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Isentress

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Isentress

CLINICAL PHARMACOLOGY

Mechanism Of Action

Raltegravir is an HIV-1 antiviral drug [see Microbiology].

Pharmacodynamics

In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log10 copies/mL by Day 10.

In the randomized, double-blind, placebo-controlled, dose-ranging trial, Protocol 005, and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.

Effects on Electrocardiogram

In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).

Pharmacokinetics - Adults

Absorption

Raltegravir (film-coated tablet) is absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. W ith twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C12hr ranged from approximately 1.2 to 1.6.

The absolute bioavailability of raltegravir has not been established. Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet.

In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 μM•hr and C12hr of 142 nM.

Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.

Effect of Food on Oral Absorption

ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1-infected patients. The effect of consumption of low-, moderate-and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers administered the 400 mg film-coated tablet. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.

Administration of the chewable tablet with a high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax, and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food.

The effect of food on the formulation for oral suspension was not studied.

Distribution

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 μM.

In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid. In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma. The clinical relevance of this finding is unknown.

Metabolism and Excretion

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravirglucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoformselective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Special Populations

Pediatric

Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 9, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age [see DOSAGE AND ADMINISTRATION] resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily.

Overall, dosing in pediatric patients achieved exposures (Ctrough) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM) [see Clinical Studies]. As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet [see DOSAGE AND ADMINISTRATION]. In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.

Table 9: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Doses

Body Weight Formulation Dose N* Geometric Mean (%CV†) AUC0-12hr (μM•hr) Geometric Mean (%CV†) C12hr (nM)
≥ 25 kg Film coated tablet 400 mg twice daily 18 14.1 (121%) 233 (157%)
≥ 25 kg Chewable tablet Weight based dosing, see Table 1 9 22.1 (36%) 113 (80%)
11 to less than 25 kg Chewable tablet Weight based dosing, see Table 2 13 18.6 (68%) 82 (123%)
3 to less than 20 kg Oral suspension Weight based dosing, see Table 2 19 24.5 (43%) 113 (69%)
*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.
†Geometric coefficient of variation.

The pharmacokinetics of raltegravir in infants under 4 weeks of age has not been established.

Age

The effect of age (18 years and older) on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

Race

The effect of race on the pharmacokinetics of raltegravir in adults was evaluated in the composite analysis. No dosage adjustment is necessary.

Gender

A study of the pharmacokinetics of raltegravir was performed in healthy adult males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.

Hepatic Impairment

Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in adult subjects with moderate hepatic impairment. Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Renal Impairment

Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in adult subjects with severe renal impairment. Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects. No dosage adjustment is necessary. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.

UGT1A1 Polymorphism

There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 adult subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 adult subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).

Drug Interactions

[see DRUG INTERACTIONS]

Table 10: Effect of Other Agents on the Pharmacokinetics of Raltegravir in Adults

