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Isentress (Raltegravir) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N -[(4-Fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt.

The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is:

Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol.

Each film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol) and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

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-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 4: 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
atazanavir400 mg daily100 mg single
dose
101.53
(1.11, 2.12)
1.72
(1.47, 2.02)
1.95
(1.30, 2.92)
atazanavir/ritonavir300 mg/100 mg daily400 mg twice
daily
101.24
(0.87, 1.77)
1.41
(1.12, 1.78)
1.77
(1.39, 2.25)
efavirenz600 mg daily400 mg single dose90.64
(0.41, 0.98)
0.64
(0.52, 0.80)
0.79
(0.49, 1.28)
etravirine200 mg twice daily400 mg twice daily190.89
(0.68, 1.15)
0.90
(0.68, 1.18)
0.66
(0.34, 1.26)
omeprazole20 mg daily400 mg single dose14
(10 for AUC)
4.15
(2.82, 6.10)
3.12
(2.13, 4.56)
1.46
(1.10, 1.93)
rifampin 600 mg daily400 mg single
dose
90.62
(0.37, 1.04)
0.60
(0.39, 0.91)
0.39
(0.30, 0.51)
rifampin600 mg daily400 mg twice daily when
administered alone;
800 mg twice daily when
administered with rifampin
141.62
(1.12, 2.33)
1.27
(0.94, 1.71)
0.47
(0.36, 0.61)
ritonavir100 mg twice daily400 mg single
dose
100.76
(0.55, 1.04)
0.84
(0.70, 1.01)
0.99
(0.70 1.40)
tenofovir300 mg daily400 mg twice daily91.64
(1.16, 2.32)
1.49
(1.15, 1.94)
1.03
(0.73, 1.45)
tipranavir/ritonavir 500 mg/200 mg twice daily400 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, raltegravir at concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors. 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. 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 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 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 48-week analysis of a randomized, double-blind, controlled, dose-ranging study, Protocol 005, in antiretroviral treatment-experienced HIV-1 infected adult subjects.

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

Table 5: Baseline Characteristics
Randomized Studies
Protocol 018 and 019
ISENTRESS 400 mg Twice Daily
+ OBT
(N = 462)
Placebo
+ OBT
(N = 237)
Gender
    Male88%89%
    Female12%11%
Race
    White65%73%
    Black14%11%
    Asian3%3%
    Hispanic11%8%
    Others6%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/mm332%33%
    >50 and ≤200 cells/mm337%36%
Plasma HIV-1 RNA
    Median (min, max), log10 copies/mL 4.8 (2 to 6) 4.7 (2 to 6)
    >100,000 copies/mL35%33%
History of AIDS
    Yes92%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 1
    No Hepatitis B or C virus83%85%
    Hepatitis B virus only8%3%
    Hepatitis C virus only8%11%
    Co-infection of Hepatitis B and C virus1%1%
Stratum
    Enfuvirtide in OBT38%38%
    Resistant to ≥2 PI97%95%

1 Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.

Table 6 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 6: 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 1  
0 36%41%
1 or more 60%58%
    Phenotypic Sensitivity Score (PSS) 2  
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%

1 Darunavir use in OBT in darunavir naïve subjects was counted as one active PI.
2 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-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.

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 7.

Table 7: 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
Subjects with HIV-1 RNA less than 50 copies/mL
72%
62%
37%
33%
Virologic Failure (confirmed) 1
      Non-responder
      Rebound
23%
3%
20%
57%
30%
26%
Death 2
Discontinuation due to adverse experiences
Discontinuation due to other reasons 3
2%
2%
2%
3%
3%
2%

1 Virologic failure: defined as non-responders who did not achieve >1.0 log10 HIV-1 RNA reduction and <400 HIV-1 RNA copies/mL by Week 16, or viral rebound, which was defined as: (a) HIV-1 RNA >400 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response with HIV-1 RNA <400 copies/mL, or (b) >1.0 log10 increase in HIV-1 RNA above nadir level (on 2 consecutive measurements at least 1 week apart).
2 Two additional subjects died while receiving open-label raltegravir therapy: one subject subsequent to discontinuing double-blind placebo and one subject subsequent to discontinuing double-blind raltegravir.
3 Includes loss to follow-up, subjects withdrew consent, noncompliance, protocol violation and other reasons.

The mean changes in plasma HIV-1 RNA from baseline were -1.71 log10 copies/mL in the group receiving ISENTRESS 400 mg twice daily and -0.78 log10 copies/mL for the control group. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving ISENTRESS 400 mg twice daily (109 cells/mm3) than in the control group (45 cells/mm3).

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 8.

Table 8: Virologic Response at Week 48 by Baseline Genotypic/Phenotypic Sensitivity Score
Randomized Studies
Protocol 018 and 019

(Noncompleters as failures approach)
Percent with HIV RNA
<400 copies/mL at
Week 48
Percent with HIV RNA
<50 copies/mL at
Week 48

n
ISENTRESS
400 mg Twice Daily
+ OBT
(N = 459) 1

n

Placebo

+ OBT

(N = 237)


n
ISENTRESS
400 mg Twice Daily
+ OBT
(N = 459)

n

Placebo

+ OBT

(N = 237)

Phenotypic Sensitivity Score (PSS) 2
0 69 5444 5 69 4844 2
1 143 7172 33 143 5872 28
2 141 8266 41 141 70 66 36
3 or more 85 7448 63 85 6848 58
Genotypic Sensitivity Score (GSS)
0 115 5066 8 115 43 663
1 175 77 96 39 175 63 96 35
2 111 86 49 65 111 76 49 59
3 or more 51 73 23 52 51 69 23 48

1 Three patients were excluded from week 48 analysis because of missing data immediately flanked by 2 successes.
2 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-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.

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