2.67)
2.78
(2.39-3.24)
Lopinavir/ ritonavir
(soft gel capsule)
400/100 mg b.i.d. 150 mg q.d.† 15 1.29
(1.18-1.40)
1.52
(1.36-1.70)
1.74
(1.46-2.08)
Co-Administration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)
Didanosine 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine 150 mg q.d.† 21 1.00
(0.90-1.10)
1.00
(0.95-1.06)
1.00
(0.92-1.09)
Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d.† 16 0.96
(0.81-1.13)
1.01
(0.87-1.18)
0.99
(0.83-1.16)
Co-Administration With HIV Integrase Strand Transfer Inhibitors
Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.12
(1.04-1.20)
1.12
(1.05-1.19)
1.03
(0.96-1.12)
Co-Administration With other Antivirals
Telaprevir 750 mg q8h 25 mg q.d. 16 1.49
(1.20-1.84)
1.78
(1.44-2.20)
1.93
(1.55-2.41)
Co-Administration With Drugs other than Antiretrovirals
Acetaminophen 500 mg single dose 150 mg q.d.† 16 1.09
(1.01-1.18)
1.16
(1.10-1.22)
1.26
(1.16-1.38)
Atorvastatin 40 mg q.d. 150 mg q.d.† 16 0.91
(0.79-1.06)
0.90
(0.81-0.99)
0.90
(0.84-0.96)
Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d.† 16 1.17
(1.08-1.27)
1.25
(1.16-1.35)
1.18
(1.09-1.28)
Ethinylestradiol/ Norethindrone 0.035 mg q.d./ 1 mg q.d. 25 mg q.d. 15 ↔* ↔* ↔*
Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose† 24 0.99
(0.84-1.16)
0.91
(0.78-1.07)
N.A.
Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose† 23 0.15
(0.12-0.19)
0.24
(0.20-0.28)
N.A.
Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose† 24 1.21
(1.06-1.39)
1.13
(1.01-1.27)
N.A.
Ketoconazole 400 mg q.d. 150 mg q.d.† 15 1.30
(1.13-1.48)
1.49
(1.31-1.70)
1.76
(1.57-1.97)
Methadone 60-100 mg q.d., individualised dose 25 mg q.d. 12 ↔* ↔* ↔*
Omeprazole 20 mg q.d. 150 mg q.d.† 16 0.60
(0.48-0.73)
0.60
(0.51-0.71)
0.67
(0.58-0.78)
Rifabutin 300 mg q.d. 150 mg q.d.† 16 0.65
(0.58-0.74)
0.54
(0.50-0.58)
0.51
(0.48-0.54)
Rifampin 600 mg q.d. 150 mg q.d.† 16 0.31
(0.27-0.36)
0.20
(0.18-0.23)
0.11
(0.10-0.13)
Sildenafil 50 mg single dose 75 mg q.d.† 16 0.92
(0.85-0.99)
0.98
(0.92-1.05)
1.04
(0.98-1.09)
CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily
* comparison based on historic controls
† This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the co-administered drug.