Coadministered Drug Coadministered Drug Dose/Schedule Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00
n Cmax AUC Cmin
aluminum and magnesium hydroxide antacid 20 mL single dose given with raltegravir 400 mg twice daily 25 0.56
(0.42, 0.73)
0.51
(0.40, 0.65)
0.37
(0.29, 0.48)
20 mL single dose given 2 hours before raltegravir 23 0.49
(0.33, 0.71)
0.49
(0.35, 0.67)
0.44
(0.34, 0.55)
20 mL single dose given 2 hours after raltegravir 23 0.78
(0.53, 1.13)
0.70
(0.50, 0.96)
0.43
(0.34, 0.55)
atazanavir 400 mg daily 100 mg single dose 10 1.53
(1.11, 2.12)
1.72
(1.47, 2.02)
1.95
(1.30, 2.92)
atazanavir/ritonavir 300 mg/100 mg daily 400 mg twice daily 10 1.24
(0.87, 1.77)
1.41
(1.12, 1.78)
1.77
(1.39, 2.25)
boceprevir 800 mg three times daily 400 mg single dose 22 1.11
(0.91-1.36)
1.04
(0.88-1.22)
0.75
(0.45-1.23)
calcium carbonate antacid 3000 mg single dose given with raltegravir 400 mg twice daily 24 0.48
(0.36, 0.63)
0.45
(0.35, 0.57)
0.68
(0.53, 0.87)
efavirenz 600 mg daily 400 mg single dose 9 0.64
(0.41, 0.98)
0.64
(0.52, 0.80)
0.79
(0.49, 1.28)
etravirine 200 mg twice daily 400 mg twice daily 19 0.89
(0.68, 1.15)
0.90
(0.68, 1.18)
0.66
(0.34, 1.26)
omeprazole 20 mg daily 400 mg single dose 14
(10 for AUC)
4.15
(2.82, 6.10)
3.12
(2.13, 4.56)
1.46
(1.10, 1.93)
rifampin 600 mg daily 400 mg single dose 9 0.62
(0.37, 1.04)
0.60
(0.39, 0.91)
0.39
(0.30, 0.51)
rifampin 600 mg daily 400 mg twice daily when administered alone; 800 mg twice daily when administered with rifampin 14 1.62
(1.12, 2.33)
1.27
(0.94, 1.71)
0.47
(0.36, 0.61)
ritonavir 100 mg twice daily 400 mg single dose 10 0.76
(0.55, 1.04)
0.84
(0.70, 1.01)
0.99
(0.70, 1.40)
telaprevir 750 mg every 8 hours 400 mg twice daily 20 1.26
(0.97, 1.62)
1.31
(1.03, 1.67)
1.78
(1.26, 2.53)
tenofovir 300 mg daily 400 mg twice daily 9 1.64
(1.16, 2.32)
1.49
(1.15, 1.94)
1.03
(0.73, 1.45)
tipranavir/ritonavir 500 mg/200 mg twice daily 400 mg twice daily 15
(14 for Cmin)
0.82
(0.46, 1.46)
0.76
(0.49, 1.19)
0.45
(0.31, 0.66)

Microbiology

Mechanism of Action

Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture

Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A, C, D, F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.

Resistance

The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Y143 (changed to C, H, or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, Q95K/R, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N). E92Q and F121C are occasionally seen in the absence of substitutions at Y143, Q148, or N155 in raltegravir-treatment failure subjects.

Treatment-Na´ve Adult Subjects: By W eek 96 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 10 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates.

Treatment-Experienced Adult Subjects: By W eek 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by W eek 48 and 78 subjects by W eek 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8-to 159-fold) compared to the wild-type reference.

Clinical Studies

Description of Clinical Studies

The evidence of durable efficacy of ISENTRESS is based on the analyses of 240-week data from a randomized, double-blind, active-control trial, STARTMRK (Protocol 021) in antiretroviral treatment-na´ve HIV-1 infected adult subjects and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult subjects.

Treatment-Na´ve Adult Subjects

STARTMRK (Protocol 021) is a Phase 3 study to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir versus efavirenz 600 mg at bedtime plus emtricitabine (+) tenofovir in treatment-na´ve HIV-1-infected subjects with HIV-1 RNA > 5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level ( ≤ 50,000 copies/mL; and > 50,000 copies/mL) and by hepatitis status.

Table 11 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the comparator group.

Table 11: Baseline Characteristics

Randomized Study Protocol 021 ISENTRESS 400 mg Twice Daily
(N = 281)
Efavirenz 600 mg At Bedtime
(N = 282)
Gender
  Male 81% 82%
  Female 19% 18%
Race
  White 41% 44%
  Black 12% 8%
  Asian 13% 11%
  Hispanic 21% 24%
  Native American < 1% < 1%
  Multiracial 12% 13%
Region
  Latin America 35% 34%
  Southeast Asia 12% 10%
  North America 29% 32%
  EU/Australia 23% 23%
Age (years)
  18-64 99% 99%
   > 65 1% 1%
  Mean (SD) 38 (9) 37 (10)
  Median (min, max) 37 (19 to 67) 36 (19 to 71)
CD4+ Cell Count (cells/microL)
  Mean (SD) 219 (124) 217 (134)
  Median (min, max) 212 (1 to 620) 204 (4 to 807)
Plasma HIV-1 RNA (log™ copies/mL)
  Mean (SD) 5 (1) 5 (1)
  Median (min, max) 5 (3 to 6) 5 (4 to 6)
Plasma HIV-1 RNA (copies/mL)
  Geometric Mean 103205 106215
  Median (min, max) 114000 (400 to 750000) 104000 (4410 to 750000)
History of AIDS*
  Yes 19% 21%
Viral Subtype
  Clade B 78% 82%
  Non-Clade B+ 21% 17%
Baseline Plasma HIV-1 RNA
   ≤ 100,000 copies/mL 45% 49%
   > 100,000 copies/mL 55% 51%
Baseline CD4+ Cell Counts
   ≤ 50 cells/mm³ 10% 11%
   > 50 cells/mm³ and < 200 cells/mm³ 37% 37%
   > 200 cells/mm³ 53% 51%
Hepatitis Status
  Hepatitis B or C Positive* 6% 6%
*Includes additional subjects identified as having a history of AIDS.
†Non-Clade B Subtypes (# of subjects): Clade A (4), A/C (1), A/G (2), A1 (1), AE (29), AG (12), BF (6), C (37), D (2), F (2), F1 (5), G (2), Complex (3).
‡Evidence of hepatitis B surface antigen or evidence of HCV RNA by polymerase chain reaction (PCR) quantitative test for hepatitis C Virus.
Notes:
ISENTRESS and Efavirenz were administered with emtricitabine (+) tenofovir
N = Number of subjects in each group.

