CLINICAL PHARMACOLOGY
Mechanism of Action
Raltegravir is an HIV-1 antiviral drug [see Clinical Pharmacology].
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-ranged 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
Absorption
Raltegravir 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. With 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.
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. 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.
Distribution
Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.
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 raltegravir-glucuronide, 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 isoform-selective 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
The pharmacokinetics of raltegravir in pediatric patients has not been established.
Age
The effect of age 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 was evaluated in the composite analysis. No dosage adjustment is necessary.
Gender
A study of the pharmacokinetics of raltegravir was performed in young healthy 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 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 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 subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 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 (7) ]
Table 7: Effect of Other Agents on the Pharmacokinetics of Raltegravir
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
|
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) |
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) |
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 non-nucleoside 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 Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R and D232N). Amino acid substitution at Y143C/H/R is another pathway to raltegravir resistance.
Treatment-Naïve Subjects: By Week 48 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 3 (1 with Y143R and 2 with Q148H/R) of the 6 virologic failure subjects with evaluable paired genotypic data.
Treatment-Experienced Subjects: By Week 48 in the BENCHMRK trials, at least one of the 3 primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 63 (64.3%) of the 98 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. Some (n=18) of those HIV-1 isolates harboring one or more of the 3 primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 47.3-fold (mean 73.1 ± 60.8-fold decrease, ranging from 0.9- to 200-fold) compared to baseline isolates.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 µM●hr) at the 400-mg twice daily human dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM●hr) at the 400-mg twice daily human dose.
No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.
No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in 3.0-fold exposure above the exposure at the recommended human dose.
|
CLINICAL STUDIES
Description of Clinical Studies
The evidence of durable efficacy of ISENTRESS is based on the analyses of 48-week data from an ongoing, randomized, double-blind, active-control trial, STARTMRK (Protocol 021) in antiretroviral treatment-naive HIV-1 infected adult subjects and from 2 ongoing, randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult subjects. These efficacy results were supported by the 96-week analysis of a randomized, double-blind, controlled, dose-ranging trial, Protocol 004, in antiretroviral treatment-naïve HIV-1 infected adult subjects and by the 48-week analysis of a randomized, double-blind, controlled, dose-ranging study, Protocol 005, in antiretroviral treatment-experienced HIV-1 infected adult subjects.
Treatment-Naïve 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-naïve 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 8 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the comparator group.
Table 8: Baseline Characteristics
Randomized Study
|
ISENTRESS
|
Efavirenz
|
Protocol 021
|
400 mg Twice Daily
|
600 mg At Bedtime
|
|
(N = 281)
|
(N = 282)
|
Notes:
ISENTRESS and Efavirenz were administered with emtricitabine (+) tenofovir
N = Number of subjects in each group. |
Gender
|
Male |
81% |
82% |
Female |
19% |
18% |
Race
|
White |
41% |
44% |
Black |
12% |
8% |
Asian |
13% |
11% |
Hispanic |
21% |
24% |
Native American |
0% |
0% |
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 (log10 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 |
18% |
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% |
Week 48 outcomes from Protocol 021 are shown in Table 9.
Table 9: Outcomes by Treatment Group through Week 48
Randomized Study
Protocol 021
|
ISENTRESS 400 mg
Twice Daily
(N = 281) |
Efavirenz
600 mg
At Bedtime
(N = 282) |
Difference
(ISENTRESS – Efavirenz) (CI ) |
Outcome at Week 48 |
|
|
|
Subjects with HIV-1 RNA less than 50 copies/mL |
87% |
82% |
4.7% (-1.3%, 10.6%) |
Subjects with HIV-1 RNA less than 400 copies/mL |
91% |
88% |
3.6% (-1.5%, 8.7%) |
Mean CD4 cell count change from baseline (cells/mm3) |
176 |
150 |
25.8 (5.0, 46.5) |
Virologic Failure (>50 copies/mL) |
6% |
7% |
|
Never suppressed through Week 48 and on study at Week 48 |
2% |
3% |
|
Rebound |
5% |
5% |
|
Discontinued study drug |
7% |
10% |
|
Reasons for Discontinuation |
|
|
|
Death |
<1% |
0% |
|
Adverse experiences |
2% |
5% |
|
Other
|
4% |
5% |
|
Treatment-Experienced 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 10 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.
Table 10: 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 |
35% |
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% |
85% |
Hepatitis B virus only |
8% |
3% |
Hepatitis C virus only |
8% |
11% |
Co-infection of Hepatitis B and C virus |
1% |
1% |
Stratum
|
Enfuvirtide in OBT |
38% |
38% |
Resistant to ≥2 PI |
97% |
95% |
Table 11 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 11: 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% |
19% |
1 |
31% |
30% |
2 |
31% |
28% |
3 or more |
18% |
20% |
Genotypic Sensitivity Score (GSS)
|
0 |
25% |
28% |
1 |
39% |
41% |
2 |
24% |
21% |
3 or more |
11% |
10% |
Week 48 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 12.
Table 12: Outcomes by Treatment Group through Week 48
Randomized Studies Protocol 018 and 019
|
ISENTRESS 400 mg Twice Daily + OBT (N = 462) |
Placebo + OBT (N = 237) |
Outcome at Week 48 |
|
|
Subjects with HIV-1 RNA less than 400 copies/mL |
72% |
37% |
Subjects with HIV-1 RNA less than 50 copies/mL |
60% |
31% |
Mean CD4 cell count change from baseline (cells/mm3) |
106 |
44 |
Virologic Failure (>50 copies/mL) |
36% |
65% |
Never suppressed through Week 48 and on study at Week 48 |
11% |
9% |
Rebound |
13% |
8% |
Non-responder by Week 48
|
12% |
48% |
Discontined study drug |
4% |
4% |
Reasons for Discontinuation |
|
|
Death |
2% |
2% |
Adverse Experiences |
<1% |
<1% |
Other
|
2% |
1% |
The mean changes in plasma HIV-1 RNA from baseline were -2.11 log10 copies/mL in the group receiving ISENTRESS 400 mg twice daily and -0.96 log10 copies/mL 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 Week 48 by baseline genotypic and phenotypic sensitivity score are shown in Table 13.
Table 13: Virologic Response at Week 48 by Baseline Genotypic/Phenotypic Sensitivity Score
Randomized Studies Protocol 018 and 019
|
Percent with HIV-1 RNA <400 copies/mL at Week 48 |
Percent with HIV-1 RNA <50 copies/mL at Week 48 |
n |
ISENTRESS 400 mg Twice Daily + OBT (N = 462) |
n |
Placebo
+ OBT
(N = 237) |
n |
ISENTRESS 400 mg Twice Daily + OBT (N = 462) |
n |
Placebo
+ OBT
(N = 237) |
Phenotypic Sensitivity Score (PSS)
|
0 |
69 |
52 |
44 |
5 |
69 |
46 |
44 |
2 |
1 |
145 |
72 |
72 |
32 |
145 |
57 |
72 |
28 |
2 |
142 |
83 |
66 |
42 |
142 |
68 |
66 |
38 |
3 or more |
85 |
72 |
48 |
60 |
85 |
67 |
48 |
46 |
Genotypic Sensitivity Score (GSS)
|
0 |
115 |
50 |
66 |
8 |
115 |
43 |
66 |
3 |
1 |
178 |
79 |
96 |
38 |
178 |
63 |
96 |
35 |
2 |
111 |
85 |
49 |
65 |
111 |
70 |
49 |
53 |
3 or more |
51 |
69 |
23 |
52 |
51 |
67 |
23 |
39 |
|