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of EDURANT

Co-administered Drug Dose/Schedule N Mean Ratio of Co-administered Drug Pharmacokinetic Parameters With/Without EDURANT (90% CI); No effect = 1.00
Coadministered Drug Rilpivirine Cmax AUC Cmin
Co-Administration With HIV Protease Inhibitors
(PIs)
Darunavir/ ritonavir 800/100 mg q.d. 150 mg q.d.† 15 0.90
(0.81-1.00)
0.89
(0.81-0.99)
0.89
(0.68-1.16)
Lopinavir/ ritonavir
(soft gel capsule)
400/100 mg b.i.d. 150 mg q.d.† 15 0.96
(0.88-1.05)
0.99
(0.89-1.10)
0.89
(0.73-1.08)
Co-Administration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors
(NRTIs/N[t]RTIs)
Didanosine 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine 150 mg q.d.† 13 0.96
(0.80-1.14)
1.12
(0.99-1.27)
N.A.
Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d.† 16 1.19
(1.06-1.34)
1.23
(1.16-1.31)
1.24
(1.10-1.38)
Co-Administration With HIV Integrase Strand Transfer Inhibitors
Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.10
(0.77-1.58)
1.09
(0.81-1.47)
1.27
(1.01-1.60)
Co-Administration With other Antivirals
Telaprevir 750 mg q8h 25 mg q.d. 13 0.97
(0.79-1.21)
0.95
(0.76-1.18)
0.89
(0.67-1.18)
Co-Administration With Drugs other than Antiretrovirals
Acetaminophen 500 mg single dose 150 mg q.d.† 16 0.97
(0.86-1.10)
0.91
(0.86-0.97)
N.A.
Atorvastatin 40 mg q.d. 150 mg q.d.† 16 1.35
(1.08-1.68)
1.04
(0.97-1.12)
0.85
(0.69-1.03)
2-hydroxy-atorvastatin 16 1.58
(1.33-1.87)
1.39
(1.29-1.50)
1.32
(1.10-1.58)
4-hydroxy-atorvastatin 16 1.28
(1.15-1.43)
1.23
(1.13-1.33)
N.A.
Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d.† 16 0.98
(0.85-1.13)
1.03
(0.95-1.13)
N.A.
Digoxin 0.5 mg single dose 25 mg q.d. 22 1.06
(0.97-1.17)
0.98
(0.93-1.04)#
N.A.
Ethinylestradiol Norethindrone 0.035 mg q.d. 1 mg q.d. 25 mg q.d. 17 17 1.17
(1.06-1.30) 0.94
(0.83-1.06)
1.14
(1.10-1.19) 0.89
(0.84-0.94)
1.09
(1.03-1.16) 0.99
(0.90-1.08)
Ketoconazole 400 mg q.d. 150 mg q.d.† 14 0.85
(0.80-0.90)
0.76
(0.70-0.82)
0.34
(0.25-0.46)
R(-) methadone 60-100 mg q.d., individualised dose 25 mg q.d. 13 0.86
(0.78-0.95)
0.84
(0.74-0.95)
0.78
(0.67-0.91)
S(+) methadone 13 0.87
(0.78-0.97)
0.84
(0.74-0.96)
0.79
(0.67-0.92)
Omeprazole 20 mg q.d. 150 mg q.d.† 15 0.86
(0.68-1.09)
0.86
(0.76-0.97)
N.A.
Rifampin 600 mg q.d. 150 mg q.d.† 16 1.02
(0.93-1.12)
0.99
(0.92-1.07)
N.A.
25-desacetylrifampin 16 1.00
(0.87-1.15)
0.91
(0.77-1.07)
N.A.
Sildenafil 50 mg single dose 75 mg q.d.† 16 0.93
(0.80-1.08)
0.97
(0.87-1.08)
N.A.
N-desmethyl-sildenafil 16 0.90
(0.80-1.02)
0.92
(0.85-0.99)#
N.A.
CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily ; b.i.d. = twice daily
† This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the co-administered drug.
# AUC(0-last)

Microbiology

Mechanism of Action

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

Antiviral Activity in Cell Culture

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510 to 10830 nM) (920 to 3970 ng/mL).

Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/ml) and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/ml).

The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the integrase strand transfer inhibitor raltegravir.

Resistance

In Cell Culture

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L.

In Treatment-Na´ve Subjects

In the Week 96 pooled resistance analysis of the Phase 3 trials C209 and C215, the emergence of resistance was greater among subjects' viruses in the EDURANT arm compared to the efavirenz arm, and was dependent on baseline viral load. In the pooled resistance analysis, 58% (57/98) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the EDURANT arm had virus with genotypic and/or phenotypic resistance to rilpivirine compared to 45% (25/56) of the resistance analysis subjects in the efavirenz arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in viruses from 52% (51/98) of the resistance analysis subjects in the rilpivirine arm compared to 23% (13/56) in the efavirenz arm.

Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 -621. The E138K substitution emerged most frequently during rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, T215S/T, or K219E/R) emerged more frequently in rilpivirine resistance analysis subjects compared to efavirenz resistance analysis subjects (see Table 8).

NNRTI-and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses from subjects with baseline viral load of ≤ 100,000 copies/mL compared to viruses from subjects with baseline viral load of > 100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI-and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline CD4+ cell counts ≥ 200 cells/mm³ compared to viruses from subjects with baseline CD4+ cell counts < 200 cells/mm³ : 37% (20/54) compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72% (36/50) of NRTI-resistance substitutions.

Table 8: Proportion of Resistance Analysis Subjects* with Frequently Emerging Reverse Transcriptase Substitutions from the Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis

  C209 and C215
N = 1368
EDURANT + BR
N = 686
Efavirenz + BR
N = 682
Subjects who Qualified for Resistance Analysis 15% (98/652) 9% (56/604)
Subjects with Evaluable Post-Baseline Resistance Data 87 43
Emerging NNRTI Substitutions†
Any 62% (54/87) 53% (23/43)
V90I 13% (11/87) 2% (1/43)
K101E/P/T/Q 20% (17/87) 9% (4/43)
K103N 1% (1/87) 40% (17/43)
E138K/A/Q/G 40% (35/87) 2% (1/43)
  E138K+ M184I‡ 25% (22/87) 0
V179I/L/D 6% (5/87) 7% (3/43)
Y181C/I/S 10% (9/87) 2% (1/43)
V189I 8% (7/87) 2% (1/43)
H221Y 9% (8/87) 0
Emerging NRTI Substitutions§
Any 57% (50/87) 30% (13/43)
M184I/V 54% (47/87) 26% (11/43)
K65R/N 9% (8/87) 5% (2/43)
A62V, D67N/G, K70E, Y115F, T215S/T or K219E/RÂ 21% (18/87) 2% (1/43)
BR = background regimen
* Subjects who qualified for resistance analysis.
† V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227 or M230
‡ This combination of NNRTI and NRTI substitutions is a subset of those with the E138K.
§ A62V, K65R/N, D67N/G, K70E, L74I, V75I, Y115F, M184I/V, L210F, T215S/T, K219E/R
 These substitutions emerged in addition to the primary substitutions M184V/I or K65R/N; A62V (n=3), D67N/G (n=3), K70E (n=4), Y115F (n=2), T215S/T (n=1), K219E/R (n=8) in rilpivirine resistance analysis subjects.