Week 240 outcomes from Protocol 021 are shown in Table 12.

Table 12: Virologic Outcomes of Randomized Treatment of Protocol 021 at 240 Weeks

  ISENTRESS 400 mg Twice Daily
(N = 281)
Efavirenz 600 mg At Bedtime
(N = 282)
Difference (ISENTRESS - Efavirenz) (CI)
Subjects with HIV-1 RNA less than 50 copies/mL 66% 60% 6.6% (-1.4%, 14.5%)
Virologic Failure* 8% 15%  
No virologic data at Week 240 Window
Reasons
  Discontinued study due to AE or death† 5% 10%  
  Discontinued study for other reasons‡ 15% 14%  
  Missing data during window but on study 6% 2%  
*Includes subjects who discontinued prior to Week 240 for lack of efficacy or subjects who are ≥ 50 copies/mL in the 240-week window (+/-6-weeks).
†Includes subjects who discontinued due to AE or Death at any time point from Day 1 through the Week 240 window if this resulted in no virologic data on treatment during Week 240 visit window.
‡Other includes: withdrew consent, loss to follow-up, moved etc., if the viral load at the time of discontinuation was < 50 copies/mL.

The mean changes in CD4 count from baseline were 295 cells/mm³ in the group receiving ISENTRESS 400 mg twice daily and 236 cells/mm³ in the group receiving Efavirenz 600 mg at bedtime.

Treatment-Experienced Adult Subjects

BENCHMRK 1 and BENCHMRK 2 are Phase 3 studies to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-1-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. > 1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.

Table 13 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.

Table 13: Baseline Characteristics

Randomized Studies Protocol 018 and 019 ISENTRESS 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
Gender
Male 88% 89%
Female 12% 11%
Race
White 65% 73%
Black 14% 11%
Asian 3% 3%
Hispanic 11% 8%
Others 6% 5%
Age (years)
Median (min, max) 45 (16 to 74) 45 (17 to 70)
CD4+ Cell Count
Median (min, max), cells/mm³ 119 (1 to 792) 123 (0 to 759)
≤ 50 cells/mm³ 32% 33%
> 50 and ≤ 200 cells/mm³ 37% 36%
Plasma HIV-1 RNA
Median (min, max), log10 copies/mL 4.8 (2 to 6) 4.7 (2 to 6)
> 100,000 copies/mL 36% 33%
History of AIDS
Yes 92% 91%
Prior Use of ART, Median (1st Quartile, 3rd Quartile)
Years of ART Use 10 (7 to 12) 10 (8 to 12)
Number of ART 12 (9 to 15) 12 (9 to 14)
Hepatitis Co-infection*
No Hepatitis B or C virus 83% 84%
Hepatitis B virus only 8% 3%
Hepatitis C virus only 8% 12%
Co-infection of Hepatitis B and C virus 1% 1%
Stratum
Enfuvirtide in OBT 38% 38%
Resistant to ≥ 2 PI 97% 95%
*Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.

Table 14 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg twice daily and subjects in the control group.

Table 14: Characteristics of Optimized Background Therapy at Baseline

Randomized Studies Protocol 018 and 019 ISENTRESS 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
Number of ARTs in OBT
Median (min, max) 4 (1 to 7) 4 (2 to 7)
Number of Active PI in OBT by Phenotypic Resistance Test*
0 36% 41%
1 or more 60% 58%
Phenotypic Sensitivity Score (PSS)†
0 15% 18%
1 31% 30%
2 31% 28%
3 or more 18% 20%
Genotypic Sensitivity Score (GSS)†
0 25% 27%
1 38% 40%
2 24% 21%
3 or more 11% 10%
*Darunavir use in OBT in darunavir-na´ve subjects was counted as one active PI.
†The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-na´ve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-na´ve subjects was counted as one active drug in OBT.

Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of ISENTRESS 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 15.

Table 15: Virologic Outcomes of Randomized Treatment of Protocols 018 and 019 at 96 Weeks (Pooled Analysis)

  ISENTRESS 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
Subjects with HIV-1 RNA less than 50 copies/mL 55% 27%
Virologic Failure* 35% 66%
No virologic data at Week 96 Window
Reasons
  Discontinued study due to AE or death† 3% 3%
  Discontinued study for other reasons‡ 4% 4%
  Missing data during window but on study 4% < 1%
*Includes subjects who switched to open-label raltegravir after Week 16 due to the protocol-defined virologic failure, subjects who discontinued prior to Week 96 for lack of efficacy, subjects changed OBT due to lack of efficacy prior to Week 96, or subjects who were ≥ 50 copies in the 96 week window.
†Includes subjects who discontinued due to AE or Death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the Week 96 window.
‡Other includes: withdrew consent, loss to follow-up, moved etc., if the viral load at the time of discontinuation was < 50 copies/mL.

The mean changes in CD4 count from baseline were 118 cells/mm³ in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm³ for the control group.

Treatment-emergent CDC Category C events occurred in 4% of the group receiving ISENTRESS 400 mg twice daily and 5% of the control group.

Virologic responses at W eek 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 16. Table 16: Virologic Response at 96 Week Window by Baseline Genotypic/Phenotypic Sensitivity Score

Table 16: Virologic Response at 96 Week Window by Baseline Genotypic/Phenotypic Sensitivity Score

  Percent with HIV-1 RNA < 50 copies/mL At Week 96
n ISENTRESS400 mg Twice Daily + OBT
(N = 462)
n Placebo+ OBT
(N = 237)
Phenotypic Sensitivity Score (PSS)*
0 67 43 43 5
1 144 58 71 23
2 142 61 66 32
3 or more 85 48 48 42
Genotypic Sensitivity Score GSS)*
0 116 39 65 5
1 177 62 95 26
2 111 61 49 53
3 or more 51 49 23 35
*The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-na´ve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-na´ve subjects was counted as one active drug in OBT.

Switch of Suppressed Subjects from Lopinavir (+) Ritonavir to Raltegravir

The SW ITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA < 50 copies/mL on a stable regimen of lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors for > 3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with ISENTRESS 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at W eek 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.

Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at W eek 24 because they each failed to demonstrate non-inferiority of switching to ISENTRESS versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the ISENTRESS group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.

Pediatric Subjects

2 to 18 Years of Age

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects were enrolled into cohorts according to age and received the following formulations: Cohort I (12 to less than 18 years old), 400 mg film-coated tablet; Cohort IIa (6 to less than 12 years old), 400 mg film-coated tablet; Cohort IIb (6 to less than 12 years old), chewable tablet; Cohort III (2 to less than 6 years), chewable tablet. Raltegravir was administered with an optimized background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of ISENTRESS [see DOSAGE AND ADMINISTRATION].

These 96 subjects had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm³ (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA > 100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At W eek 24, 54% achieved HIV RNA < 50 copies/mL; 66% achieved HIV RNA < 400 copies/mL. The mean CD4 count (percent) increase from baseline to W eek 24 was 119 cells/mm³ (3.8%).

4 Weeks to Less Than 2 Years of Age

IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.

The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log10 copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm³ (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 patients were completely treatment na´ve. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of patients greater than 6 months of age had received two or more antiretrovirals.

Of the 26 treated subjects, 23 subjects were included in the W eek 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.

At W eek 24, 39% achieved HIV RNA < 50 copies/mL and 61% achieved HIV RNA < 400 copies/mL. The mean CD4 count (percent) increase from baseline to W eek 24 was 500 cells/mm³ (7.5%).

At W eek 48, 44% achieved HIV RNA < 50 copies/mL and 61% achieved HIV RNA < 400 copies/mL. The mean CD4 count (percent) increase from baseline to W eek 48 was 492 cells/mm³ (7.8%).

Last reviewed on RxList: 4/24/2014
This monograph has been modified to include the generic and brand name in many instances.

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