Cross-Resistance

Site-Directed NNRTI Mutant Virus

Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions had decreased susceptibility to rilpivirine (fold change range of 3.7 -554) in 38% and 66% of mutants analyzed, respectively.

Treatment-na´ve HIV-1-infected subjects

Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L.

Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the Week 96 pooled analyses of the Phase 3 TMC278-C209 and TMC278-C215 clinical trials, 50 of the 87 (57%) rilpivirine resistance analysis subjects with post-baseline resistance data had virus with decreased susceptibility to rilpivirine ( ≥ 2.5 fold change). Of these, 86% (n= 43/50) were resistant to efavirenz ( ≥ 3.3 fold change), 90% (n= 45/50) were resistant to etravirine ( ≥ 3.2 fold change) and 62% (n= 31/50) were resistant to nevirapine ( ≥ 6 fold change). In the efavirenz arm, 3 of the 21 (14%) efavirenz resistance analysis subjects' viruses were resistant to etravirine and rilpivirine, and 95% (n= 20/21) were resistant to nevirapine. Virus from subjects experiencing virologic failure on EDURANT developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class compared to virus from subjects who failed on efavirenz.

Clinical Studies

Treatment-Na´ve Subjects

The evidence of efficacy of EDURANT is based on the analyses of 48-and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-na´ve adults. Antiretroviral treatment-na´ve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥ 5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.

In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 9 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms.

Table 9: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Na´ve HIV-1Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis)

  Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials
EDURANT + BR
N=686
Efavirenz + BR
N=682
Demographic Characteristics
Median Age, years (range) 36 (18-78) 36 (19-69)
Sex
  Male 76% 76%
  Female 24% 24%
Race
  White 61% 60%
  Black/African American 24% 23%
  Asian 11% 14%
  Other 2% 2%
  Not allowed to ask per local regulations 1% 1%
Baseline Disease Characteristics
Median Baseline Plasma HIV-1 RNA (range), log10 copies/mL 5.0 (2-7) 5.0 (3-7)
Percentage of Patients with Baseline Plasma Viral Load:
   ≤ 100,000 54% 48%
   > 100,000 to ≥ 500,000 36% 40%
   > 500,000 10% 12%
Median Baseline CD4+ Cell Count (range), cells/mm³ 249 (1-888) 260 (1-1137)
Percentage of Subjects with:
  Hepatitis B/C Virus Co-infection 7% 10%
Percentage of Patients with the following background regimens:
  tenofovir disoproxil fumarate plus emtricitabine 80% 80%
  zidovudine plus lamivudine 15% 15%
  abacavir plus lamivudine 5% 5%
BR=background regimen

Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 10. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.

Table 10: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96

  EDURANT + BR
N =686
Efavirenz + BR

N=682
HIV-1 RNA < 50 copies/mL* 76% 77%
HIV-1 RNA ≥ 50 copies/mL† 16% 10%
No virologic data at Week 96 window
Reasons
Discontinued study due to adverse event or death‡ 4% 8%
Discontinued study for other reasons and last available HIV-1 RNA < 50 copies/mL (or missing)§ 4% 5%
Missing data during window but on study < 1% < 1%
HIV-1 RNA < 50 copies/mL by Baseline HIV-1 RNA (copies/mL)
   ≤ 100,000 82% 78%
   > 100,000 70% 75%
HIV-1 RNA ≥ 50 copies/mL† by Baseline HIV-1 RNA (copies/mL)
   ≤ 100,000 9% 8%
  > 100,000 24% 11%
HIV-1 RNA < 50 copies/mL by CD4+ cell count (cells/mm³ )
   < 200 68% 74%
   ≥ 200 81% 77%
HIV-1 RNA ≥ 50 copies/mL† by CD4+ cell count (cells/mm³ )
   < 200 27% 10%
   ≥ 200 10% 9%
N = total number of subjects per treatment group; BR = background regimen.
* CI = Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96.
† Includes subjects who had ≥ 50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol.
‡ Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.
§ Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.
Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90-103), respectively.

At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm³ for EDURANT-treated subjects and 219 cells/mm³ for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278C215 trials.

Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-na´ve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.

Study TMC278-C204 enrolled 368 HIV-1-infected treatment-na´ve adult subjects who had a plasma HIV-1 RNA ≥ 5000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs.

At 96 weeks, the proportion of subjects with < 50 HIV-1 RNA copies/ml receiving EDURANT 25 mg (N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm³ in subjects receiving EDURANT 25 mg and 160 cells/mm³ in subjects receiving efavirenz.

At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 57% (51/89) of subjects in the control group.

Last reviewed on RxList: 7/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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